Download DVM Notes 2015 SVS CE Symposium - Seattle Veterinary Specialists

Seattle Veterinary
Specialists
Continuing Education Symposium
4.26.2015 | McCaw Hall | 8:00 am -2:30 pm
Doctor Program
www.svsvet.com | 11814 115th Ave NE | Kirkland, WA | 98034 | t. 425.823.9111
Seattle Veterinary Specialists 2015
Continuing Education Symposium
Time
8am-8:40am
8:40am
8:50am-9:30am
9:40am-10:20am
10:30am-11:10am
Doctor Program 1 | Allen Foundation
for the Arts Room
Registration | Continental Breakfast
Introduction with Michael Mison
Laryngeal Paralysis: Medical and Surgical Management Strategies
Stephen Stockdale, DVM, Surgery Resident
Tyrosine Kinase Inhibitor (TKI) Therapy: Palladia (Toceranib) &
Kinavet (Masitinib) Review
Kevin Choy, BVSc, MS, MRCVS
Prophylactic Gastropexy: Practical Pointers for
Preventing a Pernicious Problem
Kent Vince, DVM, MSpVM, Diplomate, ACVS
11:10am-12:10pm
Lunch | Grand Lobby
12:10pm-12:50pm
Too Much or Not Enough: Imaging Urinary Tract Pathology
Alaina Carr, DVM, Diplomate ACVR
1pm-1:40pm
1:50pm- 2:30pm
The Ins and Outs of Portosystemic Shunts
Michael Mison, DVM, Diplomate ACVS
Gait Analysis and Neurolocalization
Dani Powers, DVM, Neurology Resident
Seattle Veterinary Specialists 2015
Continuing Education Symposium
Time
8am-8:40am
8:40am
Doctor Program 2 | The Norcliffe Room
Registration | Continental Breakfast
Introduction with Sean Sanders
10:30am-11:10am
Electrocardiography: Basic Principles, Diagnosis, and
Treatment of Common Arrhythmias
Bryan Bottorff, DVM, Diplomate ACVIM (Cardiology)
Trilostane Therapy for Hyperadrenocorticism
Matt Vaughan, DVM, Diplomate ACVIM (Internal Medicine)
Epilepsy: New Ideas in the Cause, Diagnosis and Treatment
Sean Sanders, DVM, PhD, Diplomate ACVIM (Neurology)
11:10am-12:10pm
Lunch | Grand Lobby
12:10pm-12:50pm
Round Cell Tumor Cytology for the General Practitioner
Seung Yoo, MS, MBA, DVM, DACVP (Clinical)
8:50am-9:30am
9:40am-10:20am
1pm-1:40pm
1:50pm- 2:30pm
Hypercalcemia in dogs: Diagnostic plan, emergency stabilization,
surgical correction, and post-operative management
Jim Perry, DVM, PhD, Diplomate ACVIM (Oncology), Diplomate ACVS
What's New with Fracture Management
Kent Vince, DVM, MSpVM, Diplomate ACVS
Seattle Veterinary Specialists
Exceptional Medicine | Compassionate Care | Peace of Mind
Beyond Expectations
Seattle Veterinary Specialists (SVS) is a state-of-the-art, multi-specialty and 24 hour
emergency and critical care hospital in Kirkland, WA. SVS was founded on the concept of
providing superior, unsurpassed patient care and client service, in close cooperation with
the referring veterinary community. SVS focuses on collaborative medicine where teams
of experts work together under one roof to combine their medical expertise, skills and
experience to provide the best treatment for their patients.
SVS Services
• Ambulance
• Cardiology
• Emergency and Critical Care
• Internal Medicine
• Neurology | Neurosurgery
• Oncology
• Pathology
!
• Radiology
• Surgery
Thank you
Seattle Veterinary Specialists would like to thank our 2015 Continuing
Education Symposium Sponsors for their generous support!
!
Dr. Bryan Bottorff, Diplomate ACVIM (Cardiology)
Dr. Bryan Bottorff received his Doctorate of Veterinary
Medicine degree from Purdue University in 2008. He then
completed a rotating small animal internship at the
Virginia-Maryland Regional College of Veterinary Medicine,
and moved to the Pacific Northwest for a Cardiology
residency at Oregon State University in 2009.
After
completing his residency and obtaining board certification
by the American College of Veterinary Internal Medicine in
Cardiology, Dr. Bottorff joined Seattle Veterinary Specialists
in the summer of 2012. Dr. Bottorff’s professional interests
include minimally invasive cardiac procedures and
advanced imaging of cardiac and pericardial disorders. In
!
his spare time, Dr. Bottorff enjoys spending time with his
wife and pets, traveling, and outdoor adventures in the Pacific Northwest.
Dr. Alaina Carr, Diplomate ACVR
Dr. Carr received her veterinary medical degree from
Washington State University. After graduation, Dr. Carr
joined a small animal referral and emergency hospital for
a year-long internship and then went on to complete a
residency in Diagnostic Imaging at the University of
California-Davis Veterinary Medical Teaching Hospital. In
addition to her clinical duties as a resident, which
included clinical and didactic teaching of veterinary
students, Dr. Carr taught basic and advanced abdominal
ultrasound to veterinarians through continuing education
courses. Throughout her post-graduate training, Dr. Carr
! has maintained active research projects that have
culminated in published peer-reviewed manuscripts. Dr.
Carr’s primary research interest is in comparative imaging of the urinary tract utilizing
computed tomography and ultrasound.
Dr. Kevin Choy, MS (Oncology), MRCVS
Dr. Kevin Choy received a Bachelor of Veterinary Science
from the University of Melbourne, Australia in 2006 with
first class honors, after earning Bachelor of Science degree
in Animal Science from the University of British Columbia,
Canada in 2003 with honors. He worked in small animal
private practice in the heart of Melbourne, Australia from
2006 to 2009 before pursuing specialist training back in
the United States. He completed an internship in small
animal medicine and surgery at Oregon State University
in 2009 and a Master's degree and residency in small
animal medical oncology at Washington State University
in 2013.
!
As a resident at Washington State University, Dr.
Choy received multiple honors including the Thibodaux Oncology Award, Strickler Award
in Oncology, Pera Scholarship in Oncology in addition to resident of the year distinction.
While in Melbourne Dr. Choy has also served as an emergency relief veterinarian on
behalf of Wildlife Victoria to assess and treat injured Australian fauna including Koalas,
Wombats and Kangaroos as well as provide veterinary access to aboriginal communities
in Australia.
Dr. Choy's professional interests include lymphoma, transitional cell carcinomas, localized
tumor treatment with electrochemotherapy and translational cancer research through
co-operative clinical trials and research projects with the Fred Hutchinson Cancer
Research Center to improve patient care in both animals and their owners.
He has presented both at national cancer conferences and continuing education
seminars during his residency at Washington State University with published research in
transitional cell carcinoma therapy in dogs and co-authored book chapters in Feline
lymphoma and mammary tumors.
In his spare time he enjoys spending time with his wife and two children, two cats and
two parrots. Personal interests include Kendo, wildlife photography, following his
hometown hockey team the Vancouver Canucks and traveling the Pacific Northwest.
Dr. Michael Mison, Diplomate ACVS
Dr. Michael B. Mison received a Doctorate of
Veterinary Medicine degree from the University of
Florida in 1998 with high honors, after earning a
Bachelor of Science Degree in Microbiology and Cell
Science from the University of Florida in 1994. He
completed an internship in small animal medicine and
surgery at Michigan State University in 1999, and
completed a residency in small animal surgery at MSU
from 1999 to 2002. As an intern and resident at MSU,
Dr. Mison was awarded the intern and resident of the
year by several graduating classes. While at East
Lansing, MI, he also served as an emergency
veterinarian at MSU’s Laboratory Animal Resource
! and Potter Park Zoo. Dr. Mison has been a faculty
member at WSU from 2002 – 2004 and earned board certification from the American
College of Veterinary Surgeons in 2003. He received the Carl Norden-Pfizer
Distinguished Teaching Award as faculty at WSU.
He continues to serve as a locum faculty at Washington State University, Oregon State
University, University of California Davis, University of Illinois, Oklahoma State University,
Michigan State University, and Virginia Tech and also holds a position as Affiliate
Assistant Professor in the Department of Comparative Medicine at the University of
Washington School of Medicine. He currently serves on the soft tissue surgery Journal of
the American Animal Hospital Association (JAAHA) review board. Dr. Mison brings to
Seattle Veterinary Specialists particular interest and experience in soft tissue surgery,
including minimally invasive, oncological, laser, reconstructive, cardiothoracic,
hepatobiliary/portosystemic shunt, and gastrointestinal surgery. He is also well versed in
the many orthopedic and neurosurgical procedures routinely performed at SVS including
Tibial Plateau Leveling Osteotomy, laminectomy, and fracture repair. Dr. Mison also
enjoys and is experienced in exotic animal and avian surgery. He has presented nationally
and internationally on various topics and has authored numerous journal articles and
book chapters.
Dr. Jim Perry, PhD, Diplomate ACVIM (Oncology), Diplomate ACVS
!
Dr. Perry, originally from Portland, Oregon,
received his bachelor degree in biochemistry and
cellular biology at the University of Washington in
Seattle. He then went on to complete his
veterinary medical degree and doctor of
philosophy in cellular immunology at Colorado
State University. After working in private practice
for a year, he returned to the clinics at CSU 2008
for his residency and board certification in
medical oncology followed by a surgery residency
at Aspen Meadow Veterinary Specialists in
Longmont Colorado. Dr. Perry’s clinical and
research interests include orthopedics/orthopedic
oncology,
immunology,
targeted
chemotherapeutics, and surgical oncology.
Dr. Perry is a diplomate of the American College of Veterinary Internal Medicine (ACVIM)
and the American College of Veterinary Surgeons (ACVS). He is a member of the
American Veterinary Medical Association, Veterinary Orthopedic Society, Veterinary
Cancer Society, Veterinary Society of Surgical Oncology and the American Association of
Immunologists. In his free time, Dr. Perry enjoys biking, kayaking, and backcountry skiing
with his Tolling Retriever and Border Collie.
Dr. Dani Powers, Neurology | Neurosurgery Resident
Dr. Powers received her bachelor’s degree at
Washington State University and then continued to
complete her Doctorate of Veterinary Medicine at
Washington State University in 2011. She completed
a small animal rotating internship at Seattle
Veterinary Specialists in 2012. She is currently a
Neurology and Neurosurgery Resident at Seattle
Veterinary Specialists. Her areas of interest include
seizure management, neurosurgery and physical
rehabilitation techniques following neurosurgical
interventions. Dr. Powers enjoys spending time with
her family including her husband Jon and son
Francis as well as their two cats Tux and Moto. They
like to explore the Pacific Northwest including the
! great hiking, local sports, food, and wine.
Dr. Sean Sanders, PhD, Diplomate ACVIM (Neurology)
!
Dr. Sean Sanders is a native of Washington. He graduated
from Washington State University College of Veterinary
Medicine in 1998. He completed a three-year residency in
Neurology and Neurosurgery in 2002 and a Ph.D. in
Neuroscience in 2003. Dr. Sanders has been practicing
Neurology and Neurosurgery in the Seattle area since
2002. He has a special interest in brain surgery, epilepsy,
spinal column stabilization and electroencephalography.
He is the author of Seizures in Dogs and Cats, several book
chapters and numerous journal articles. Dr. Sanders is an
AOVet faculty member and teaches spinal column
stabilization as part of AO Spine. In his free time he enjoys classic car restoration, hiking,
mountain biking and spending time with his wife and dogs.
Dr. Stephen Stockdale, Surgery Resident
Dr. Stephen Stockdale grew up in the eastside of Seattle.
He attended Washington State University from 20052008 where he graduated magna cum laude with a
Bachelor of Science degree in Animal Sciences with a
minor in Biology. He then attended Washington State
University College of Veterinary Medicine and obtained
his DVM in 2013. His interests are soft tissue surgery,
cardiology, and emergency medicine. After his
internship Dr. Stockdale stayed with SVS for a surgical
residency beginning in July, 2014. In his free time, he
enjoys traveling, road cycling, bike touring, rock
! climbing, running, and mountain biking with his dog,
“Finnegan."
Dr. Matt Vaughan, Diplomate ACVIM (SAIM)
Dr. Matt Vaughan is originally from Philadelphia,
Pennsylvania. He attended the University of California,
Santa Cruz for his undergraduate schooling where he
graduated with highest honors in 1997. After some well
spent time traveling and exploring the world, he attended
veterinary school at the University of California, Davis
(UCD) and graduated in 2004. He then completed a one
year small animal internship at Texas A&M University
before returning to UCD for a small animal internal
medicine residency between 2005 and 2008. At UCD, Dr.
Vaughan served as chief resident during the third year of
his residency. After receiving his board certification in
Internal Medicine, Dr. Vaughan joined Seattle Veterinary
Specialists in 2008. Dr. Vaughan holds a special interest in endocrinology and spent
much of his residency involved in research projects focused on canine Cushing's disease
and diabetes mellitus. He also has an interest in interventional radiology and performs
procedures such as tracheal, urethral, and ureteral stents.
Dr. Kent Vince, MSpVM, Diplomate ACVS
Dr. Kent Vince joined Seattle Veterinary Specialists
after spending 12 years of service as a Veterinary
Corps Officer in the United States Army. Originally
from Michigan, Dr. Vince received his officer
commission through the Army ROTC program and
earned his Bachelor’s of Science in Animal Science in
1996 and his Doctor of Veterinary Medicine in 2001
from Michigan State University. Upon completion of a
one-year internship at Rood and Riddle Equine
Hospital in Lexington, Kentucky, he entered active
duty military service at Fort Hood, Texas where he
served as veterinary treatment facility officer in charge. Dr. Vince deployed to the Middle
East in support of Operation Iraqi Freedom in 2003. He was then selected to complete a
small animal surgical residency at North Carolina State University where he also earned a
Master’s of Specialized Veterinary Medicine degree. Dr. Vince became a Diplomate of the
American College of Veterinary Surgeons in 2010. In addition to his assignments at Fort
Hood and NC State, Dr. Vince was the Chief of Veterinary Services in Okinawa, Japan and
most recently Director of Dog Center Europe; the US Army’s premier veterinary referral
hospital in Germany supporting military working dogs throughout Europe, Africa and the
Middle East. While no longer his primary job, he continues to serve as a Lieutenant
Colonel in the United States Army Reserve.
Dr. Seung Yoo, MS, MBA, DVM, Diplomate ACVP (Clinical)
Dr. Seung Yoo grew up in South Pasadena, a quiet
suburb in balmy Southern California. He received both
a Bachelor of Science and a Master of Science at the
University of California at Davis. After graduating from
Colorado State University in 2010 with a combined
MBA/DVM degree, he arrived at Michigan State
University for a one-year small animal rotating
internship. He then completed a Clinical Pathology
residency at Colorado State University in 2014 with
additional training in Anatomic Pathology and
accepted a position as a clinical Pathologist at Seattle
Veterinary Specialists. His professional interests
include hemostasis, mineral metabolism, and
autoimmune diseases. When not at work, he enjoys
spending time with his wife, dog, and two cats. His hobbies include wood working,
skiing, snowboarding, rock climbing, hiking, bread baking, fishing, and ice hockey.
Doctor Program 1 | Allen Foundation
for the Arts Room
Speakers
Dr. Stephen Stockdale, Surgery Resident
Dr. Kevin Choy, BVSc, MS, MRCVS
Dr. Kent Vince, Diplomate ACVS
Dr. Alaina Carr, Diplomate ACVR
Dr. Michael Mison, Diplomate ACVS
Dr. Dani Powers, Neurology | Neurosurgery Resident
Notes
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Laryngeal Paralysis: Medical and Surgical Management Strategies
Stephen Stockdale DVM
Seattle Veterinary Specialists
Kirkland, WA
Anatomy
The larynx is a fibroelastic membranous tube in which several hyaline cartilages are
embedded to maintain a patent airway. The larynx is comprised of the epiglottic
cartilage, the thyroid cartilage, two arytenoid cartilages, and the cricoid cartilage. The
two arytenoid cartilages are lined by mucosa and project toward the opening of the
larynx, the aditus larynges. The arytenoid cartilages can be adducted and abducted by
the muscles of the larynx to control airflow and to protect the airway. Vocal folds and
adjacent laryngeal ventricles control phonation. Basenji breed dogs have severely
reduced or absent laryngeal ventricles which fits with the speculation that they cannot or
do not bark.
Figure 1: Recurrent laryngeal nerve anatomy
There are extrinsic muscles of the
larynx, which help to suspend the larynx
from the hyoid apparatus. The intrinsic
muscles of the larynx work to control the
arytenoid cartilages. The cricoarytenoid
lateralis, cricothyroid and thyroarytenoid
muscles adduct the arytenoid cartilages.
The cricoarytenoid dorsalis muscle is
the only abductor of the arytenoid
cartilages. The recurrent laryngeal nerve
(Figure 1) is a branch of the vagus nerve
that innervates all intrinsic muscles of
the larynx besides the cricothyroid
(tensor) muscle. The somatic nerve
fibers arise from the nucleus ambiguus
before joining the vagus nerve. The
recurrent laryngeal nerve branches from
the vagus nerve at the level of the aortic
arch where the left recurrent laryngeal
nerve wraps around the aortic arch
before ascending cranially. On the right
side, it arises from a similar level and wraps around the right subclavian artery before
continuing on its course cranially. The nerve courses over the lateral aspects of the
trachea to the level of the larynx and esophagus. The nerve terminates as the caudal
laryngeal nerve bilaterally. The cricothyroid muscle is innervated by the external branch
of the cranial thyroid nerve.
A less cited recurrent laryngeal nerve branch is the perarecurrent laryngeal nerves
which innervate the cervical and cranial thoracic esophagus.
Pathophysiology
The larynx functions to regulate airflow and phonation as well as to protect the airway
from food inhalation. These functions are regulated by the intrinsic musculature and
innervation of the larynx. The cricoarytenoideus dorsalis muscle is responsible for
arytenoid cartilage abduction during inspiration. The recurrent laryngeal nerve
innervates this muscle. Any injury to the length of the recurrent laryngeal nerve or the
cricoarytenoideus dorsalis muscle can lead to laryngeal paralysis (Figure 1). Paralysis
can be unilateral or bilateral.
Etiology of paralysis
Congenital laryngeal paralysis occurs at a young age (typically before year 1) in the
Bouvier de Flanders, bull terriers, Dalmatians, Rottweiler, and huskies. Bouviers and
bull terriers tend to be European lineages while Dalmatians and huskies tend to be from
the United States. Wallerian degeneration of the recurrent laryngeal nerves and
abnormalities of the nucleus ambiguus are present histopathologically.1
Acquired laryngeal paralysis occurs later in life (average 9 years) and is over
represented in Labrador retrievers, Golden Retrievers, Saint Bernards, and Irish setters.
Idiopathic laryngeal paralysis is by far the most common cause for acquired paralysis
although other causes should be ruled out. Reported causes of acquired laryngeal
paralysis include compressive cranial mediastinal masses, neck masses, cervical
trauma from dog fighting, cervical surgery, bilateral thyroidectomy in a cat, and
polyneuropathy or myopathy of the intrinsic laryngeal musculature associated with
hypothyroidism. Hypothyroidism and myasthenia gravis have inconsistent correlation
with laryngeal paralysis but are reported.
History and exam findings
Presenting signs are similar for both congenital and acquired forms of laryngeal
paralysis. Signs can be progressive over months to years or acute depending on
etiology. Early signs may include a change in voice and gagging or coughing associated
with eating and drinking. Exercise tolerance decreases over time and inspiratory stridor
becomes more apparent. The most severely effected animals may have episodes of
severe dyspnea, cyanosis, and syncope. Various degrees of dysphagia may also
accompany laryngeal paralysis due to pararecurrent laryngeal nerve dysfunction and is
correlated with an increased likelihood of aspiration pneumonia.2
The physical exam findings of an animal with laryngeal paralysis are typically
unremarkable with the exception of the respiratory system. Inspiratory stridor that does
not improve with open-mouthed breathing is often present. Referred upper airway noise
can be ausculted on thoracic auscultation. Animals with concurrent pneumonia or noncardiogenic pulmonary edema may have pulmonary crackles on auscultation.
Feline idiopathic laryngeal paralysis is very rare but does occur. Cats tend to present
with nebulous signs of inspiratory wheezes, exercise intolerance, and appetite loss. The
remaining treatment strategies are similar to that of dogs.
Laboratory findings
Consistent blood work abnormalities are uncommon for patients with laryngeal
paralysis. If concurrent pneumonia is present, leukocytosis with neutrophilia may be
present. For chronic cases, compensatory polycythemia may be present. Animals with
hypothyroidism can have hypercholesterolemia, hyperlipidemia, and elevated liver
enzymes. Thyroid testing is recommended in these cases. If myasthenia gravis is
suspected, tensilon testing or acetylcholine antibody titers can be performed.
Radiographic examination
Radiographic examination is typically utilized to evaluate the thoracic cavity for evidence
of pneumonia, megaesophagus, or any mediastinal mass effects that could be the
cause of laryngeal paralysis. Cervical radiographs tend to be unremarkable although
caudal retraction of the larynx can be seen in animals that are dyspneic.
Laryngeal examination
A sedated laryngeal examination is the most definitive diagnostic tool for laryngeal
paralysis. Historically thiopental was used as an induction agent and more recently,
propofol is used. To evaluate the larynx, the patient must be under a deep enough plane
of anesthesia to facilitate opening the mouth but not so deep that the laryngeal reflex is
compromised. If the patient is deemed to be under too deep of an anesthetic plane, they
should be given time to recover from the anesthetic event until laryngeal function
returns. The patient is positioned in sternal recumbency and the mouth opened at the
level of normal head carriage. With normal laryngeal function the arytenoid cartilages
and ventrally located vocal folds retract laterally on each inspiration and return to a
neutral position on exhalation (Figure 2). With laryngeal paralysis the cartilages and
vocal folds do not retract on inspiration and can even draw axially if the paralysis is
severe enough, a condition known as “paradoxical motion of the arytenoid cartilages.”
For animals taking short
Figure 2: Normal laryngeal anatomy
shallow breaths, doxopram
(1mg/kg IV) can be
administered intravenously to
increase the respiratory pattern
within several seconds. It is
recommended that an assistant
call out each inspiratory breath
during the exam so that you
may focus on the corresponding
laryngeal motion. With chronic
upper airway obstruction signs
or a recent dyspneic event, the
laryngeal cartilages may show
varying degree of edema and erythema due to turbulent instead of laminar airflow.
Emergency treatment
Patients present in a variety of ways depending on the severity of the paralysis. In an
emergency situation, patients present with signs of dyspnea, acute cyanosis, or
collapse as a result of upper airway obstruction. Excitement, exercise, or increased
ambient temperature are usually the catalyst for such an event. With prompt medical
therapy, most patients recover initially. Excitement and increased ambient temperature
lead to an increased respiratory rate and secondary edema to the laryngeal cartilage
mucosa as they contact each other during rapid breathing. Based on the Bernoulli
principle, as the speed of air flowing over the arytenoid cartilages increases, the air
pressure decreases, which creates lift (much like an airplane airfoil). This in turn leads
to further axial motion of the arytenoid cartilages. The upper airway obstruction itself
then stresses the animal and leads to inspiratory dyspnea which propagates the
laryngeal edema and paradoxical laryngeal motion.
Initial stabilization should include heavy sedation with high dose opioids (butorphanol,
oxymorphone or methadone; avoid hydromorphone as it tends to cause panting and is
emetogenic in some patients and should be avoided if possible) and/or acepromazine
intravenously. If the patient stress level is too exacerbated by restraint to facilitate
intravenous injection, intramuscular injection is a reasonable second option.
Corticosteroids are a second hallmark treatment to reduce laryngeal edema.
Dexamethasone at a dose of 0.2-1.0 mg/kg IV q 12hr is used initially. Supplemental
oxygen therapy is indicated after the sedation has been administered. Patients in an
acute crisis are often hyperthermic (temperatures above 105 degrees Fahrenheit) and
active cooling should be instituted using water baths, ice packs, or alcohol applied to the
footpads. Room temperature intravenous fluid therapy (cold fluids lead to peripheral
vasoconstriction and are not beneficial) can be beneficial in regulating body temperature
but should be used with caution as non-cardiogenic pulmonary edema is a common
sequelae for animals with acute upper airway obstruction. Finally, for animals with
refractory upper airway obstruction, intubation or emergency tracheostomy can be
considered.
Medical management
Medical management is considered conservative management and is reserved for
patients with mild clinical signs. Laryngeal paralysis is a progressive disease and clinical
signs will worsen with time. The hallmarks of medical management are lifestyle
changes. This means avoiding strenuous exercise, maintaining a low ambient
temperature, and sedation as needed. Owners need to be counseled on the fact that
clinical signs will progress and that their pet could have an acute respiratory event at
any time. Ultimately, surgery is recommended when medical management is not
sufficient to control clinical signs.
Surgical
The goal of surgery for correction of laryngeal
paralysis is removing or repositioning the laryngeal
cartilages to unobstruct the rima glottis. Based on
Poiseuille’s Law (Figure 3), the difference in air
resistance between two ends of a cylinder is
inversely proportional to the radius of that cylinder
to the fourth power. Stated another way, with all
other variables constant, it does not take much of
a change in glottis diameter to make a profound
difference in airway resistance.
Reported procedures include unilateral arytenoid
lateralization (cricoarytenoid or thyroarytenoid),
bilateral arytenoid lateralization, ventricular
cordectomy and partial arytenoidectomy via an
oral or ventral approach, modified castellated
laryngofissure, reinnervation of the laryngeal
musculature, nitinol stenting, or permanent
tracheostomy.
Figure 3: Poiseulle’s Law
= pressure difference between
ends of a cylinder
= length of pipe
= the viscosity
= the volumetric flow rate
= the radius of the pipe
The technique with the best reported outcome is unilateral arytenoid lateralization and is
the procedure that we perform at SVS (Figure 4).3,4 Patients do well with unilateral
surgery and the risk of aspiration pneumonia is
Figure 4: Unilateral cricoarytenoid
minimized. Both a cricoarytenoid technique and a
lateralization
thyroarytenoid technique have been described
with good clinical outcomes. The increase in total
rima glottis size with cricoarytenoid lateralization is
significantly more but does not have a clinical
significance long term compared to thyroarytenoid
Figure 5: Pre- and postoperative images of a
unilateral cricoarytenoid lateralization.
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lateralization (Figure 5).5,6 Regardless of the technique performed, one or two
monofilament, nonabsorbable sutures are placed to retract the arytenoid cartilage. A
swaged on needle is preferred to reduce the possibility of fracturing the fragile
cartilages. The suture is tightened to the point of abduction created by the indwelling
endotracheal tube. Extubation and laryngeal exam should be performed at that time of
surgery to confirm appropriate placement before closure of the surgical site.
With regards to the other listed techniques, most are not utilized routinely due to
increased complication rates. Partial arytenoidectomy can be performed through an oral
or ventral approach. While it provides immediate patency of the rima glottides, with time,
the risk of ventral laryngeal webbing becomes high as the tissues scar down. To avoid
this risk, a ventral approach should be
utilized so that the laryngeal mucosa
can be strictly apposed to prevent
exuberant granulation tissue and scar
formation. A similar risk is present with
ventricular cordectomy. Both
techniques are not recommended due
to postoperative risks. Castellated
laryngofissure utilizes a ventral
laryngotomy approach where the
thyroid cartilage is cut in a stepwise
fashion to facilitate removal of the
vocal folds and to appose the mucosa.
When the laryngotomy is closed, the central step of the thyroid cartilage is advanced
cranially and apposed with the contralateral thyroid cartilage segment to effectively
widen the rima glottis. Castellated laryngofissure is not recommended due to high
propensity for postoperative bleeding and requiring a temporary tracheostomy.
Figure 6: Castellated Laryngofissure Technique
Reinnervation utilizing the C1 or phrenic nerves by anastomosis to the recurrent
laryngeal nerve as it inserts onto the cricoarytenoid dorsalis muscle. Animals may still
require tracheostomy while the innervation takes place. This technique is infrequently
used.
Nitinol stenting has recently been proposed for laryngeal paralysis. Nitinol is a nickeltitanium alloy with amazing elastic properties and amazing memory capability. This
means that an implant can be made to a desired shape and it will return to that shape
consistently when at a standard temperature. Nitinol stenting was proposed as an
implant for laryngeal paralysis because it can keep the arytenoid cartilages abducted at
rest while the animal still has the ability to adduct as needed because the arytenoid
cartilages are not permanently fixed. In theory, the risk of aspiration pneumonia could
be obviated. Ex vivo studies have shown good results with decreasing airway resistance
while having normal airway resistance with a closed glottis as would be expected in a
living patient.7 Published clinical results of this technique in vivo are not available at this
time.
A final salvage procedure is permanent tracheostomy which effectively bypasses the
upper airway all together. This is a viable option for animals with significant risk for
aspiration pneumonia (myasthenia gravis, diffuse myopathy, hiatial hernia, or other
compounding gastrointestinal disease) because the laryngeal anatomy is not altered.
This technique is fraught with management complications as animals are more prone to
inhaling foreign material, require grooming around the tracheal stoma, and must be
prohibited from swimming ever in their life.
Postoperative complications and care
The benefit of the arytenoid lateralization technique is that no temporary tracheostomy
is necessary. There is no disruption of the laryngeal mucosa and therefore the risk of
scar formation is removed. The risk of this procedure is cartilage fracture and suture
failure if animals are anxious or barking. Aspiration pneumonia postoperatively is the
most concerning risk with reported rates of around 20-25% at some point during their
life postoperatively. By utilizing a unilateral technique instead of bilateral, the risk of
aspiration pneumonia is diminished. Certain strategies can be employed to bring this
risk to near zero in the perioperative period, which is the highest risk period. With
regards to anesthesia, we recommend strict fasting for 12-18 hours prior to surgery.
Premedications with high emetogenic properties (hydromorphone) should be avoided.
Animals are also premedicated with maropitant (1mg/kg SC q 24hr) and famotidine
(1mg/kg IV/SC/IM q 24hr) at the time of induction to reduce the risk of vomiting and
regurgitation in the perioperative period. Dexamethasone sodium phosphate (0.2mg/kg
IV once) is administered to reduce airway edema during the perioperative period.
Patients are intubated swiftly at the time of surgery to reduce the time where their
airway is not protected and the endotracheal cuff inflation is thoroughly checked.
Postoperatively, patients are only extubated when they have a strong swallow reflex.
Patients are maintained on intravenous fluids with a prokinetic (metoclopramide
0.4mg/kg SC loading dose follow by 1mg/kg/day CRI) until they are consistently eating
and drinking on their own. Animals are kept strictly NPO for 12-18 hours
postoperatively. When it is time to introduce food and water, the technique is important
to decrease the risk of aspiration. Patients should be offered hand formed dog food
“meatballs” one at a time initially so that they consciously eat them. This is most critical
for the dogs that routinely eat vigorously and “inhale” their food. Soft food is
recommended because it does not particulate when they chew their food. With regards
to water, it should be offered in small shallow volumes with a large amount of ice cubes
to slow the rate of drinking. This strategy should be continued for the first two weeks
postoperatively. Initially animals will often cough when eating and drinking which is a
normal response to their altered airway. Coughing is a sign of them protecting their own
airway as food and water contact the laryngeal mucosa. Coughing only becomes
concerning when not associated with eating and drinking and could be associated with
developing pneumonia.
After two weeks of hand feeding, patients can be transitioned to eating from a bowl and
over the course of a couple weeks, transitioned to soaked kibble and then normal kibble
as they learn to protect their own airway. For patients that eat vigorously, owners can be
creative with ways to slow the rate down. This can include placing a large rock in the
food bowl, purchasing a manufactured bowl with obstacles built into it, or even
spreading the food across the floor so that they have to find each individual piece.
These patients cannot use a neck lead for the remainder of their lives and a head leader
or harness is recommended. These animals are also at a higher risk for aspiration when
swimming and therefore swimming is prohibited indefinitely.
Prognosis
The overall prognosis for laryngeal paralysis is variable based on severity of signs and
confounding factors. Animals with polyneuropathy are at a higher risk for postoperative
aspiration pneumonia. With certain lifestyle adjustments, animals can live a good quality
of life without surgery but ultimately the clinical signs will progress as the cricoarytenoid
muscle degenerates. Once clinical signs progress to the point of affecting quality of life,
surgical intervention is strongly recommended. Animals have an immediate resolution of
upper airway obstruction. Reported owner perception of improvement in quality of life is
around 90% with unilateral arytenoid lateralization. While the reported incidence of
aspiration pneumonia should not be dismissed, with the specific management strategies
listed prior, the risk can be minimized.
References
rd
1) Monnet E, Laryngeal Paralysis and Devocalization. Textbook of Small Animal Surgery: 3 ed.
Philadelphia, PA: Saunders Elsevier, 2003.
2) Stanley BJ, Hauptman JG, Fritz MC, et al. Esophageal dysfunction in dogs with idiopathic laryngeal
paralysis: a controlled cohort study. Veterinary Surgery. 2010; 39:139-149.
3) Griffen, JF and Karhwinkel DJ. Laryngeal Paralysis: Pathophysiology, diagnosis, and surgical repair.
Veterinary Compendium. 2005.
4) Hammel SP, Hottinger HA, and Novo RE. Postoperative results of unilateral arytenoid lateralization for
treatment of idiopathic laryngeal paralysis in dogs: 39 cases (1996-2002).
5) Griffiths LG, Sullivan M, Reid SWJ. A comparison of the effects of unilateral thyroarytenoid
lateralization versus cricoarytenoid laryngoplasty on the area of the rima glottidis and clinical outcome in
dogs with laryngeal paralysis. Veterinary Surgery. 2001; 30:359-365.
6) Demetriou JL and Kirby BM. The effect of two modifications of unilateral arytenoid lateralization on rima
glottidis area in dogs. Veterinary Surgery. 2003; 32:62-68.
7) Cabano NR, Greenberg MJ, Bureau S, et al. Effects of bilateral arytenoid cartilage stenting on canine
laryngeal resistance ex vivo. Veterinary Surgery. 2011; 40:97-101.
Notes
Tyrosine Kinase Inhibitor (TKI) Therapy: Palladia (Toceranib) &
Kinavet (Masitinib) Review
Kevin Choy BVSc (Hons) MS (Oncology) MRCVS
Medical Oncology – Seattle Veterinary Specialists
Introduction
Achieving local and systemic tumor control is the primary aim of oncologic therapy,
traditionally requiring combination therapy of surgery, radiation and systemic cytotoxic
chemotherapy. With increasing understanding of the molecular pathways associated
with the development and growth of cancer cells, a new class of treatment known as
Targeted cancer therapies has emerged in the treatment of patients with cancer with the
development of monoclonal antibodies (mAbs) and small molecular inhibitors such as
tyrosine kinase inhibitors (TKIs).
While traditional cytotoxic chemotherapeutic drugs are typically non-specific and act
against all actively dividing cells, targeted cancer therapies are drugs or substances that
interfere with specific molecules or cell pathways involved with cancer cell growth and
survival. Targeted therapies are currently at the forefront of cancer research and drug
development, allowing more precise therapy based on information about a patients
individual genes and proteins to diagnose and treat specific cancers. Many targeted
cancer therapies have been approved by the FDA and dramatically improved the
outcomes for some human cancers and become the new standard of care. Similarly in
veterinary medicine, the approval of two veterinary specific drugs Palladia (toceranib)
and Kinavet (Masitinib) have increased the treatment options and prognosis for many
canine and feline patients.
Protein Kinases & Dysfunction in Cancer
Protein kinases are enzymes that play a critical role in regulating normal cell signaling,
controlling key cellular processes such as cell growth, survival, differentiation and
migration. Tyrosine kinases are specific protein kinases that target tyrosine amino acid
residues that can be found on both the cell surface (receptor tyrosine kinases; RTKs)
and intracellular (cytoplasmic tyrosine kinases; cTKs). These kinases act through
phosphorylation (transfer of a phosphate group from ATP) to key amino acids found on
specific molecules, activating a downstream effect/signal cascade to exert specific
cellular actions.
Dysfunction in protein kinases are frequently found in human cancers, and recent
studies in canine and feline tumors indicate that this is likely the case in many
malignancies diagnosed in veterinary medicine. Mutation, overexpression, generation of
fusion proteins and the presence of self-activing feedback pathways (autocrine loops) of
protein kinases are common mechanisms cancer development and progression. For
example, point mutation in kinases such as the BRAF gene is found in 60% of human
cutaneous melanomas, and BCR-ABL fusion proteins caused by abnormal
chromosomal rearrangement in 90% of human chronic myelogenous leukemia (CML)
cause abhorrent activation of cell signaling pathways that are “always on” regardless of
stimulus, leading to uncontrolled cell growth, a classic hallmark of cancer.
Similarly in dogs, approximately 25-30% of Patnaik Grade 2 and 3 mast cell tumors are
found to have activating mutations in c-KIT, a receptor tyrosine kinase that is normally
found on stem cells, melanocytes, and interstitial cells of Cajal (found in the intestinal
tract) and the central nervous system. Dogs with mast cell tumors containing these
mutations have a higher risk of local, recurrence. Mutations in c-Kit have also been
identified in other canine malignancies including gastrointestinal stromal tumors (GIST),
melanoma and myelogenous leukemia (CML). Early studies in cats have also found
similar activing mutations in specific cancers including mast cell tumors and squamous
cell carcinoma.
Kinase Inhibitors in Cancer Therapy
With increased understanding of the cell signaling dysregulation leading to cancer
development and progression, these pathways have emerged as clinically useful targets
for development of drugs and molecules that block the specific proteins that initiate
these processes. At the forefront of this research is the class of small molecule
inhibitors known as tyrosine kinase inhibitors (TKI).
TKIs exert effect by inhibiting the function of kinase protein by either blocking the energy
binding site of enzyme (as a competitive inhibitor to ATP) or by blocking enzyme-protein
interactions by changing the binding site conformation (known as allosteric inhibition).
These actions help to stop activation of cell surface receptors or cytoplasmic cell
pathways critical for survival/growth that can result in tumor death. TKIs can also exert
anti-tumor effects separate from direct action on cancer cells with abnormal signal
pathways. Local tumor microenvironment including stromal endothelial cells that provide
oxygen, nutrients and carry away locally injected chemotherapy are also sensitive to TKI
therapy. Thus, disruption of angiogenesis (formation of new blood vessels) can reduce
additional oxygen and nutrients critical for tumor growth and survival to either stabilize
or slow tumor progression. This combination of increased tumor specific cytotoxicity,
endothelial vascular inhibition improved tumor cell control, even in the face of known
chemotherapy and resistant cell lines in vivo. This knowledge has stimulated further
research into in vivo clinical trials in human medicine and more recently, veterinary
oncology.
Tyrosine Kinase Inhibitors in Human Medicine
The first small molecule inhibitor approved for human use in 2001 was imatinib
(Gleevec; Norvartis) that targeted aberrant cytoplasmic TK activation in patients with
CML that dramatically improved treatment response and overall survival compared to
chemotherapy alone. Over the past decade, continued research into TK inhibition has
led to development of other more specific TKIs in humans including erlotinib, gefitinib,
crizotinib, vermurafenib and sunitinib (Sutent) with approval to treatment of many other
cancers and non-oncologic disorders with dysregulated TKs including gastrointestinal
stromal tumors (GISTs), melanoma, non-small cell lung cancer, poorly controlled
rheumatoid arthritis/asthma, adjunctive therapy for Alzheimers.
Kinase Inhibitors in Veterinary Medicine
Initial small studies utilizing the human TKI imatinib have shown efficacy in dogs and
cats but it’s use has been largely superseded by two TKIs that have been approved for
use specifically in veterinary patients; Palladia and Kinavet.
Palladia (toceranib) is a small molecule inhibitor that blocks a variety of RTKs including
VEGFR-2, PDGFR-α and c-Kit. It is most similar to the human TKI sunitinib (Sutent) and
was first approved in 2009. Initial phase I clinical trial in dogs with a variety of cancers
including sarcomas, carcinomas, melanomas, myeloma and mast cell tumors exhibited
a biological response rate of 54% (tumors stabilized or reduced in size). Highest
response rate was observed mast cell tumors and expanded placebo-controlled
randomized studies for inoperable grade 2 and 3 mast cell tumors (MCT) exhibited an
overall response rate of 42.8%. Dogs with MCT that had c-kit mutations were more
likely to response to toceranib and those without (69 vs 37%). Further phase I safety
studies have also suggested that synergistic benefits may be obtained through
combination with other treatments such as Piroxicam, vinblastine, and coarse
fractionated radiation therapy which were all found to be generally well tolerated and
further studies to evaluate clinical benefit prospectively in future randomized trials.
Following its approval, Palladia has been used off label by many oncologists to treat a
variety of other canine tumors often as a second line therapy following clinical
resistance to primary therapy or metastatic disease. Tumors that showed clinical
evidence of activity included apocrine gland anal sac adenocarcinoma (AGASACA),
metastatic osteosarcoma, head/neck carcinomas (such as squamous cell carcinoma),
nasal carcinoma and neuroendocrine tumors such as thyroid carcinoma,
chemodectomas (heart base tumors). Clinical benefit (tumor shrinkage or stabilization)
was observed in 74% of dogs within the initial follow-up period of 4 months with many
patients in the speakers experience that maintain response within the first 4-6 months
having durable remissions of a year or longer.
Kinavet (masitinib) is a RTK that blocks activity of PDGFR-α/-β, c-Kit and cytoplasmic
kinases such as Lyn first approved in Europe in 2009 with conditional FDA approval for
use within the United States since 2010. Initial large-scale randomized studies in over
200 dogs with MCTs significantly improved time to progression compared to placebo,
particularly in dogs possessing c-Kit mutations. Subsequent follow-up studies in dogs
treated long term (>1-2 years) revealed increased long term survival of patients that
responded and were maintained on masitinib (40%) compared with placebo (15%) at 2
years. Recent studies evaluating masitinib for metastatic and non-resectable cutaneous
mast cell tumors resulted in a overall response rate of 50% with median survival time of
630 days in responding patients vs 137 days for those that did not. Subsequent in-vitro
have also indicated potential anti-tumor activity from canine hemangiosarcoma,
osteosarcoma and squamous cell carcinoma cell lines. Non-neoplastic inflammatory
conditions that may benefit from TKI inhibition with masitinib include canine atopy
(Phase III European trial) and potentially chronic feline asthma based on animal models.
Treatment Administration & Side Effects
Palladia (toceranib)
Manufacturer:
Zoetis/Pfizer Animal Health, Madison, NJ, USA
Tablet Sizes:
10mg, 15mg, 50mg
Label Dosing:
3.25mg/kg PO q48hr*
(Reported dose reductions to 2.2-2.75mg/kg to MWF 3x/week)
Kinavet (masitinib)
Manufacturer:
AB Sciences, Paris, France
Tablet Sizes:
50mg, 150mg
Label Dosing:
12.5mg/kg POq24hr*
(Reported dose reductions to 9mg/kg to q48hr)
As with all anti-neoplastic medications, chemotherapy safety handling, regulations and
proper client education on safety and potential side effects apply (as per WA regulation
senate bill WAC-5594 /-5149). Tablets should not be crushed, cut, dissolved or mixed
without approved chemotherapy protection equipment. Most commonly reported
adverse events included gastrointestinal upset (diarrhea, decreased appetite, vomiting,
and intestinal bleeding), weight loss or lameness. Neutropenia was the most commonly
reported lab finding and uncommonly kidney toxicity (elevated renal values or
proteinuria). As with most anti-neoplastic drugs, side effects can be serious in patients
receiving Palladia or Kinavet TKI therapy but most were mild to moderate. If toxicity is
observed, strategies including use of concurrent prophylactic medications (anti-emetics,
gastro protectants, anti-diarrheal), dose reductions or “drug holidays” (breaks of 2-3
doses) is generally sufficient to optimize patient dosing to balance tumor response and
manage side effects with most patients managed with little to no side effects with long
term administration.
Due to these potential side effects, regular monitoring of patients on TKI therapy is
paramount to assess for continued tumor response / development of resistance and
dose modification / intervention if side effects are noted. During start of therapy; along
with complete staging diagnostics (as a baseline to assess response to therapy)
minimum database to start TKI therapy typically includes: Complete Blood Count (CBC)
/ Biochemistry / Urinalysis / UP:C / Fecal occult blood (if diarrhea already present).
CBCs are then performed at regular intervals every week for the first 6 weeks to monitor
for anemia, immunosuppression or other cytopenias that may indicate the need for dose
reductions. If patients tolerate therapy well and show a clinical benefit at the end of the 6
week trial; the therapy is continued long term with regular rechecks (Physical,
CBC/Chemistry/UA, +/- UP:C, Fecal occult blood, imaging) every 6-8 weeks long term
for as long as it is effective.
Conclusion & Future Applications
Dysfunction of protein kinases occurs frequently in human cancers and newer studies
indicate that similar mechanisms of cancer development and proliferation is observed in
many dog and likely feline cancers as well. Targeted therapies designed to specifically
inhibit such pathways including tyrosine kinase inhibitors (TKI) are now available for use
in both human and veterinary oncology and many have shown significant clinical benefit
to improve treatment outcomes for patients with cancer.
Ongoing studies are underway in Europe and North America to research new
applications in other cancer types with larger randomized studies comparing against
traditional standard of care therapy in addition to evaluating the efficacy of TKIs
combined with traditional cytotoxic chemotherapy, NSAIDs and radiation therapy to
bolster our armamentarium in the treatment of cancer in all species.
Selected References & Recommended Reading
1. Withrow SJ, McEwen EG, editors. Small animal clinical oncology: Signal transduction and
cancer, the protein kinases – 4th edition. St. Louis, MI: Saunders (Elsevier); 2013. pp 221-248.
2. London CA. Kinase dysfunction and kinase inhibitors.Vet Derm. 2013;24:181-e40
3. London CA. Tyrosine kinase inhibitors in veterinary medicine. Top Comp Anim Med. 2009
Aug;24(3):106-1012. Review.
4. London CA. The role of small molecule inhibitors for veterinary patients. Vet Clin Small Anim 37.
2007; 1121-1136
5. Debreuil P, Letard S, Ciufolini M Gros L, Humbert M, Casteran N, Borge L, Hajem B, Lermet A,
Sippl W, Voisset E, Arok M, Auclair C, Leventhal PS, Mansfield CD, Moussy A, Hermine O.
Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One.
2009 Sep 30;4(9):e7258.
6. Gentinlini F. Masitinib is safe and effective for the treatment of canine mast cell tumors. J Vet Int
Med 2010 Jan-Feb;24(1):6:5.
7. Hanh KA, Legendre AM, Shaw NG, Phillips B. Ogilve GK, Prescott DM, Atwater SW, Carreras
JSk, Lana SE, Ladue T, Rusk A, Kinet JP, Dubreuil P, Moussy A, Hermine O. Evaluation of a 12and 24-month survival rates after treatment with masitinib in dogs with nonresectable mast cell
tumors. Am J Vet Res. 2010 Nov;71(11):1354-1361.
8. Masivet – Prescribing information for veterinarians [Internet]. Paris, France: AB Science;
[Updated 2008 Aug 28; cited 2010 Dec 10]. Available from: http://www.masivet.com/
9. Masitinib mesylate [Internet]. Bethesda (MD): National Cancer Institute [updated 2008 Dec 2;
cited 2010 Dec 10]. http://www.cancer.gov/drugdictionary/?CdrID=629109
10. Bellamy F, Bader T, Moussy A, Hermine O. Pharmacokinetics of masitinib in cats. Vet Res
Comm. 2009 Jun 16. Epub 2009.
11. London CA, Phyllis BM, Wood-Follis SL, Boucher JF. Multi-center, Placebo-controlled, Doubleblind, Ramdomized Study of Oral Toceranib Phosphate (SU11654), a Receptor Tyrosine Kinase
Inhibitor, for the Treatment of Dogs with Recurrent (Local or Distant) Mast Cell Tumor Following
Surgical Excision. Clin Cancer Res. 2009 15; 3856.
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Prophylactic Gastropexy: Practical Pointers for Preventing a
Pernicious Problem
Kent J. Vince, DVM, MSpVM, DACVS-SA
Seattle Veterinary Specialists
Kirkland, WA
Gastric dilatation volvulus (GDV) is a life threatening condition that many dogs,
especially deep chested, large breed dogs, can face during their lifetime. While the
exact cause of GDV is not completely understood, there are many factors that are
thought to contribute to this condition. Mitigating those risk factors is a very good
approach to prevent such a serious life threatening condition. In addition, performing a
prophylactic gastropexy can virtually eliminate the chance of dogs suffering from GDV.
GDV has a high mortality rate reported to range 16-49%. Large and giant breed dogs,
such as the Great Dane, have a 21-24% chance of suffering from GDV. In my
experience, most cases that present on emergency with GDV and are treated quickly
and aggressively with surgery have a very good chance for a successful outcome.
The most common risk factors in increasing risk for GDV are:
•
Male gender
•
Feeding followed by exercise
•
Underweight
•
One meal daily
•
Increased age (10-12yrs is typical)
•
Dry foods with oil/fat in first 4 ingredients
•
Eating rapidly (large but not giant breeds)
•
‘Fearful’ temperament / stress
•
1st degree relative with GDV
•
Raised food bowl
Based on the above-mentioned factors, the typical GDV patient is Brutus the 7 year-old,
male castrated, German Shepherd. His father suffered from GDV. He is anxious,
nervous and stressful, and usually eats from an elevated dish once a day.
In the US military, the majority of working dogs (MWD) are German Shepherd and
Belgian Malinois, both deep chested large breed dogs. In a study evaluating the cause
of death of US Military Working Dogs, GDV was the 5th leading cause and contributed
to 9% of all MWD deaths. Since this study was published, the US Army, which provides
veterinary care for all Department of Defense owned working dogs, has actively pushed
to perform prophylactic gastropexies in all of the MWDs under their care. Laparoscopic
and minimal grid approach prophylactic gastropexy surgeries have enabled Army
veterinarians to perform these procedures with minimal morbidity. Since many of the
MWDs are deployed to austere environments without quick access to a veterinarian,
preventing GDV with a prophylactic gastropexy has saved dozens of MWD lives. While
the numbers of GDVs treated by the US Army and decrease in GDV rates have not yet
been published, I can say that in the 12 years of active duty service, I never once
treated a gastropexied MWD for GDV.
Surgical Procedure:
The minimal grid approach prophylactic gastropexy is a relatively simple outpatient
procedure that can be performed by most well trained veterinarians. With practice, this
procedure can be completed within 15-20 minutes. It is often performed at the time of
spay or neuter when patients are at least 9-months of age.
A ventral abdominal hair clip is performed and extended just beyond the ventral border
of the ribs on the right side. Just prior to final positioning of the patient, the head and
chest are held higher than the abdomen to help shift the spleen and abdominal contents
caudally. The patient is placed in dorsal recumbency. A routine sterile scrub of the
surgery site is performed. The patient is widely draped so that the minimal approach
procedure can be converted into a full abdominal laparotomy if needed. I routinely use
an adhesive plastic drape, such as IobanTM, to help maintain a sterile field.
An approximately 4 cm incision is made on the right lateral ventrum, just lateral from the
lateral margin of the rectus abdominus muscle, cranial to the umbilicus, medial to the
costochondral junction of the 12th rib and lateral to the cranial abdominal nipple. The
subcutaneous tissue is incised along the same line. Hemostasis is achieved with
electrocautery. The aponeurosis of the internal and external abdominal oblique muscles
is incised along the same line using metzenbaum scissors. Lone-star retractors are
placed around the margins of the incision site to aid in retraction. The transversus
abdominus and peritoneum are elevated using forceps and is incised in a medio-lateral
direction and extended using Metzenbaum scissors. Digital palpation and retraction are
used to displace the falciform and omental fat away from the incision. The greater
curvature of the stomach is identified using digital traction of the omental fat. The
stomach can be grasped with Babcock forceps. The vascular arcades of the greater
and lesser curvature are identified and the pylorus is palpated. The right lateral edge of
the hepatogastric ligament is easily palpated and you should palpate a slip of the
mucosa/submucosa when grasping the sero-muscular layer of the stomach. A stay
suture of 2-0 PDS is placed in the sero-muscular layer of the stomach to aid in
retraction.
®
The sero-muscular layer of the stomach is digitally elevated approximately 10 cm orad
to the pylorus, mid-distance between the vascular arcades of the greater and lesser
curvature. The slip of the sero-muscular layer is verified and a 4cm incision is made
into the sero-muscular layer of the antrum using electrocautery or Metzenbaum
scissors. The cranial margin of the sero-muscular layer is sutured to the cranial margin
of the transversus abdominus muscle using 2-0 PDS on a taper needle (CT-2 or SH),
beginning at the medial margin, using a simple continuous suture pattern. The cranial
suture line is tied off at the lateral margin of the incision, and the same technique is
used on the caudal incision margin, tying off again at the medial point.
®
The transversus abdominus incision is then closed using 2-0 PDS in a simple cruciate
or simple continuous pattern. The aponeuroses of the external and internal abdominal
oblique muscles are closed using 2-0 PDS in a simple continuous pattern, tacking down
several bites to close dead space. The subcutaneous tissue is closed using 3-0
Monocryl on a taper needle in a simple continuous pattern, and the skin is then closed
with the 3-0 Monocryl in an intra-dermal pattern. External skin sutures or skin staples
are placed to aid in skin closure.
®
®
®
®
Post-operatively, antibiotic ointment is applied to the incision line followed by a Telfa
and TegadermTM adhesive bandage. Ice packing of the surgery site is performed for 10
minutes 3-4 times daily for the first 2-3 days after surgery. Pain relief is provided with
an NSAID for 3-5 days and tramadol may also be prescribed for 2-5 days postoperatively. The patient can resume a bland diet fed in a smaller quantity 3-4 times
daily for the first 3 days after surgery. An Elizabethan collar should be worn at all times
until suture/staple removal and activity restricted to short (5-10 minutes) leash walks
during the 10-14 day recovery period.
®
The most common complication from the minimal approach prophylactic gastropexy is
seroma formation followed by self-induced surgical site infection. It is important to
minimize dead space with suture tacking during the muscular and subcutaneous closure
of the surgery site to help prevent serum formation. Most seromas will resolve with
warm packing, activity restriction and time.
Conclusion:
The minimal grid approach prophylactic gastropexy is a relatively simple surgical
procedure that can be performed on an outpatient basis to prevent a pernicious problem
in many large breed, deep chested dogs.
References and Recommended Reading:
!
1) Benitez ME1, Schmiedt CW, Radlinsky MG, Cornell KK. Efficacy of incisional gastropexy for prevention
of GDV in dogs. J Am Anim Hosp Assoc. 2013 May-Jun;49(3):185-9.
2) United States Department of Defense. Military Working Dog Paracostal Gastropexy. DOD Video. April
2010.
3) Raghavan M, Glickman N, McCabe G, Lantz G, Glickman LT. Diet-related risk factors for gastric
dilatation-volvulus in dogs of high-risk breeds. J Am Anim Hosp Assoc. 2004 May-Jun;40(3):192-203.
4) Raghavan M, Glickman NW, Glickman LT. The effect of ingredients in dry dog foods on the risk of
gastric dilatation-volvulus in dogs. J Am Anim Hosp Assoc. 2006 Jan-Feb;42(1):28-36.
5) Ward MP, Patronek GJ, Glickman LT. Benefits of prophylactic gastropexy for dogs at risk of gastric
dilatation-volvulus. Prev Vet Med. 2003 Sep 12;60(4):319-29.
6) Steelman-Szymeczek SM, Stebbins ME, Hardie EM. Clinical evaluation of a right-sided prophylactic
gastropexy via a grid approach. J Am Anim Hosp Assoc. 2003 Jul-Aug;39(4):397-402.
7) Rawlings CA, Mahaffey MB, Bement S, Canalis C. Prospective evaluation of laparoscopic-assisted
gastropexy in dogs susceptible to gastric dilatation. J Am Vet Med Assoc. 2002 Dec 1;221(11):1576-81.
8) Herbold JR, Moore GE, Gosch TL, Bell BS. Relationship between incidence of gastric dilatationvolvulus and biometeorologic events in a population of military working dogs. Am J Vet Res. 2002
Jan;63(1):47-52.
9) Moore GE, Burkman KD, Carter MN, Peterson MR. Causes of death or reasons for euthanasia in
military working dogs: 927 cases (1993-1996). J Am Vet Med Assoc. 2001 Jul 15;219(2):209-14.
10) Glickman LT, Glickman NW, Schellenberg DB, Raghavan M, Lee TL. Incidence of and breed-related
risk factors for gastric dilatation-volvulus in dogs. J Am Vet Med Assoc. 2000 Jan 1;216(1):40-5.
11) Glickman LT, Glickman NW, Schellenberg DB, Raghavan M, Lee T. Non-dietary risk factors for
gastric dilatation-volvulus in large and giant breed dogs. J Am Vet Med Assoc. 2000 Nov
15;217(10):1492-9.
12) Glickman LT, Lantz GC, Schellenberg DB, Glickman NW. A prospective study of survival and
recurrence following the acute gastric dilatation-volvulus syndrome in 136 dogs. J Am Anim Hosp Assoc.
1998 May-Jun;34(3):253-9.
Notes
Notes
Too Much or Not Enough: Imaging Urinary Tract Pathology
Alaina H. Carr, DVM, Diplomate ACVR
Seattle Veterinary Specialists
Kirkland, WA
Introduction
One of the more common presenting complaints for veterinarians is the pet that either
urinates more frequently than normal or is unable to urinate normally. This discussion is
intended as an overview of urinary tract pathology that may be detectable with
diagnostic imaging, rather than an all-inclusive list. Disease processes are loosely
grouped based on their clinical manifestation in the text, but it is important to note that
many disease processes differ in their clinical manifestation depending on duration,
severity and concurrent etiologies. One of the absolutely most important things to
remember is that imaging findings will not necessarily correlate with organ
function, especially if disease is unilateral with contralateral compensation.
Appearance of the kidneys or urinary bladder should always be interpreted in light of
patient signalment, clinical signs, laboratory findings, and response to therapy. Also, as
with other organs, while radiographic or ultrasonographic findings can be specific or
even pathognomic for a certain disease process, tissue sampling is almost always
needed for definitive diagnosis. When creating a list of differentials for a soft tissue
mass, use of the mnemonic CHANG can be a useful starting point when combined with
potential tissues of origin. CHANG stands for Cyst, Hematoma, Abscess, Neoplasia,
Granuloma.
Too much urine: polyuria, pollakiuria, incontinence
One of the more common causes for polyuria is chronic kidney disease due to loss of
nephron function. There are many underlying etiologies of chronic kidney disease but
they often manifest similarly in dogs and cats and result in progressive interstitial
fibrosis: look for decreased size, irregular margins, diminished corticomedullary
distinction (CMD), mineral accumulation within the diverticuli or pelvis, pyelectasia or
even hydronephrosis. Neoplastic disease is an exception and appearance is variable
depending on specific tumor type (see Tables 1 and 2). FNA or biopsy is often needed
for definitive diagnosis.
Potential etiologies of chronic kidney disease:
• Vascular: systemic hypertension, coagulopathy, chronic hypo-perfusion,
glomerular hypertension
• Parenchymal: glomerulonephritis, amyloidosis, allergic and immune-mediated
nephritis, low-grade or chronic nephrotoxicity, prior or ongoing infectious disease
(abscess or granuloma formation: bacterial, fungal, FIP)
• Collecting system: pyelonephritis, low-grade or chronic obstructive uropathy
• Neoplastic disease (of any underlying tissue type)
• Dysplasia, congenital collagen defects, other development disorders in young
patients
Of course, many of the disease processes listed above may also cause polyuria without
concurrent chronic renal degeneration. Other potential causes for increased urine
volume production include metabolic disease (see introduction) and post-obstructive
diuresis.
Increased frequency of urination (pollakiuria) may be secondary to inflammation or
irritation of the urinary bladder due to urinary tract infection, mechanical irritation from
urinary calculi or neoplasia. Patients with recurrent or resistant urinary tract infections
should have further workup (including abdominal ultrasound) to look for underlying
causes such as radiolucent calculi (if none are identified radiographically), cystitis or
neoplasia. Patients may also have decreased ability to store urine in the bladder. This
may be secondary to inflammation (calculi, infection, secondary to neoplasia or
hemorrhage in the urine), space occupying lesions (masses-CHANG, calculi), lack of
bladder wall distensibility or incontinence. Incontinence must be distinguished from
polyuria, pollakiuria and behavioral problems, but many differentials for true
incontinence exist.
Potential causes for urinary incontinence include:
• Neurologic- more commonly lower motor neuron
o Sacrococcygeal dysgenesis in Manx cats
o Trauma affecting relevant spinal nerves (vertebral/sacral/pelvic fractures)
o Lumbosacral disease
• Non-neurologic (functional)
o Sphincter incompetence
o Detrusor instability
• Non-neurologic (anatomic)
o Ectopic ureters
o Pelvic bladder
Not enough urine: diminished urine output and stranguria
Inadequate production of urine may result from pre-renal, renal or post-renal causes.
Renal causes are usually acute, but acute injury to the kidneys often does not produce
recognizable findings in the renal parenchyma on diagnostic imaging (see Tables 1 and
2). One of the exceptions to this rule was originally thought to be the medullary rim sign,
which is defined as a hyperechoic, curved band in the outer portion of the medulla,
parallel to the corticomedullary junction. This finding was first described as on
ultrasound related to ethylene glycol toxicity. However, this appearance has since been
described with chronic interstitial nephritis, FIP, and in patients with normal renal
1
function (Table 2). Variations on the medullary rim sign have been reported in patients
with leptospirosis (medullary band) and in normal smaller breed dogs as well.2,3
However, peri-renal fluid accumulation is identified with acute renal failure, thought to
represent an ultrafiltrate associated with tubular back-leak into the renal interstitium that
overwhelms regional lymphatic drainage.4 Peri-renal fluid accumulation may also be
identified in renal or ureteral obstruction. Chronic renal damage is less likely to result in
diminished urine production unless there are other factors such as concurrent pre-renal
azotemia, mechanical obstruction, or severe stage IV disease.
Potential causes for acute kidney injury include:
• Toxins: ethylene glycol, aminoglycosides, NSAIDS, hemoglobinuria,
hypercalcemia, melamine, grapes/raisins
• Ischemia: severe prolonged hypo-perfusion from shock or hypovolemia, embolic
showering from DIC or other causes for thromboembolic disease
• Infection: leptospirosis, borreliosis, ascending infections
Diminished overall urine production may also result from interference with passage of
urine to the urinary bladder from the kidneys. Obstruction of the renal pelvis or ureter is
usually mechanical in etiology, most commonly ureterolithiasis. Ureteroliths may be
identified radiographically, but are commonly obscured by GI contents (especially the
colon). Additionally, the radiographic presence of calculi does not necessarily equal
obstruction and additional imaging (ultrasound, excretory urography, CT) may be
needed to determine the significance of ureteral calculi. Serial radiography can be a less
expensive, subjective way to determine if medical therapy (such intravenous fluids,
diuresis, and ureteral relaxants) has resulted in passage of ureteral calculi towards the
urinary bladder.
Differentials for ureteral obstruction:
• Mechanical: calculi, stricture, masses (CHANG), severe ureteritis (most often
ascending infection)
• Functional: laceration, avulsion, longstanding mechanical obstruction resulting in
loss of muscular tone
Ureters need not be obstructed to lose function; ureteral laceration or avulsion
(traumatic or iatrogenic) can also result and are extremely difficult to diagnose without
intravenous contrast, but there is frequently a higher index of suspicion in those patients
due to recent trauma or abdominal surgery.
When discussing renal or ureteral pathology, differentiation between pyelectasia
hydronephrosis is important. Pyelectasia specifically refers to dilation of the renal pelvis,
whereas hydronephrosis is defined as dilation of the renal collecting system to an extent
that overall renal volume is increased. The author usually reserves the term
hydronephrosis for diverticular dilation, which is extremely variable. The degree of
pyelectasia (or hydronephrosis) is also key to note, as the width of the renal pelvis can
help distinguish between obstructive and non-obstructive pathologies. A recent study
took found that pyelectasia can be seen in normal patients, those with various causes
for diuresis, urinary tract infection, obstruction, and other disease. Pyelectasia 13mm or
greater always indicated obstruction, but measurement should be interpreted with
caution. Mild pyelectasia has been specifically described as a manifestation of canine
renal lymphoma, and was rarely reported as the only architectural derangement.5 To
make matters more complicated, accurate measurement of the renal pelvis depends on
the sonographer’s ability to consistently measure the renal pelvis in an exact transverse
plane, and may be compromised by destruction of the renal pelvis from active or
previous pyelonephritis.
Finally, and perhaps most frequently, decreased urine production may result from an
inability to move urine out of the bladder. Assessment of urinary bladder volume
(physical exam, imaging) will help differentiate diminished urine production from lower
urinary tract obstruction. Many causes for obstruction may require ultrasound or contrast
administration to diagnose, but radiopaque calculi are usually easily identifiable;
patterns of mineralization that do not change in orientation with varied positioning may
indicate a mineralized mass. Additionally certain types of calculi are radiolucent (most
notably urate and cysteine stones, although a recent study indicates that urate calculi in
cats are often visible).6 Lack of visualization of the urinary bladder in its normal location
is a very important imaging finding as it may indicate anuria/collapse, rupture or
displacement of the bladder (see Table 3).
Differentials for urinary bladder or urethral obstruction include:
• Mechanical obstruction
o Urinary bladder neck/trigone: mass, calculi, hematoma (coagulopathy,
iatrogenic)
o Urethral spasm, stricture or mucosal flap, calculi, mucus or inflammatory
debris, mucus plug (cats), neoplasia, granulomatous urethritis, bacterial
urethritis
o Prostatic disease: benign prostatic hyperplasia (BPH), abscess, prostatitis,
neoplasia, para-or intra- prostatic cyst
o External compression: colon, sublumbar lymph nodes, uterus, intra-pelvic
masses
o Bladder herniation
• Functional obstruction
o Decreased bladder contraction/detrusor function, inability to coordinate
urination reflexes
• Reluctance/inability to posture due to orthopedic disease
• Bladder rupture or herniation
Other variations on urinary tract pathology and imaging
Cavitary effusion may not specifically affect renal function, but may be an important
sequelae of a protein-losing nephropathy, resulting in a transudate secondary to
hypoalbuminemia. Additionally, perinephric pseudocysts deserve mention- although the
exact pathophysiology is still open, fluid accumulation within the renal capsule is
commonly seen with concurrent degenerative renal changes in older male cats. This is
a notable differential for other causes of renomegaly such as hydronephrosis and
neoplastic infiltration. Contrast studies of the urinary tract can be very useful but are
beyond the scope of this discussion. Excretory urography (especially when combined
with computed tomography) can be highly diagnostic for the more difficult cases where
survey radiography and ultrasound have failed to define an exact lesion.
Cystourethrography can also be of great diagnostic value but has in many instances
been replaced by endoscopy at the level of the specialty hospital.
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Table 1: Alterations in the radiographic appearance of the kidneys1
Those in bold more commonly also cause irregularity of shape
Non-visualization
Normal right kidney: deep chested dogs, underexposure, overlying GI,
little abdominal fat
Severe peritoneal or retroperitoneal effusion
Retroperitoneal hemorrhage: trauma, coagulopathy (anticoagulant
rodenticide), vascular invasion (adrenal neoplasia)
Retroperitoneal urine accumulation: trauma, excessive hydrostatic
pressure from obstruction, mass (CHANG) with consequent rupture
Nephrectomy
Unilateral agenesis
Normal
Small
Enlargement:
unilateral
(more mild)
----------
Acute nephritis
Acute toxicity
Dysplasia
Degenerative change
Chronic renal infarction
Chronic obstructive uropathy
Developmental cortical hypoplasia or dysplasia
Compensatory hypertrophy (contralateral disease)
Nephritis
Abscess (peri-renal, sub-capsular)
Acute infarction
Hydronephrosis
Perirenal pseudocyst
(more variable or
severe)
Enlargement:
bilateral
(more mild)
---------(more variable or
severe)
Hematoma
Abscess/Granuloma
Neoplasia: primary (LSA, renal cell adenoma/carcinoma, TCC,
nephroblastoma, histiocytic sarcoma, hemangioma/hemangiosarcoma,
anaplastic sarcoma, cystadenocarcinoma), metastatic lesions
Acute renal failure
Nephritis
Acute pyelonephritis
Amyloidosis
Portosystemic shunt
Cystic disease: secondary to degeneration, PCKD (Persians, Persian
crosses),
Hydronephrosis
Perirenal pseudocyst
Neoplasia: Primary (LSA , most common- cats), metastatic lesions
FIP
Table 2: Alterations in the ultrasonographic appearance of the kidneys1
Focal anechoic or
hypoechoic lesions
Thin/smooth wall: cysts (Persians with polycystic kidneys, degenerative)
Thick/irregular wall: complex cyst, hematoma, abscess, cystic neoplasia
Neoplasia: especially LSA or metastatic lesions
Focal hyperechoic
parenchymal lesions
Acute renal infarction: mimics neoplasia with hypoechoic rounded
lesions, bulging from cortex
Neoplasia: primary vs. metastatic (see list in Table 1)
Chronic infarctions (wedge shaped, concurrent defect in cortical margin)
Parenchymal calcification or calculi: metabolic disease, degeneration
Focal complex
lesions
Increased
echogenicity of
medulla (medullary
rim sign, medullary
band)2,3,7
Large number of small cysts (appear hyperechoic due to distal acoustic
enhancement)
Parenchymal gas: reflux from negative cystogram, penetrating wound,
abscess
Neoplasia: primary vs. metastatic (see list in Table 1)
Other masses (CHANG)
Large number of small cysts
Subacute/remodeling infarction
Normal variant
Ethylene glycol toxicity
Chronic interstitial nephritis
FIP
Leptospirosis (medullary band)
Nephrocalcinosis: chronic renal disease, ethylene glycol toxicity,
nephrotoxic drugs, hypervitaminosis D, hyperadrenocorticism,
hyperparathyroidism, hypercalcemia of malignancy
Diffuse parenchymal
lesions- ↑ CMD or
cortical
echogenicity2
Normal variant (older male neutered cats most commonly)
Inflammatory disease: glomerulonephritis, interstitial nephritis, FIP,
leptospirosis
Acute tubular necrosis/nephrosis
Nephrocalcinosis (see above)
Neoplasia: LSA in cats, metastatic squamous cell carcinoma
Diffuse parenchymal
lesions- ↓CMD
Peri-renal fluid or
hypoechoic
tissue2,5,8
Chronic inflammatory and degenerative disease (non-specific)
Multiple small cysts
Renal dysplasia
Perirenal pseudocyst (sub-capsular)
Blood, urine, exudate, transudate from: trauma, neoplasia, infection
(Leptospirosis), toxicities, renal or ureteral laceration/rupture
Differential (NOT fluid): Irregular hypoechoic capsular thickening due to
LSA in cats. Not present in dogs.
Table 3: Alterations in the radiographic appearance of the urinary bladder (UB) or
prostate1
Diminished or nonvisualization of UB
or prostate
Technical factors: obscured by hind limbs, underexposure
Empty bladder: recent urination, severe cystitis, bilateral ureteral ectopia
Displacement
-Variable: herniation (perineal, inguinal, body wall) or prepubic tendon
rupture, obesity in cats
-Ventral: severe sublumbar lymphadenopathy, colonic distension or
mass, uterine enlargement (pyometra, masses)
-Cranial: prostatomegaly (displacing UB), urethral rupture, full bladder
(displacing prostate)
-Caudal: pelvic bladder/short urethra syndrome
Rupture of UB: external trauma, iatrogenic
Normal prostate is usually not visible in castrated male dogs
Decreased size of
UB
Recent urination
Anuria or oliguria
Non-distensible: severe infectious or chemical (doxorubicin) cystitis,
mechanical cystitis due to calculi, traumatic cystitis, diffuse mural
neoplasia
Ureteral rupture or ectopia
Bladder hypoplasia or previous cystectomy of a large portion of the wall
Defect in bladder wall
Increased size of
UB
Voluntary retention: training, stress
Non-obstructive retention: psychogenic, neurologic dysfunction,
orthopedic disease leading to reluctance/inability to posture
Outflow obstruction (functional vs. obstructive)
Changes in shape
of UB
Artifactual: paraprostatic cyst, superimposition of limbs or GI
Extensive bladder neoplasia
Bladder rupture
Congenital diverticulum or patent urachus
Variation in opacity
within UB or
prostate
Enlargement or
irregularity of
prostate
Mineral: radiopaque calculi, dystrophic mineralization (neoplasia- usually
carcinomas, abscess, chronic prostatitis), cystic disease
Gas in UB: iatrogenic (recent cystocentesis or catheterization),
emphysematous cystitis
Gas in prostate: iatrogenic, abscess formation
Benign prostatic hyperplasia (BPH)
Androgen-producing testicular neoplasia
Intra- or para-prostatic cysts
Prostatic abscess or prostatitis
Prostatic neoplasia
Table 4: Alteration in the ultrasonographic appearance of the urinary bladder (UB) and
prostate1
Diminished or nonvisualization of UB
or prostate
Thickening of UB
wall
Irregularity of the
UB wall
Similar to differentials in Table 3
Diffuse, smooth: lack of distension, chronic cystitis (mainly cranioventral),
muscular hypertrophy due to chronic obstruction
Diffuse, irregular: chronic cystitis, diffuse neoplasia (including LSA- rare)
Ulcerative or polypoid cystitis
Diffuse neoplasia (rare)
Focal neoplasia: TCC most common, also squamous cell carcinoma,
adenocarcinoma, leiomyoma/sarcoma, rhabdomyoma/sarcoma,
fibrosarcoma, metastatic disease)
Ureterocele, patent urachus, diverticulum
Abnormal UB
contents
Focal parenchymal
changes within the
prostate
Diffuse
parenchymal
change within the
prostate
Hypoechoic lesions
adjacent to
prostate/UB
Calculi
Freely moveable foci or sediment: cellular debris, mucus, lipid, crystals
Hypo/hyperechoic masses, non-shadowing: blood clot, polyp, neoplasia
Hyperechoic masses: artifact from colon, calcified mass (usually
neoplasia)
Anechoic, smooth thin walls: intra-prostatic cyst , less likely abscess
Anechoic or hypoechoic contents, thick irregular walls: abscess or
necrotic/cystic neoplasm
Hyperechoic: calculus, dystrophic calcification (see Table 3)
Increased echogencity, uniform or striated architecture: BPH
Heterogenous/abnormal architecture: chronic bacterial prostatitis,
granulomatous prostatitis (fungal disease), neoplasia
Decreased echogencity: acute prostatitis or abscessation, neoplasia (less
common)
Paraprostatic cysts (may be benign or malignant in origin)
Focal accumulation/loculation of peritoneal effusion
Hydroureter
Ureterocele
Urachal cyst (cranial to bladder), urachal or traumatic diverticulum
Uterine/vaginal lesions
REFERENCES
1.
Dennis R, Kirberger R, Wrigley R, et al. Handbook of Small Animal Radiological
Differential Diagnosis: WB Saunders, 2001.
2.
Forrest LJ, O'Brien RT, Tremeling MS, et al. SONOGRAPHIC RENAL FINDINGS IN 20
DOGS WITH LEPTOSPIROSIS. Veterinary Radiology & Ultrasound 1998;39:337-340.
3.
Hart DV, Winter MD, Conway J, et al. ULTRASOUND APPEARANCE OF THE OUTER
MEDULLA IN DOGS WITHOUT RENAL DYSFUNCTION. Veterinary Radiology & Ultrasound
2013;54:652-658.
4.
Holloway A, O'Brien R. PERIRENAL EFFUSION IN DOGS AND CATS WITH ACUTE
RENAL FAILURE. Veterinary Radiology & Ultrasound 2007;48:574-579.
5.
Taylor AJ, Lara-Garcia A, Benigni L. ULTRASONOGRAPHIC CHARACTERISTICS OF
CANINE RENAL LYMPHOMA. Veterinary Radiology & Ultrasound 2014;55:441-446.
6.
Dear JD, Shiraki R, Ruby AL, et al. Feline urate urolithiasis: a retrospective study of 159
cases. J Feline Med Surg 2011;13:725-732.
7.
Mantis P, Lamb CR. MOST DOGS WITH MEDULLARY RIM SIGN ON
ULTRASONOGRAPHY HAVE NO DEMONSTRABLE RENAL DYSFUNCTION. Veterinary Radiology &
Ultrasound 2000;41:164-166.
8.
ValdÉS-MartÍNez A, Cianciolo R, Mai W. ASSOCIATION BETWEEN RENAL
HYPOECHOIC SUBCAPSULAR THICKENING AND LYMPHOSARCOMA IN CATS. Veterinary Radiology
& Ultrasound 2007;48:357-360.
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The Ins and Outs of Portosystemic Shunts
Michael B. Mison, DVM, Diplomate ACVS
Seattle Veterinary Specialists
Kirkland, WA
Introduction:
Portosystemic Vascular Anomalies (PSVA) or Portosystemic Shunts (PSS) are
anomalous vessels that allow normal portal blood to pass directly into the systemic
circulation without first passing through the liver. PSS in dogs and cats can either be
congenital or acquired. The congenital form is the most common. Congenital PSS are
anomalous vessels that usually occur as single intrahepatic or extrahepatic shunts and
are not secondary to portal hypertension. Congenital PSS commonly occur in miniature
and toy-breed dogs such as Yorkshire Terriers, Lhasa Apso, Pekingese, Poodles, and
Miniature Schnauzers. In cats, Persians and Himalayans appear to be at increased
risk. Acquired PSS form in response to portal hypertension. These shunts are typically
multiple extrahepatic shunts that connect the portal system and the caudal vena cava.
Single intrahepatic PSS is a communication between the portal vein and the caudal
vena cava. These shunts can be classified as left, central, or right divisional. The
pathogenesis of intrahepatic PSS that occur in the right medial (central divisional) or
right lateral (right divisional) liver lobes is unknown. A left divisional shunt (via the left
hepatic vein) is consistent with patent ductus venosus. Single intrahepatic PSS are
most common in large breed dogs.
Clinical Presentation:
Many affected animals have a history of stunted growth, failure to gain weight compared
with unaffected littermates, or weight loss. A history of prolonged recovery after general
anesthesia or excessive sedation after treatment with tranquilizers, anticonvulsants, or
organophosphates can be attributed to impaired hepatic metabolism of these
substances. Clinical signs of hepatic encephalopathy (HE) predominate on history and
physical examination because of inadequate hepatic clearance of enterically derived
toxins such as ammonia, aromatic amino acids, mercaptans, short-chain fatty acid,
gamma-aminobutyric acid, and endogenous benzodiazepines. Ammonia is often
considered the most important neurotoxic substance because increased concentrations
trigger a sequence of metabolic events that have been implicated in hepatic
encephalopathy in rats, humans, and dogs. Ammonia is excitotoxic and associated with
an increased release of glutamate, the major excitatory neurotransmitter of the brain.
Over activation of glutamate receptors, mainly NMDA receptors have been implicated
as one of the causes HE-induced seizures. With chronicity, inhibitory factors such as
GABA and endogenous benzodiazepines surpass the excitatory stimulus, causing signs
more suggestive of central nervous system depression. Decreased hepatic blood flow
and lack of hepatotropic factors such as insulin, glucagons, and nutrients result in
hepatic atrophy. The most consistent signs of HE are often subtle, such as anorexia,
depression, and lethargy. Other common findings indicative of diffuse cerebral disease
include episodic weakness, ataxia, head pressing, disorientation, circling, pacing,
behavioral changes, amaurotic blindness, seizures, and coma. Hypersalivation is a
prominent sign in cats but also occurs in dogs. Copper colored irises inappropriate for
the breed have also been documented with PSS, particularly in cats. Signs of HE may
be exacerbated by a protein-rich meal; gastrointestinal bleeding associated with
parasites, ulcers, or drug therapy; or administration of methionine-containing urinary
acidifiers or lipotropic agents. Gastrointestinal signs of intermittent anorexia, vomiting,
and diarrhea are common nonspecific features of hepatic dysfunction and are not
necessarily accompanied by overt signs of HE. A complaint of polyuria and polydipsia
is very common in dogs. Urate urolithiasis, an important complication of PSS, occurs
because of increased urinary excretion of ammonia and uric acid. Renal, cystic, or
urethral calculi may occur.
Diagnostics:
Routine hematologic findings are often unremarkable in dogs and cats with congenital
PSS. Hematologic findings include erythrocytic microcytosis, target cells, poikilocytosis
(especially in cats), and mild nonregenerative anemia. These red blood cell changes
can be subtle but important diagnostic clues in an otherwise normal CBC. The cause of
microcytosis is not known; however, decreased serum iron concentration, normal to
increased ferritin concentration, and accumulation of stainable iron in the liver suggest
that microcytosis is associated with abnormal iron metabolism rather than absolute iron
deficiency. Leukocytosis may occur due to inadequate hepatic endotoxin and bacterial
clearance from the portal circulation.
Biochemical findings are suggestive of hepatocellular dysfunction. These include
hypoproteinemia, hypoalbuminemia, hypoglobulinemia, hypoglycemia, decreased BUN,
and hypocholesterolemia. Hypoglycemia, especially after a prolonged fast, is most
likely in affected toy breeds of dogs. Potential mechanisms for hypoglycemia include
decreased hepatic glycogen stores, decreased insulin catabolism, and endotoxemia.
The total serum bilirubin concentration is typically normal. The serum liver enzyme
activity (ALP, ALT, and AST) is normal to mildly (two or three times) increased,
consistent with a lesion of hepatic atrophy and minimal hepatocellular injury or
intrahepatic cholestasis. Coagulation tests in dogs may show increased partial
thromboplastin times and hypofibrinogenemia, but clinical evidence of a bleeding
problem is rare.
Isosthenuria or hyposthenuria is frequently detected by urinalysis of dogs that are
polyuric and polydipsic. Low urine specific gravity likely results from hepatic
encephalopathy and associated psychogenic polydipsia and a poor medullary
concentration gradient from the decreased urea production in the liver. Ammonium
biurate crystals are a common finding on urine sediment examination and are an
important clue to underlying liver disease in dogs and cats. If urolithiasis is a
complication of congenital PSS, additional findings may include hematuria, proteinuria,
and pyuria.
Serum bile acid (SBA) concentrations should be determined to document hepatic
dysfunction in dogs and cats suspected to have congenital PSS. The fasting SBA is
often increased but can be normal, because during prolonged fasting, the liver may
eventually clear the bile acids from the systemic circulation. Postprandial SBA is
consistently abnormal and is a good screening test for animals suspected to have PSS.
Postprandial SBA concentrations typically exceed 100 umol/L. If postprandial SBA
concentrations are consistently in the normal range, a diagnosis of congenital PSS is
unlikely. Hyperammonemia is a common finding in dogs and cats with PSS, although a
fasting blood ammonia concentration may be normal. The ammonia tolerance test is
consistently abnormal and is equal in sensitivity to postprandial SBA in detecting hepatic
dysfunction associated with congenital PSS.
Protein C is a vitamin K – dependent serine protease enzyme that is activated by
thrombin. In normal dogs, protein C activity is 70% or greater. Deficiencies in protein C
can occur with decreased production such as liver disease, consumption such as DIC,
renal disease, and malignancy. Measurement of protein C activity has been suggested
for differentiation of PSS and microvascular dysplasia. In one study, 88% of dogs with
PSS had protein C levels below 70%, and 95% of dogs with microvascular dysplasia
had protein C level 70% or above.
Survey abdominal radiographs are often obtained for animals with suspected PSS to
evaluate for microhepatica or presence of urinary calculi and to investigate other causes
of gastrointestinal or urinary tract signs. Microhepatica is a common finding on survey
abdominal radiographs of dogs with congenital PSS. Ammonium urate calculi are not
usually visible on survey radiographs unless they also contain substantial amounts of
magnesium and phosphate. Additional radiographic imaging techniques, such as
ultrasonography, contrast portography, or transcolonic portal scintigraphy, can provide
important information about the presence, location, and type-of PSS. Although
ultrasonography and transcolonic portal scintigraphy have the advantage of being
noninvasive, contrast portography is still considered the "gold standard" for the
anatomic evaluation of the portal vasculature. Cross sectional imaging such as CT
angiography and MRI have also been shown to be helpful in detecting portosystemic
vascular anomalies.
Medical Management:
Medical management of HE in dogs and cats with congenital PSS is indicated before
anesthesia and definitive surgical correction. A diet that is moderately protein restricted
with the bulk of calories derived from carbohydrates, fat, and dairy (cottage cheese,
yogurt) proteins are preferred. Meat and egg proteins are poorly tolerated. The
recommended dietary protein intake on a dry matter basis for patients with HE is 18 to
22 per cent (dogs) and 30 to 35 percent (cats). The protein content of the diet should be
increased to the maximum amount tolerated without signs of HE. Dietary
supplementation with soluble fiber (psyllium 1 to 3 teaspoons per day) appears to be
beneficial in managing HE by mechanisms similar to those with lactulose and may allow
higher levels of dietary protein to be tolerated. Lactulose, a non-metabolizable
disaccharide, acidifies colonic contents (causing ammonia trapping), shortens the
intestinal transit time, alters colonic flora, promotes incorporation of ammonia into
bacterial proteins, and reduces production of potentially toxic short-chain fatty acids
(SCFA) by producing the nontoxic SCFA acetate. The dose is 0.1 to 0.22 mL/lb by
mouth every 8 to 12 hours to achieve two or three soft stools per day. It can be safely
given on a long-term basis. Antibiotics such as neomycin (10 mg/lb by mouth every 8 to
12 hours) or metronidazole (4 mg/lb by mouth every 12 hours) are commonly used on a
short-term basis to alter the urease-producing intestinal bacterial population. Systemic
antibiotics such as amoxicillin or ampicillin are also effective.
When severe CNS depression or coma prevents oral administration of lactulose and
neomycin, these drugs are administered by enema. Acute decompensation of HE
requires fluid therapy for correction of dehydration, correction of electrolyte and acidbase imbalances, and maintenance of blood glucose. Lactated Ringer's solution should
be avoided. Precipitating causes of HE such as hypoglycemia, gastrointestinal bleeding,
hypokalemia, and alkalosis should be identified and corrected whenever possible.
Benzodiazepines, sedatives, and tranquilizers should be avoided. In addition to routine
management of HE, control of seizures with anticonvulsant therapy (potassium bromide
or phenobarbital) is indicated before general anesthesia and surgery. Other options
include levetiracetam (Keppra) or zonisamide. At this point, there is little literature to
support the use of levetiracetam in veterinary medicine to control hepatic
encephalopathy associated seizures, although this medication is preferred by many
neurologists.
The short-term response to therapy for HE in dogs with congenital PSS is often
dramatic. Most dogs are clinically normal with therapy, even before surgical shunt
ligation. The response of cats to medical management of HE may not be as rewarding.
If surgical shunt correction is not feasible or is declined by the owner, long-term medical
management can adequately control clinical signs for as long as 2 to 4 years in some
dogs. However, most dogs managed medically on a long-term basis are not clinically
normal and eventually have refractory neurologic signs. Medical therapy does not
reverse the progressive hepatic atrophy and associated alterations in carbohydrate,
lipid, and protein metabolism.
Surgical Management:
The treatment of choice for dogs and cats with a congenital PSS is surgical attenuation
or ligation of the anomalous vessel. Single intrahepatic shunts are technically more
difficult to correct than single extrahepatic shunts. Total surgical ligation of a single
congenital PSS is preferred; however, in many cases only partial ligation of the shunt
can be safely performed because of the risk of portal hypertension (PH). PH occurs
because the intrahepatic vasculature cannot accommodate the additional volume of
portal blood that is diverted back to the liver after total occlusion of the shunt vessel.
Many animals with partial suture ligation of a single extrahepatic PSS eventually have
complete closure of their shunt, as assessed by transcolonic scintigraphy. However,
recurrence of clinical signs (41 to 50 per cent of dogs) is more likely if a partial rather
than complete ligation has been performed. A liver biopsy specimen is also taken at the
time of surgery to rule out presence of other disease processes such as microvascular
dysplasia.
Use of an ameroid constrictor for gradual occlusion of single extrahepatic PSS has been
described. The ameroid constrictor is a specialized device consisting of hydrophillic
casein material in a stainless steel ring. The device is surgically placed around the
shunt, and as fluid is absorbed the lumen of the ring becomes progressively smaller,
causing shunt occlusion. Advantages of this procedure include gradual progressive
occlusion of the shunt over a 30- to 60-day period (thus preventing acute postoperative
PH), decreased surgical and anesthesia time, and lack of need to monitor portal
pressures during surgery. This technique appears preferable to suture ligation for single
extrahepatic PSS and makes the surgical issue of partial versus complete shunt ligation
obsolete. Cellophane banding of the PSS have led to similar outcomes when compared
to the ameroid constrictor. The use of cellophane may be more advantageous in really
small patients when the weight of the constrictor or kinking of the constrictor is of
concern. Suture ligation may still indicated for most intrahepatic PSSs because ameroid
constrictors may not be available in large enough sizes and surgical access to the shunt
is more difficult. Successful use of transvenous coil embolization for gradual occlusion
of a patent ductus venosus/intrahepatic shunts under fluoroscopic guidance has also
been described.
When suture attenuation or ligation is performed, PH may occur 2 to 24 hours after
surgery. Signs of acute severe PH include abdominal distention and pain, bloody
diarrhea, ileus, endotoxic shock, and peracute cardiovascular collapse. In the
postoperative period, ascites may be exacerbated by severe hypoalbuminemia or
overzealous fluid therapy. Moderate to severe ascites may also occur postoperatively.
Ascites usually resolves within 14 to 21 days after surgery. Sustained PH that is not
immediately life threatening can result in the development of multiple acquired PSSs
after 1 to 2 months. On occasion, seizures and status epilepticus are a complication of
surgical shunt ligation. The use of an ameroid constrictor appears to prevent the
likelihood of this complication. Dogs older than 18 months of age may be at increased
risk. The pathogenesis is obscure, but seizures do not appear to be caused by simple
hypoglycemia or HE. It is possible that the brain may have adapted to an altered
metabolism. Sudden withdrawal of the anticonvulsant effects of endogenous
benzodiazepines (produced in the gut) after ligation of the PSS has been hypothesized.
The prognosis for recovery from this complication is poor.
Post-operative Care:
Routine postoperative management consists of systemic antibiotics and fluid therapy.
Oral lactulose and neomycin (or metronidazole) and a protein-restricted diet are usually
continued for at least 4 to 8 weeks or longer, depending on the individual patient's
clinical response. On a long-term basis, many dogs are clinically normal and do not
require a protein-restricted diet or medications for HE, especially if total shunt ligation
has been performed. After shunt ligation, hepatic regeneration and an increase in liver
blood flow result in liver enlargement and reversal of histopathologic abnormalities.
Indicators of hepatic function such as SBA concentrations often improve but do not
usually return to normal, even in dogs that become clinically normal. Persistent hepatic
dysfunction may be related to coexisting hepatic microvascular dysplasia and persistent
microscopic shunting of portal blood. In one study, there was no correlation between
follow-up SBA concentrations and the clinical response.
Prognosis:
The prognosis in dogs for resolution of signs after total surgical ligation of the shunt is
excellent if the dog survives the immediate postoperative period. In dogs with partial
shunt ligation, the prognosis is not as good. Although clinical signs may resolve after
surgery and the response appears favorable in the first few years, long-term follow-up
(more than 3 years) suggests that signs recur in 40 to 50 percent of dogs with partial
shunt ligations. On the basis of this information, dogs who have previously undergone a
partial ligation should be reevaluated by transcolonic scintigraphy. If shunting persists,
surgical exploration to perform complete suture ligation or ameroid constrictor
placement is indicated.
The response to surgical correction of a congenital PSS in cats appears to be less
encouraging than in dogs. With partial shunt ligation, clinical improvement is usually
noted after surgery, but relapse of clinical signs is common. Persistent seizures and
blindness are also more likely to occur when partial rather than total ligation is
performed. Total shunt ligation may not be possible because of the high likelihood of
severe intrahepatic portal atresia and associated PH. The development of multiple
acquired PSS after surgery appears to be more likely in cats than in dogs.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
16.
17.
Christiansen JS et al., HMD in Dogs: A Retrospective Study of 24 Cases. JAAHA Sept/Oct 2000,
Vol. 36
Allen L et al. Clinicopathologic features of dogs with HMVD w/ and w/o PSS: 42 cases (19911996). JAVMA 1999
Holt DE, et al. Correlation of US findings with surgical, portography, and necropsy findings in
dogs and cats with PSS (1987-1993). JAVMA 1995
Tiemessen I. Ultrasonography in the diagnosis of CPSS in dogs. Vet Q 1995
Swami VF et al. Evaluation of interoperator variance in shunt fraction calculation in transcolonic
scintigraphy for diagnosis of PSS in dogs and cats. JAVMA 2001
Watson PJ, Herrtage ME. Medical management of congenital portosystemic shunts in 27 dogs--a
retrospective study. J Small Anim Pract 1998
Murphy ST, et al. A comparison of the Ameroid constrictor vs. ligation in the surgical management
of single extrahepatic PSS. JAAHA 2001
Vogt JC, Krahwinkel DJ, Bright RM, et al. Gradual occlusion of EPSS in dogs and cats using the
ameroid constrictor. Vet Surg 25:495-502, 1996
Taboada J. Medical management of animals with PSS, Semin Vet Med Surg 1990
Kyles AE et al. Evaluation of portocaval venograft and ameroid ring for the occlusion of
intrahepatic portocaval shunts in dogs. Vet Surg. 2001
Poy NS et al. Splenocaval shunting for alleviation of portal hypertension in a dog: a case report.
Vet Surg 1998
Boothe HW et al. Multiple extrahepatic PSS in dogs: 30 cases (1981-1993). JAVMA 1996
Gonzalo-Orden JM et al. Transvenous coil embolization of an IPSS in a dog. Vet Radiol
Ultrasound 2000
Aroson LR et al. EBZ activity in the peripheral and portal blood of dogs with CPSS. Vet Surg
1997Bellah JR, et al. Results of surgical management of PSS in dogs: 20 cases (1985-1990).
JAVMA 1992
Hottinger HA, et al. Long-term results of complete and partial ligation of CPSS in dogs. Vet Surg
1995
Bellah JR, et al. Results of surgical management of PSS in dogs: 20 cases (1985-1990). JAVMA
1992
Notes
Gait Analysis and Neurolocalization
Dani Powers DVM, Resident Neurology and Neurosurgery
Seattle Veterinary Specialists
Kirkland, WA
Introduction
Gait generation is a complex system involving the upper motor neurons from motor
cortex, midbrain structures including the red nucleus, pontine nuclei and pontine spinal
tracts as well as medullary nuclei and medullary spinal tracts. The UMN tracts
communicate with the ventral gray column interneurons and LMNs to initiate a response
in end organs; the muscles. de Lahunta 2009.
There are two phases of gait, which includes a postural phase and a protraction phase.
The postural phase is the facilitation of extensor muscles with simultaneous inhibition of
flexor muscles. The postural phase activates the anti-gravity muscles, which allows
weight supporting. The protraction phase or swing phase of the gait facilitates the flexor
muscles allowing movement followed by activation of extensor muscles for the
completion of the swing phase and movement. The postural phase and protraction
phase cycle back and forth during normal gait. De Lahunta 2009, Dewey 2008, Lorenz 2011, Parent 2010.
Brainstem nuclei are considered to be the most important for generation of gait, though
the motor cortex and transmission of UMN pathways via the internal capsule are also
important, there is minimal loss of gait generation with damage to the latter two
components. Brainstem nuclei, when damaged, cause more significant loss of gait
generation. There are also spinal gait generators at the level of thoracic and pelvic
intumescences. de Lahunta 2009, Dewey 2008, Lorenz 2011,
Paresis is defined as weakness and specifically is a result of upper or lower motor
neuron dysfunction. Paresis results in incomplete (paresis) or complete (paralysis) loss
of motor function, and some use it to describe loss of sensory function as well. Motor
pathways within the spinal cord are located within the lateral, dorsal and ventral
columns.
Ataxia refers to incoordination and lack of an axis, which is related to general
proprioceptive deficits and afferent sensory pathways. It does not mean spasticity,
paresis or involuntary movements; though they are often seen simultaneously. Lorenz 2011.
Ataxia can result from general proprioceptive deficits, vestibular lesions or cerebellar
lesions.
General proprioceptive pathways are located within the dorsolateral and dorsal columns
of the spinal cord, which project to the cerebellum (unconscious) and cerebrum
(conscious). Lorenz 2011.
You cannot distinctly separate motor dysfunction (paresis) and loss of conscious aspect
of general proprioception (ataxia) in the cerebral cortex as the motor cortex and
somatosensory cortex are in close association spatially. This is also true in spinal
pathways for efferent motor pathways and afferent proprioceptive pathways. In most
naturally occurring lesions both motor pathways and general proprioceptive pathways
are affected. Dewey 2008, Lorenz 2011, de Lahunta 2009
Both the prosencephalon and brainstem are important for gait generation and the
system is complex. Unilateral damage to either area causes paresis, but with
prosencephalic lesions you would expect contralateral paresis, whereas caudal to the
mid brain you would expect ipsilateral paresis and more pronounced gait deficits. Ataxia
can occur with lesions in these areas as well.
In particular, the cerebellum is important for controlling fine motor movement in both the
rate and range of the movement. Cerebellar ataxia often results in dysmetria or more
specifically hypermetria is seen. The cerebellum also results in intention tremors, which
is a dysmetria of the head and neck.
The neurologic exam is the most important aspect for any clinician to help localize a
problem to the nervous system. However, it does not end there. Some diseases can
look like neurologic disease and be easily mistaken if a full neurologic and physical
exam is not performed. Probably most importantly would be evaluation of the
musculoskeletal system, followed by cardiac system and then generalized systemic
illness.
Some diseases can lead to generalized weakness and be wholly outside the nervous
system; this is where confusion may play a role and inaccurate lesion localization and
misdiagnosis.
Within the musculoskeletal system weakness can result from degenerative joint
disease, other forms of arthrosis, hip dysplasia, cruciate ligament disease, and
generally any muscle, tendon, or ligament pathology can cause weakness or perceived
weakness secondary to pain. Parent 2010
Within the metabolic or systemic illness category any disease causing generalized
weakness can result in perceived neurologic deficits without true structural disease of
the nervous system. For example, dyspnea of many causes, hepatic failure, renal
failure, endocrine disease, toxin, vascular disease (aortic thromboembolism), neoplasia
(most commonly insulinoma and pheochromocytoma, or paraneoplastic disease) can all
lead to confusing clinical signs that may appear neurologic in origin, but truly are not. In
this scenario you would treat for the apparent metabolic disease and if signs of
neurologic dysfunction do not improve, then further investigation may be warranted.
Within cardiac disease, most commonly the confusion lies as to whether events are
causing seizures or syncope. In most cases this is distinguished with further cardiac
evaluation, history and physical exam. Likely the confusion for this disease is an
owner’s description of weakness and collapse with drunken gait before, during or after
an event. Owners can be further confused and refer to any loss of consciousness as a
seizure; just as it is important to distinguish vomiting from regurgitation, it is important to
differentiate seizures and syncope.
Beyond the neurologic and physical exam, an important aspect for any illness or
disease is a baseline database. This will help to rule out obvious underlying causes or
concurrent illness. Baseline database includes CBC and serum biochemical profile, T4,
urinalysis, blood pressure and for geriatric patients thoracic radiographs. Bile acids may
also be important if seizures or abnormal behavior are part of the presenting complaint.
Additional testing should be performed as indicated by exam finding and/or baseline
database results. If you find renal or hepatic disease, an abdominal ultrasound is useful,
where as an arrhythmia should prompt ECG and echocardiogram. Endocrine testing
should be used as indicated based on all the results and history.
Spinal Disease
Spinal disease is a common cause for gait change in dogs. The most common causes
of spinal disease include intervertebral disk disease, neoplasia, diskospondylitis,
meningitis, trauma, fibrocartilagenous embolism and degenerative disease. All of the
aforementioned diseases can result in similar clinical signs, but in relation to rapidity of
onset, progression, presence or absence of pain and signalment we can often narrow
the differential list.
The most common cause of painful spinal disease in dogs is intervertebral disk disease
Parent2010
. When considering clinical signs with neurolocalization to the spine, the first
differential that should be considered is intervertebral disk disease, however the
definitive diagnosis will be dependent on advanced imaging and possible spinal fluid
analysis.
Other conditions must be considered when patients present with spinal pain, however
not all conditions result in pain. Classically, fibrocartilagenous embolism (FCE) and
degenerative disease are non-painful. In most cases of FCE, the dog will exhibit
transient pain, which resolves within 12-24 hours. In some cases of intervertebral disk
disease, specifically Type II disk disease, pain may not be a component of the clinical
picture.
Lesion localization within the spinal cord results in specific signs.
Cervical 1st to 5th spinal cord segments. Parent 2010
•
All four limbs are affected.
•
UMN weakness and ataxia can occur, though in many cases the neurologic
exam is normal.
•
Neck pain is a common finding, and often with no neurologic deficits.
•
The nature of the gait with UMN weakness and ataxia is similar from the thoracic
to the pelvic limbs, however with extramedullary lesions (IVDD), often the pelvic
limbs are more severely affected than the thoracic limbs. This is related to the
spatial location of the pelvic limb pathways being more peripherally located within
the spinal cord as compared to the thoracic limbs.
•
Intramedullary lesions result in more significant weakness in the thoracic limbs,
for the same reason listed above.
•
Reflexes and tone are normal to exaggerated.
•
Progression of disease can result in non-ambulatory tetraparesis.
•
Most severe lesions result in tetraplegia with respiratory failure and death.
•
Horner syndrome may be present with cervical disease and usually is a
lateralizing sign associated with damage to the lateral tecto-tegmental spinal
tract. The sympathetic pathways are resistant to damage and it is uncommon
with compressive lesions, and more commonly seen with intraparenchymal
lesions.
•
With severe intraparenchymal lesions severe curvature of the neck may be seen
due to loss of facilitation of extensors ipsilateral and loss of inhibition of
contralateral extensors due to damage in the vestibulospinal tracts.
•
Respiratory difficulty can arise from damage to the spinal segments which give
rise to the phrenic nerve, including C5, C6, and C7 (rarely C4). Severe lesions of
the cervical spine can result in respiratory failure and death.
•
In non-ambulatory cervical lesions with retained respiratory function, you can
assume there is some purposeful voluntary movement preserved (no matter how
little).
•
Lameness rarely occurs with cranial cervical lesions as most of the thoracic limb
input is found more caudal (C6-T2), but some dogs do have contribution of C5 to
the brachial plexus, so occasionally lameness can be seen.
Cervical 6th to thoracic 2nd spinal cord segments: Parent 2010
•
All four limbs are affected.
•
UMN weakness and ataxia can occur, though in many cases the neurologic
exam is normal.
•
Neck pain is a common finding, and often with no neurologic deficits.
•
Lameness is a common finding of C6-T2 spinal cord lesions due to the effects on
the brachial plexus and nerve root impingement. This is often referred to as nerve
root signature.
•
The nature of the gait with UMN weakness and ataxia is disparate from the
thoracic to the pelvic limbs. Weakness and ataxia may be more pronounced in
the pelvic limbs.
•
With C6-T2 lesions reduced thoracic limb reflexes may be evident, which is
accurate about 65% of the time. This is suggestive of gray matter (with
concomitant white matter) involvement.
•
With chronic lesions, such as cervical spondylomyelopathy, the thoracic limbs
are often stiff and stilted, the legs during protraction are thrown forward in
extension. Pelvic limbs are distinctly different with ataxia and weakness noted.
•
When looking at the entire dog, the gait is characterized by a short and choppy
thoracic limb gait (toy soldier) and pelvic limb weakness and ataxia.
Thoracic 3rd to Lumbar 3rd spinal cord segments: Parent 2010
•
Neurologic abnormalities are limited to the pelvic limbs.
•
Ataxia and paresis of the pelvic limbs, including ambulatory and non-ambulatory
paraparesis.
•
Asymmetry can be seen depending on the side of the lesion and etiology.
•
Paraplegia occurs with severe lesions, which would be the one and only reason
deep pain should be tested.
•
When patients have motor function still present (no matter how little) deep pain
can be presumed present and testing is unnecessary.
•
Cutaneus trunci cut-off can suggest the area of concern more specifically; the
point at which the reflex is observed suggests the lesion is just caudal to that
point.
•
Pain is common, though the underlying etiology may or may not be painful.
•
Upper motor neuron bladder, which is difficult to express or for the patient to
urinate.
Lumbar 4th to Sacral 1st spinal cord segments: Parent 2010, Lorenz 2011, Dewey 2008
•
Only the pelvic limbs are affected, asymmetry can occur with lateralization of the
lesion
•
Lameness can be observed
•
If the femoral nerve is spared weight bearing is preserved, but a plantigrade
stance may be seen.
•
Pain is common and may be the only clinical sign, especially early in the course
of disease. This may be elicited with direct digital palpation or lordosis testing.
•
•
You must ensure when pain is evaluated that other aspects are not under
pressure, such as pushing down on the spine and up on the abdomen, or
pain with downward force to the hips or stifles. Pain can be elicited from
many areas when pressure is applied to the lumbar spine, and can cause
confusion in hyperesthesia response.
Pelvic limb reflexes are reduced or absent
•
Sciatic nerve damage can cause reduced or absent withdrawal reflex.
Most commonly the flexion of the hip and stifle are preserved, but the
tarsal flexion is reduced or absent. A terminal kick with the withdrawal
reflex is commonly confused with the patient being annoyed with digital
pressure applied, but a normal dog will hold the withdrawal strongly
without kicking.
•
Femoral nerve dysfunction will result in loss of patellar reflexes
•
It is important to note that the patellar reflex is often lost with disease of
the stifle or as dogs’ age.
•
A confusing response in the patellar reflex can be a pseudohyperpatellar
reflex, resulting from lack of tone in the caudal thigh muscles due to sciatic
nerve damage. You see an exaggerated kick phase of the reflex, which
appears normal or increased, but is actually normal or reduced.
•
Hypotonia can be present
•
Muscle atrophy
•
Reduced tail function.
•
Fecal and urinary incontinence. Easy to express bladder.
•
Reduced or absent perineal reflex and anal tone.
•
Reduced desire and ability to jump, go up stairs, and holding a posture for
elimination. Some dogs with walk and defecate with lumbosacral disease, but
many dogs do this regardless.
Brain Disease
The three main areas, which can result in gait deficits, include the forebrain, cerebellum
and brainstem.
Forebrain: The forebrain causes less severe gait deficits than other areas of the brain,
but still may result in proprioceptive deficits. Forebrain disease can result in circling
towards the side of the lesion with proprioceptive deficits contralateral to the lesion.
Other clues the forebrain is affected include seizures, vision deficits, facial sensation
deficits and mentation changes.
Brainstem: Damage from midbrain and caudal to this, can lead to severe gait changes
secondary to spinocerebellar pathways, vestibulospinal pathways, general
proprioceptive pathways, corticospinal pathways and extrapyramidal pathways, which
all traverse this area (afferent and efferent) to reach the final destinations. Damage to
the brainstem results in ipsilateral deficits in most cases. Indications of brainstem
disease besides gait deficits (paresis and ataxia) include cranial nerve deficits, most
easily recognized include cranial nerve III, V, VII, VIII, IX, X and XII. In addition,
brainstem disease often results in mentation changes or mental dullness, due to
damage of the ascending reticular activating system (ARAS). Dewey 2008, Lorenz 2011,
Cerebellum: The cerebellum is primary responsible for controlling movement for fine
motor function, and it is intimately associated with the motor centers of the brain.
Information to and from the cerebellum comes from spinocerebellar pathways,
vestibulocerebellar pathways and pyramidal and extrapyramidal input from the
cerebrum. This allows fine coordination of motor activity including the limbs, head and
neck. Damage in the cerebellum usually results in ipsilateral deficits. Pure cerebellar
disease does not result in paresis (weakness). Signs of cerebellar dysfunction include
dysmetria, most commonly hypermetria, though hypometria can also occur and intention
tremors. Menace deficits can be observed with cerebellar disease with intact vision.
Ataxia results in a wide based stance and swaying from side to side. Vestibular signs
can also be seen with vestibulocerebellar involvement, including strabismus,
nystagmus, head tilt (towards or away from the side of the lesion) and loss of balance.
Severe cerebellar abnormalities can cause decerebellate rigidity resulting in
opisthotonus, rigid extension of the forelimbs and alternating flexed or extended hind
limbs with maintained consciousness. In some cases diseases of the cerebellum can
cause disorders of micturition, usually loss of inhibition and therefore pollakiuria. Dewey
2008, Lorenz 2011,
Disease Progression:
When considering any disease it is important to think through the natural course of
disease progression. Over time every disease is expected to progress in a defined
manner, although some diseases can have variable progression. Generally speaking all
disease will stay the same, get better or get worse. What occurs is dependent on the
underlying disease, treatment applied and response to treatment. The graph depicts
what to expect with non-progressive, progressive and static (or improving) disease
progression.
Generalities of disease progression based on the specific disease for natural
courses:
•
Intervertebral disk disease: IVDD can stay the same, get better or get worse at
any time.
•
Neoplasia (brain or spine): Neoplasia is expected to get worse, usually within a
defined time frame (6-10 months).
•
Diskospondylitis: Infection is expected to get worse with time.
•
Meningitis/Myelitis: Regardless of the cause, this is expected to get worse with
time.
•
Encephalitis: Regardless of the cause, this is expected to get worse with time.
•
Trauma (brain or spine): Most often trauma is as bad as it will be at the moment,
then stay the same or get better.
•
Fibrocartilagenous embolism: FCE can get better over time (highly dependent on
the site of FCE) or stay the same, it is not expected to get worse.
•
Degenerative disease (brain or spine): This is expected to get worse gradually
over time.
Generalities of specific spinal disease to consider when making a differential list:
•
•
•
Intervertebral disk disease:
•
IVDD can stay the same, get better or get worse at any time.
•
Type I is often painful and sudden, but type II can be slowly progressive
and non-painful.
•
Signalment is important, but should not be the sole reason IVDD does or
does not make the list.
•
Radiographs, although usual for ruling out obvious bony spinal disease,
are not a definitive diagnosis for disk disease. Advanced imaging is the
gold standard for diagnosis and provides much needed information about
laterality, compression and appearance of the surrounding spinal cord.
•
Deep pain does not need to be tested in any dog that has motor function,
even if it is minimal.
Neoplasia (brain or spine):
•
Neoplasia is expected to get worse, usually within a defined time frame (610 months).
•
Neoplasia can be painful (usually bone involvement or compression) or
non-painful (usually parenchymal neoplasia).
•
Signalment is important, but should not be the sole reason you list
neoplasia on the differential list. Golden Retrievers do get disk disease,
albeit rarely.
•
Radiographs are a good diagnostic tool to rule out bony neoplasia.
•
Although gradual progression of disease and insidious onset are common
with neoplasia, there are sudden onset and progression with neoplasia
too.
Diskospondylitis:
•
Infection is expected to get worse with time.
•
Most cases are primarily painful and cause little if any weakness or ataxia.
•
•
•
•
In the rare cases diskospondylitis causes weakness, it is usually related to
secondary abscessation and spinal cord compression. In these cases,
likely surgical intervention will be indicated.
•
Signalment is important; this disease is more common in younger intact
male dogs.
•
Radiographs are a good tool to rule out diskospondylitis. Remember it
may take up to 3 weeks for radiographic evidence of diskospondylitis to be
apparent on radiographs.
Meningitis/Myelitis:
•
Regardless of the cause, this is expected to get worse with time.
•
Most cases are primarily painful and cause little if any weakness or ataxia.
•
A spinal tap is necessary to rule out meningitis, however some forms
strictly within the parenchyma (myelitis) may not be evident on spinal tap.
Encephalitis:
•
Regardless of the cause, this is expected to get worse with time.
•
Signalment is important; this disease is more common in younger dogs
and commonly within small toy breeds, though any breed can have
encephalitis.
•
A spinal tap may help to diagnose encephalitis, however some forms
strictly within the parenchyma may not be evident on spinal tap. In the
latter case a brain biopsy is the only definitive way to diagnose
encephalitis, which is not recommended. An MRI may or may not be
abnormal.
Trauma (brain or spine):
•
Most often trauma is as bad as it will be at the moment, then stay the
same or get better.
•
Trauma that can cause neurologic disease usually has to be sufficient to
cause obvious signs of a problem at the time. You would not expect
trauma from years or even months ago to cause gait deficits now. Normal
physical play is not enough to result in traumatic cases of brain or spinal
injury. Think hit by car, fall from high places, or
•
•
Fibrocartilagenous embolism:
•
FCE can get better over time (highly dependent on the site of FCE) or stay
the same; it is not expected to get worse.
•
An FCE classically is non-painful, asymmetric and sudden in onset.
Degenerative disease (brain or spine):
•
This is expected to get worse gradually over time.
•
This is considered non-painful and slowly progressive.
•
The most well defined degenerative condition (i.e. Degenerative
Myelopathy) is considered to result in progression to non-ambulatory
status within 14 months of clinical signs first appearing. If this does not
occur, then DM is considered highly unlikely.
•
DM is usually a symmetrical T3-L3 lesion localization.
References
•
de Lahunta A, Glass E. Veterinary Neuroanatomy and Clinical Neurology. Third Edition. Elsevier
– Saunders 2009.
•
Dewey CW. A Practical Guide to Canine and Feline Neurology. Second Edition. Wiley-Blackwell.
2008.
•
Foss K, et. al. Force Plate Gait Analysis in Doberman Pinschers with and without Cervical
Spondylomyelopathy. J Vet Intern Med 2013; 27:106-111.
•
Foss K, et. al. Three Dimensional Kinematic Gait Analysis of Doberman Pinschers with and
without Cervical Spondylomyelopathy. J Vet Intern Med 2013; 27:112-119.
•
Goddard MA, et. al. Gait characteristics in a canine model of X linked myotubular myopathy.
Journal of Neurological Sciences 346 (2014) 221-226.
•
Gordon Evans WJ, et. al. Characterization of spatiotemporal gait characteristics in clinically
normal dogs and dogs with spinal cord disease. AJVR, Vol 70, No. 12, December 2009.
•
King AS. Physiological and Clinical Anatomy of the Domestic Mammals. Volume 1 Central
Nervous System. Oxford Science Publications. 1994
•
Lorenz MD, Coates JR, Kent M. Handbook of Veterinary Neurology. Fifth edition. Elsevier –
Saunders 2011.
•
McDonnel JJ, et. al. Neurologic conditions causing lameness in companion animals. Vet Clin
Small Anim 2001 Jan; 31(1):17-38.
•
Olby N, et. al. Long-term functional outcome of dogs with severe injuries of the t-thoracolumbar
spinal cord: 87 cases (1996-2001). JAVMA Vol 222, No. 6, March 15, 2003.
•
Olby N, et. all. Gait scoring in dogs with thoracolumbar spinal cord injuries when walking on a
treadmill. BMC Veterinary Research 2014, 10:58.
•
Parent J. Clinical approach and lesion localization in patients with spinal disease. Vet Clin Small
Anim 40 (2010) 733-753.
•
Thomas W. Evaluation of Veterinary Patients with Brain Disease. Vet Clin Small Anim 40 (2010)
1-19.
•
Van Klaveren NJ, et. al. Force plate analysis before and after dorsal decompression for
treatment of degenerative lumbosacral stenosis in dogs. Vet Surg 34:450-456, 2005.
Notes
Doctor Program 2 | The Norcliffe Room
Speakers
Dr. Bryan Bottorff, Diplomate ACVIM (Cardiology)
Dr. Matt Vaughan, Diplomate ACVIM (SAIM)
Dr. Sean Sanders, PhD, Diplomate ACVIM (Neurology)
Dr. Seung Yoo, MS, MBA, DACVP (Clinical)
Dr. Jim Perry, PhD, Diplomate ACVIM (Oncology),
Diplomate ACVS
Dr. Kent Vince, MSpVM, Diplomate ACVS
!
Notes
Electrocardiography: Basic Principles, Diagnosis, and Treatment of
Common Arrhythmias
Bryan Bottorff, DVM, DACVIM (Cardiology)
Seattle Veterinary Specialists
Kirkland, WA
INTRODUCTION
Despite its at times challenging nature, electrocardiography is an extremely useful
diagnostic modality in the evaluation of cardiovascular disease. Electrocardiography is
specifically most valuable for evaluation of patient heart rate and rhythm, however it also
gives information regarding cardiac chamber enlargement, pericardial disease, and
various metabolic conditions such as hypoxia and electrolyte abnormalities. Proper
understanding of the diagnostic utility of ECG requires basic knowledge of the normal
cardiac electrical system.
NORMAL CARDIAC CONDUCTION
Myocardial activation via the normal cardiac conduction system results in sequential
activation of the atria and ventricles, allowing for an organized and efficient cardiac
contraction. This allows for proper filling and emptying of the heart to ensure
appropriate cardiac output. The conduction system of the heart is composed of:
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Sinoatrial (SA) node
Atrial internodal fibers
Atrioventricular (AV) node
Bundle of His
Right and Left Bundle Branches
Purkinje fibers
The cells of the SA node, AV node, and Purkinje fibers all have the properties of
automaticity, with the SA node demonstrating the most rapid rate of spontaneous
diastolic depolarization (i.e., 60-180 bpm in dogs, 120-240 bpm in cats). The wave of
depolarization initiated by the SA node is propagated via atrial internodal tracts through
the atrial myocardium (resulting in the P-wave), and ultimately to the AV node.
The AV node is located in the interatrial septum just above the ventricles, and is the only
normal conduction tissue from atrial to ventricular myocardium. Due to its small size,
depolarization of the AV node cannot be detected as an amplitude on the surface ECG.
As conduction velocity through this tissue is relatively slow (compared to atrial and
ventricular myocardium), the duration of the ‘P-R interval’ on the surface ECG is largely
contributed to by AV nodal depolarization. The AV node also normally demonstrates
the property of automaticity. Cells in this region are therefore capable of spontaneous
depolarization in the event of failure of SA nodal depolarization, however this occurs at
a slower rate (i.e., 40-60 bpm in dogs, 100-150 bpm in cats).
Following activation through the AV node, the Bundle of His and bundle branches
conduct impulses to the Purkinje fibers and ventricular myocardium. Conduction
velocity in His, bundle branch, and Purkinje fibers is extremely rapid, and the Purkinje
fibers also demonstrate spontaneous automaticity. With failure of SA and/or AV nodal
stimulation, the Purkinje fibers can depolarize to result in ventricular contraction albeit at
a much slower rate (i.e., 20-40 bpm in dogs, 70-120 bpm in cats). When depolarization
of the ventricular myocardium occurs through stimulation following AV nodal, His, and
bundle branch activation, a normal QRS complex occurs.
With ventricular
depolarization via Purkinje fiber automaticity without using the normal cardiac
conduction system, a wide and bizarre QRS complex occurs.
ECG INTERPRETATION
Although pattern recognition may allow for recognition of obvious arrhythmias, proper
evaluation of the ECG requires a systematic approach to ensure accuracy. The
following ECG characteristics should be evaluated with every diagnostic ECG:
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Recognition of ECG settings
Determination of heart rate
Evaluate cardiac rhythm
Measure amplitude and intervals
Determination of Mean Electrical Axis (MEA)
Assess for chamber enlargement patterns
NORMAL CARDIAC RHYTHMS
Sinus rhythm
A sinus rhythm represents the normal sequence of cardiac electrical activity. Based
upon normal P-QRS-T morphology and synchrony, consistent P-P and R-R intervals,
and normal heart rate, activation of atrial and ventricular myocardium following initial
depolarization of the SA node is assumed. The rate of a sinus rhythm varies between
species (i.e., dog 60-180 bpm, cat 140-240 bpm).
Sinus arrhythmia (and wandering pacemaker)
A sinus arrhythmia results from phasic variation in vagal (parasympathetic) tone.
Although this often in is conjunction with the respiratory cycle (with increasing heart rate
upon inspiration, and decreasing with exhalation), other causes of increased vagal tone
are also possible. This ‘arrhythmia’ is considered a variant of normal in dogs however is
typically associated with disease entities resulting in increased parasympathetic tone in
cats (i.e., gastrointestinal, respiratory, and/or CNS disease).
In dogs, a sinus arrhythmia is often accompanied by the phenomenon referred to as a
‘wandering pacemaker’. Although this title is frequently inaccurately associated with a
pathologic arrhythmia, a wandering pacemaker is the result of depolarization of different
locations within the SA node due to changes in vagal tone. This results in slight
differences in the vector of depolarization of atrial myocardium, thus affecting the Pwave morphology. Typically, P-wave size increases with elevations in heart rate (within
inspiration) and is reduced with decreasing heart rate (with exhalation).
BRADYARRHYTHMIAS
Sinus bradycardia
A sinus bradycardia occurs due to decreased automaticity of the SA node, and can be
recognized electrocardiographically when all criteria for sinus rhythm are present,
however the heart rate is considered bradycardic (< 60 bpm in dogs; < 140 bpm in cats).
Common causes of a sinus bradycardia include elevated vagal tone, heart-rate reducing
drugs, sedation/anesthesia, and hypothermia. However, hypothyroidism, athletic
conditioning, hyperkalemia, and Sick Sinus Syndrome can also contribute to this finding.
Patients with intact sinus node function typically respond appropriately to anticholinergic
therapy (i.e., atropine). In the absence of sinus node disease, treatment should be
aimed at the contributing cause, if necessary.
Sinus node dysfunction (Sick Sinus Syndrome)
Sick sinus syndrome (SSS) is used to describe a condition in which many different ECG
abnormalities may be present indicating sinus node dysfunction. These typically include
sinus arrest and/or sinus bradycardia, however, even supraventricular tachycardia
(SVT) can be present. ECG may show many periods of sinus arrest followed by
supraventricular (as above) or by ventricular escape beats. Co-existing AV nodal
dysfunction resulting in AV block is also common in patients with SSS. Patients
typically present for weakness, exercise intolerance, or syncope, however a surprising
number of patients are asymptomatic. Sudden death is exceedingly rare in SSS
patients. Patients presenting for syncope are typically affected with bradyarrhythmias,
however concurrent tachyarrhythmias are possible (‘bradycardia-tachycardia
syndrome’). Such patients can be difficult to manage as treatment for one rhythm
disorder may exacerbate the other.
Sick sinus syndrome is almost exclusively recognized in canine patients, with Miniature
Schnauzers, West Highland White Terriers, and Cocker Spaniels over-represented.
The exact cause is unknown, however fibrous degeneration of the SA node and other
cardiac conductive tissues is suspected. Some humans with SSS display autoantibodies directed at SA nodal tissue or cholinergic receptors, however this has not
been demonstrated in veterinary patients.
Treatment of bradycardia associated with Sick Sinus Syndrome is dependent upon the
clinical signs present (if any) and presence of concurrent tachyarrhythmias.
Asymptomatic patients may require no treatment, while those with mild clinical signs
may benefit from oral positive chronotropic therapy (Terbutaline 0.2 mg/kg PO q 8-12 h
or Theophylline 10-15 mg/kg PO q 12 h). Patients with severe bradycardia requiring
hospitalization may require parenteral treatment (Atropine 0.02-0.04 mg/kg IV/IM/SQ, or
isoproterenol 0.04-0.08 mcg/kg/min IV) prior to permanent pacemaker placement.
Treatment of patients with ‘brady-tachy’ syndrome often requires pacemaker placement
for bradycardia which will allow for safe administration of anti-arrhythmic therapies for
associated tachycardia. Treatment for SVT should not be performed in these patients
unless pacing is available as such anti-arrhythmics will exacerbate bradycardia.
Atrial Standstill
Atrial standstill occurs secondary to severe hyperkalemia or fibrous destruction of the
atrial myocardium. As a result, patients with this rhythm disturbance should always
have serum potassium levels assessed. The ECG findings associated with this
arrhythmia include a bradycardia with absence of atrial depolarization (no P-waves) and
a junctional or ventricular escape rhythm.
In the absence of hyperkalemia, a diagnosis of atrial myocardial disease is inferred.
With destruction of the normal atrial myocardium (also called ‘silent atrium’ or Atrioventricular myopathy) the atrial musculature becomes unresponsive to SA nodal
impulses with total absence of both atrial depolarization and contraction. Patients
affected with AV myopathy may present for symptoms of bradycardia (lethargy, exercise
intolerance, syncope) or congestive heart failure (pulmonary edema, ascites, pleural
effusion). This unique disease is most commonly reported in the English Springer
Spaniel, however other canine breeds and feline patients can be affected.
If hyperkalemia is present, emergent treatment of this electrolyte disturbance is advised
(i.e., 0.9% NaCl, Calcium gluconate, insulin and dextrose containing fluids) as well as
identifying any contributing cause. In patients without hyperkalemia, treatment is aimed
at increasing heart rate and controlling congestion, if present. This typically involves
placement of a permanent pacemaker, however due to worsening fibrosis of the
myocardium, progressive myocardial disease and symptoms of congestive heart failure
is inevitable.
Atrioventricular block
Atrioventricular (or AV) block, refers to rhythm disturbances that delay or inhibit
conduction of electrical impulses from the atria to the ventricles through the AV node.
Due to variable degrees of conduction delay or ‘block’, three main forms of AV block are
described:
First degree AV block
First degree AV block is identified as delayed conduction through the AV node and is
observed on ECG as a prolonged PR interval (PR interval > 0.13 seconds in dogs: >
0.09 seconds in cats). Although the electrical impulse takes longer to travel through the
AV node, there remains synchrony of all P-waves to QRS complexes with first degree
AV block. Causes typically include increased vagal tone, electrolyte disturbances,
hypothermia, and various medications that can slow AV nodal conduction (i.e., digoxin,
beta-blockers, Ca+ channel blockers, opioids). In some patients, recognition of this
finding is indicative of emerging AV nodal disease. Treatment is typically not required,
however periodic monitoring is beneficial if AV nodal disease is suspected.
Second degree AV block
Second degree AV block occurs when there is intermittent conduction through the AV
node. As a result, some P-waves do not result in associated QRS complexes on the
ECG however proper synchrony is maintained in those P-waves that are conducted.
Causes can include high vagal tone, electrolyte disturbances, medications (i.e., digoxin,
beta-blockers, Ca+ channel blockers, more rarely opioids), and AV nodal disease (i.e.,
fibrosis, myocarditis/endocarditis). The ratio of P-waves to QRS complexes gives an
indication of severity (i.e., 4:1 block represents four atrial contractions for each
ventricular contraction and is a ‘high-grade’ block relative to 2:1, as above).
Assessment of remaining AV nodal function should include performance of an atropine
response test. Similar to patients with SSS, patients with inherent AV nodal disease
that are asymptomatic may require no treatment, while those with mild clinical signs
may benefit from oral positive chronotropic therapy (Terbutaline 0.2 mg/kg PO q 8 12 h
or Theophylline 10-15 mg/kg PO q 12 h). Patients with severe bradycardia requiring
hospitalization may require parenteral treatment (Atropine 0.02-0.04 mg/kg IV/IM/SQ
and/or isoproterenol 0.04-0.08 mcg/kg/min IV) prior to permanent pacemaker
placement.
Third degree AV block
Third degree AV block is a complete dissociation of atrial to ventricular impulses. As a
result, the patient's cardiac output is maintained by a junctional or ventricular escape
focus. Given the substantially slower automaticity of the HIS-Purkinje system in canine
patients (30-60 bpm), symptoms of decreased cardiac output are often present including
severe lethargy, exercise intolerance, and syncope. Feline patients, however, rarely
display overt clinical signs due to a more adequate ectopic pacemaker rate (90-130
bpm). Patients with long standing bradycardia may also develop severe myocyte
stretch due to prolonged diastolic filling times, elevated ventricular filling pressures, and
ultimately left- or right-sided congestive heart failure. Sudden death can also occur with
cessation of impulse generation from escape foci. Possible causes of 3rd degree AV
block are numerous including AV nodal degeneration or fibrosis, myocarditis,
endocarditis, infiltrative heart disease, or an immune-mediated disorder. Additionally,
severe hyperkalemia or digoxin toxicity can rarely produce this arrhythmia.
Electrocardiographically, 3rd degree AV block appears as non-conducted P waves with
a junctional or ventricular escape rhythm. It is important to recognize the life-saving
function of the escape focus. Although ventricular escape complexes appear of similar
morphology to ventricular premature complexes, ventricular anti-arrhythmic therapy
(lidocaine, procainamide, mexiletine, beta-blockers, potassium channel blockers, etc.) is
absolutely contraindicated. An isoproterenol CRI (0.04-0.08 mcg/kg/min) can be
initiated prior to pacemaker placement in patients with severe hemodynamic
compromise.
TACHYARRHYTHMIAS
Sinus tachycardia
A sinus tachycardia occurs due to increased automaticity of the SA node, and can be
recognized elecrocardiographically when all criteria for a sinus rhythm are present
however the heart rate is considered tachycardic (i.e., > 160-180 bpm in dogs or > 240
bpm in cats). A sinus tachycardia is not considered pathologic, and is the result of
another influence resulting in increased sympathetic tone. Common causes include
excitement, stress, fever, pain, hyperthyroidism, anemia, hypovolemia, severe cardiac
disease, and administration of positive chronotropic medications (i.e., terbutaline,
theophylline, atropine, ketamine, dobutamine/dopamine). Treatment should be aimed at
correction of the underlying cause, if necessary.
Atrial premature complexes (APCs) and Supraventricular tachycardia (SVT)
Ectopic supraventricular arrythmias resulting in premature complexes or tachycardia are
typically associated with atrial myocardial disease. This typically includes atrial stretch
(due to AV valve disease or DCM), but can also occur with atrial tumors and pericardial
disease. Occasionally, such arrhythmias are seen in patients with a primary cardiac
electrical disturbance (i.e., accessory pathway), electrolyte imbalances, or non-cardiac
contributing causes (i.e., splenic disease, pheochromocytoma). On surface ECG
tracings, atrial premature complexes demonstrate an abnormal P-wave conformation
(called a P’ wave) or an indiscernible P-wave due to blending with the preceding Twave. Associated QRS complexes typically demonstrate normal morphology due to
normal activation of the AV node, His-Purkinje system, and then ventricles, despite
abnormal atrial activation. In most cases, this can be easily distinguished from
ventricular ectopy, which results in wide and bizarre QRS complexes due to lack of
conduction through the normal His-Purkinje system.
With the detection of greater than three atrial ectopic complexes in rapid succession,
supraventricular tachycardia (SVT) is present. Supraventricular tachycardia can be
difficult to distinguish from sinus tachycardia, however is it characterized by an abrupt
onset and termination (compared to sinus tachycardia which is more gradual) and is
typically much faster than expected from a sinus tachycardia (i.e., > 240 bpm in dogs; >
270 bpm in cats). Patients affected with intermittent APCs rarely demonstrate clinical
signs, however SVT may contribute to decreased cardiac output with associated
symptoms of lethargy and syncope. Chronic SVT can depress ventricular function
resulting in a DCM-like state with possible CHF.
Treatment of infrequent, isolated APC’s is typically not necessary. In patients with
associated supraventricular tachycardia, negative chronotropic therapy is advised. With
emergent SVT resulting in symptoms of severely decreased cardiac output (i.e.,
collapse, HR > 300 bpm, severe hypotension), vagal maneuvers should be tried first
(i.e., carotid body massage, direct ocular pressure). If ineffective, intravenous diltiazem,
beta-blocker therapy, or procainamide may be required. Given the lack of availability of
oral procainamide, diltiazem is often considered the first-line choice. Intravenous beta-
blockers (i.e., esmolol or propranol) may be required to due to refractory tachycardia,
however should be used with caution due to significant negative inotropic effects as
many patients with SVT have severe myocardial disease. Similarly, oral therapy for
SVT often consists of diltiazem, digoxin, sotalol, or atenolol.
Atrial fibrillation (AF) and Atrial flutter
Atrial'fibrillation!
Atrial'flutter'
Atrial fibrillation and atrial flutter are unique forms of supraventricular tachycardia that
result in chaotic depolarization of the atrial myocardium with associated lack of
coordinated atrial contraction. Atrial fibrillation occurs due to multiple micro-retrant
circuits within the atria producing no discernible P-waves and a ‘quivering’ baseline
(called ‘F’ waves). Other characteristics include an irregularly irregular pattern of QRST complexes with relatively normal conformation (due to the supraventricular origin) that
are typically tachycardic in nature.
Atrial flutter shares many features of atrial fibrillation including an irregularly irregular
rhythm, supraventricular originating QRS complexes, and tachycardia, however due to a
repeatable macro-reentrant circuit atrial activity is seen as distinct ‘f’ waves creating a
characteristic ‘sawtooth’ baseline. The proportion of ‘f’waves followed by QRS
complexes is a function of AV nodal refractoriness (i.e., 1:1, 2:1, 3:1 represents the
number of ‘f’waves to QRS complexes).
Atrial fibrillation and flutter occur typically due to atrial stretch from structural cardiac
disease (i.e., degenerative valve disease or DCM).
In general, these rhythm
disturbances are more likely with increases in atrial mass, and therefore large breed
dogs are much more susceptible particularly with myocardial disease. Some giant
breed dogs can develop atrial fibrillation with no significant structural heart disease
which is termed ‘primary’ or ‘lone’ atrial fibrillation (similar to horses). Occasionally,
atrial fibrillation occurs in patients with normal cardiac chamber size due to increases in
vagal tone (typically due to GI disease).
Treatment of atrial fibrillation and flutter is often similar with two main treatment
methods: rhythm control or rate control. Rhythm control is typically employed in
patients without severe atrial enlargement and involves chemical or electrical
cardioversion. As most patients display atrial enlargement that often results in return to
atrial fibrillation following attempts at cardioversion, rate control is a more common goal
when structural heart disease is present. This is also true for atrial flutter. Rate control
therapy is aimed at reducing the ventricular rate associated with these arrhythmias by
slowing conduction through the AV node. A realistic goal is a reduction in the
ventricular rate to less than 150-160 bpm. This most commonly involves use of digoxin
(0.002-0.003 mg/kg PO q 12 h) and diltiazem (1.0-1.5 mg/kg PO q 8 h or 2.5-3.0 mg/kg
of extended release PO q 12 h) as combination therapy. In some patients, the
potassium channel blocker sotalol (1.0 mg/kg PO q 12 h) or beta-blocker atenolol (0.25
mg/kg initially PO q 12 h) is more effective. Similar to SVT, beta-blockers should be
used with caution as these therapies are also potent negative inotropes and many
patients with such atrial tachyarrhythmias have severe myocardial disease.
Ventricular premature complexes (VPCs) and Ventricular tachycardia (VT)
Ventricular premature complexes and ventricular tachycardia are relatively common
arrhythmias that can be seen with not only structural cardiac disease but also extracardiac influences. The cardiac diseases most commonly associated include dilated
cardiomyopathy (DCM) and Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC),
formerly referred to as ‘Boxer’ Cardiomyopathy. Although the exact mechanism
remains unknown, extra-cardiac diseases including splenic disease, gastric dilatation
volvulus (GDV), liver disease, pancreatitis, and sepsis, amongst others, can also result
in significant ventricular ectopy.
The decision to initiate anti-arrhythmic therapy for ventricular arrhythmias is complex. In
general, ventricular tachycardia or frequent multiform VPCs in the presence of
underlying cardiac disease should be treated. In patients with sustained ventricular
tachycardia or associated hemodynamic consequence (i.e., hypotension, collapse),
emergent therapy may be necessary. In-hospital treatment typically involves use of
bolus lidocaine therapy (in 1-2 mg/kg IV increments over 5-10 minutes to a total of 6-8
mg/kg) until cardioversion or adequate rate reduction is achieved. If necessary, a
lidocaine CRI can be initiated thereafter (25-100 mcg/kg/min IV). When lidocaine is
deemed ineffective, procainamide bolus therapy (6-12 mg/kg IV) can be attempted
followed by a CRI (20-40 mcg/kg/min). As lidocaine and procainamide are both sodium
channel blockers, toxicity of these drugs is increased and treatment should be
separated by 30-60 minutes, if possible. Symptoms of sodium channel blocker toxicity
include nausea, vomiting, ataxia, and seizures (diazepam responsive). Oral therapy for
ventricular ectopy most commonly includes sotalol (1-3 mg/kg PO q 12 h) and/or
mexiletine (4-10 mg/kg PO q 8 h with food). As sotalol has beta-blocking properties, it
should be used with greater caution in patients with suspected dilated cardiomyopathy
due to negative inotropic effects. Directed treatment at an extra-cardiac morbidity
expected to contribute to VPCs and VT should always be performed, if possible.
Accelerated Idioventricular rhythm (AIVR)
An accelerated idiovenricular rhythm (AIVR) is a ventricular rhythm that is sometimes
referred to as ‘slow V-tach’. This rhythm occurs when there are foci of ventricular
ectopy that exceed the sinus rate but are not tachcyardic in nature (typically 100-150
bpm in the dog). Most commonly, AIVR occurs due to extra-cardiac disease such as
splenic tumors, GDV, pancreatitis, sepsis, etc., however can also be present with
structural cardiac disease. Due to the lack of tachycardia, this rhythm often does not
result in hemodynamic consequence. Treatment should be aimed at correction of the
suspected underlying cause, however if progression to VT occurs, therapy is advised as
above.
Ventricular fibrillation (VF)
Ventricular fibrillation is indicative of chaotic and unorganized ventricular electrical
activity. As a result, the ventricles do not present a coordinated contraction and cardiac
output is completely absent. In the absence of immediate intervention, progression to
death is inevitable. Electrical defibrillation to attempt to restore normal sinus activity or a
more treatable form of ectopy (i.e., ventricular tachycardia) is the goal of therapy.
External defibrillation should begin at approximately 2 J/kg however can be increased to
5 J/kg, if necessary. Internal cardiac defibrillation requires less electrical energy and is
often initiated at 0.2 J/kg with an increased to 1.0 J/kg, if necessary. Other treatments
such as establishment of an airway, thoracic compressions, and bolus fluid therapy
should also be initiated concurrently, but do not replace defibrillation as the treatment of
choice.
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Trilostane Therapy for Hyperadrenocorticism
Matt Vaughan DVM, Dip ACVIM Internal Medicine
Seattle Veterinary Specialists
Kirkland, WA
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Diagnosis of Hyperadrenocorticism (HAC)
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Indications for testing
o Clinical signs and physical exam findings
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PU/PD, polyphagia, panting, abdominal distension, alopecia,
hepatomegaly, muscle weakness, hypertension
Lethargy, hyperpigmentation, comedones, thin skin, poor hair regrowth,
urinary incontinence, insulin-resistant diabetes mellitus
Thromboembolism, ligament rupture
Pituitary tumor: anorexia, stupor, circling, pacing, behavioral changes
Adrenal tumor: Hemorrhage, thrombus (ascites)
o Laboratory Findings
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CBC: Stress leukogram, thrombocytosis, eythrocytosis
Chemistry Panel: Elevated ALP, ALT, Chol, TGs, glucose
UA: USG <1.020, proteinuria, UTI
Ultrasound: Adrenal mass, bilateral adrenomegaly
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Greater number abnormalities, stronger suspicion of disease
Lack of any of above does not rule out
Avoid testing during times of other serious illness
Presence of pituitary or adrenal tumor should prompt testing
Unexplained insulin resistance should prompt testing
Screening tests
o Accuracy will increase when testing higher prevalence population
o Any screening test can be negative and so if suspicion is high, another
test should be performed or repeat test in 3-6 months
o Cortisol Assay
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Results may vary by assay and among laboratories
Ideally, centrifuge and refrigerate (freeze -20 if >24hrs)
Cross reactivity from various steroids, wait >24 hours from last dose
Adrenal suppression will last longer in dogs on chronic steroids
o Low Dose Dexamethasone Suppression Test (LDDST)
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Screening test of choice (unless iatrogenic suspected)
Sensitivity 85-100%, Specificity 44-73%
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0.01 mg/kg dexamethasone SP IV
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Serum cortisol levels at 0, 4 and 8 hours
8 hour point used to diagnose HAC, most normal dogs will be close to or
below detection limit (<1.0)
Fasting not necessary unless lipemia affects assay used
Phenobarbital MAY occasionally cause lack of suppression and can
cause similar clinical signs. If HAC is suspected, recommended to switch
anti-convulsants and then test if signs persist
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o ACTH Stim Test
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Gold standard for testing for iatrogenic HAC
Sensitivity 57-95%, specificity 59-93%
Synthetic ACTH recommended
5 ug/kg or 250 ug/dog IV or IM
Serum cortisol at 0 and 1 hour post
Cosyntropin can be reconstituted and frozen in aliquots at -20C for 6
months
Phenobarbital does not affect
Glucocorticoids, progestagens, ketoconazole can suppress
o Urine cortisol creatinine ratio
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Sensitivity 75-100%, specificity 20-25%
If home caught (>2 days after vet visit) in patients with HIGH degree of
suspicion of disease, sensitivity increases to 99% and specificity 77% if
two samples are both elevated
Morning urine best as represents more hours
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Differentiating Tests
o Should ONLY be done after a positive screening test
o Endogenous ACTH
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PDH dogs no different than normal dogs so poor screening test
Sensitivity of assay is biggest potential problem and may not discriminate
between PDH and ADH
Chilled EDTA tube and centrifuged within 15 minutes
Freeze plasma immediately, -20C
o Dexamethasone Suppression
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Pituitary disease if:
• If suppression below lab cut off or suppressed >50% baseline at 4
hours
• If suppression >50% at 8 hours but still ABOVE lab cutoff
Picks up about 60% of PDH on LDDST
Lack of suppression can be EITHER PDH or ADH
High dose dex suppression test does not pick up much more than LDDST
(~12% more)
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o Diagnostic Imaging
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Ultrasound
• PDH has norm or bilaterally symmetric adrenomegaly
• Asymmetry with contralateral atrophy suggests ADH
• Bilateral tumors can occur
• Mets, vascular invasion or size >4cm suggest malignancy
CT/MRI
• Abdomen: More sensitive to identify vascular invasion
• Pituitary: can be normal or may be macrotumors in dogs with PDH
• Radiation or hypophysectomy more effective for smaller tumors
and so screening in any new PDH case is recommended
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Occult Hyperadrenocorticism aka “Atypical”
o Over-production of sex hormones or cortisol precursors?
o Considered if clinical signs highly suggestive of HAC yet diagnostics tests
all are normal, ESPECIALLY if resting cortisol below normal
o Ultrasound to screen for adrenal mass or adrenomegaly
o Specificity of adrenal sex hormones is low
o Many of these cases may be early “typical” HAC
Trilostane Therapy
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Starting Dose
o Dose extremely variable and unpredictable.
o Larger dogs in general may need less per kg dose than small dogs.
o Author starts at 1 mg/kg PO BID
o Compounding pharmacy? ACTH stim test will tell you if compounded medication is
working
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Rechecks
o One to two weeks after starting
o One to two weeks after any increase in dose
o One month after first recheck when dose is NOT changed
o Every 4 months if dose continues to look good
o ACTH stim tests should be performed starting 2-4 hours post pill
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Treatment Goals
o *******Resolution of clinical signs*******
o Post stim cortisol between 2-5
o Most important monitoring parameter are the clinical signs, so if an owner says the dog is
now acting great with no PU/PD and you have a post-stim cortisol of 6.5, I wouldn’t
change the dose.
o
If there is a question about duration of action, a home caught urine sample (just prior to
pill) can be submitted for a UCCR. For example, a dog with persistent clinical signs but a
post stim cortisol of 2.0 and an elevated UCCR of 50 would need an increase in
frequency, not dose.
o
USG can also be helpful as a way to objectively monitor PU/PD and don’t forget periodic
urinalysis in an “uncontrolled” dog to evaluate for concurrent diabetes mellitus.
o
When increasing the dose, I usually go up by about 0.5-1 mg/kg but this depends on how
close to the target you are as well as prior dose increases.
o
Dose requirements can change and can drift up or down which is why monitoring every 4
months is important. Author lets his clients know to watch for V/D, anorexia, lethargy and
to stop if these occur.
References
Diagnosis of spontaneous canine hyperadrenocorticism: 2012 ACVIM consensus statement (small
animal). Behrend EN1, Kooistra HS, Nelson R, Reusch CE, Scott-Moncrieff JC. J Vet Intern Med. 2013
Nov-Dec;27(6):1292-304.
Evaluation of 2 trilostane protocols for the treatment of canine pituitary-dependent hyperadrenocorticism:
twice daily versus once daily. Arenas C, Melián C, Pérez-Alenza MD.
J Vet Intern Med. 2013 Nov-Dec;27(6):1478-85.
Effect of trilostane on hormone and serum electrolyte concentrations in dogs with pituitary-dependent
hyperadrenocorticism. Griebsch C, Lehnert C, Williams GJ, Failing K, Neiger R.
J Vet Intern Med. 2014 Jan-Feb;28(1):160-5.
Long-term survival of dogs with adrenal-dependent hyperadrenocorticism: a comparison between
mitotane and twice daily trilostane treatment. Arenas C, Melián C, Pérez-Alenza MD.
J Vet Intern Med. 2014 Mar-Apr;28(2):473-80.
Comparison of adrenocorticotropic hormone stimulation test results started 2 versus 4 hours after
trilostane administration in dogs with naturally occurring hyperadrenocorticism. Bonadio CM, Feldman EC,
Cohen TA, Kass PH. J Vet Intern Med. 2014 Jul-Aug;28(4):1239-43.
Evaluation of baseline cortisol, endogenous ACTH, and cortisol/ACTH ratio to monitor trilostane treatment
in dogs with pituitary-dependent hypercortisolism. Burkhardt WA, Boretti FS, Reusch CE, SieberRuckstuhl NS. J Vet Intern Med. 2013 Jul-Aug;27(4):919-23.
Efficacy of low- and high-dose trilostane treatment in dogs (&lt; 5 kg) with pituitary-dependent
hyperadrenocorticism. Cho KD, Kang JH, Chang D, Na KJ, Yang MP. J Vet Intern Med. 2013 JanFeb;27(1):91-8.
Trilostane dose versus body weight in the treatment of naturally occurring pituitary-dependent
hyperadrenocorticism in dogs. Feldman EC, Kass PH. J Vet Intern Med. 2012 Jul-Aug;26(4):1078-80.
Pharmaceutical evaluation of compounded trilostane products. Cook AK, Nieuwoudt CD, Longhofer SL. J
Am Anim Hosp Assoc. 2012 Jul-Aug;48(4):228-33.
Evaluation of twice-daily lower-dose trilostane treatment administered orally in dogs with naturally
occurring hyperadrenocorticism. Feldman EC. J Am Vet Med Assoc. 2011 Jun 1;238(11):1441-51.
Evaluation of the use of baseline cortisol concentration as a monitoring tool for dogs receiving trilostane
as a treatment for hyperadrenocorticism. Cook AK, Bond KG.J Am Vet Med Assoc. 2010 Oct
1;237(7):801-5.
Urinary corticoid: creatinine ratios in dogs with pituitary-dependent hypercortisolism during trilostane
treatment. Galac S, Buijtels JJ, Kooistra HS. J Vet Intern Med. 2009 Nov-Dec;23(6):1214-9.
Effects of trilostane on the pituitary-adrenocortical and renin-aldosterone axis in dogs with pituitarydependent hypercortisolism. Galac S, Buijtels JJ, Mol JA, Kooistra HS. Vet J. 2010 Jan;183(1):75-80.
Evaluation of twice-daily, low-dose trilostane treatment administered orally in dogs with naturally occurring
hyperadrenocorticism. Vaughan MA, Feldman EC, Hoar BR, Nelson RW. J Am Vet Med Assoc. 2008 May
1;232(9):1321-8.
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Notes
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Epilepsy: New Ideas in the Classification, Cause, Diagnosis and
Treatment
(adapted from: Sanders S. Seizures in Dogs and Cats, 2015. Wiley-Blackwell.)
Sean G. Sanders DVM, PhD, DACVIM (Neurology)
Seattle Veterinary Specialists
Kirkland, WA
INTRODUCTION
Epileptology, as a science, embodies the definition of comparative medicine. About
50,000 years ago, the first protohuman witnessed an animal having a seizure and made
a connection noting the similarity of the animal's behavior to that of another soon to be
human. The identification of this relationship may have been one of the first
observations of comparative medicine along with other similarities such a vomiting,
giving birth or bleeding. Our modern understanding of comparative medicine is primarily
applied to the relationship focusing on the similarities between humans and animals
(and to a much lesser degree plants, bacteria and other forms of life on the planet).
Over a period of thousands of years, the study of epilepsy has been a continual give
and take between animals and humans. Dogs and cats were the first research vehicles
used during the enlightenment as a springboard into modern anatomy, physiology and
medicine. The experimentation on dogs and cats led early researchers to develop a
better understanding of why epilepsy occurs and, more importantly, how to treat it. As
we enter into the 21st century, the development of molecular and cellular based
research has shifted the experimental focus from animals to cells, receptors and
proteins. With this new knowledge we can now incorporate and apply research primarily
intended to benefit humans to animals. In the field of epileptology, this has particular
relevance to benefiting dogs and cats. It truly exemplifies the statement, "take what you
need and in taking, give".
CHANGES IN CLASSIFICATION
The purpose of classification is to organize items into their functional (practical)
relationships in order to provide a common reference framework. In regards to epileptic
seizures, a common terminology for ictal semiotics (descriptive signs) and classification
is the end goal. Seizure semiology is the study of the clinical signs and their descriptions
relative to epileptic seizures. A classification scheme can provide valuable information
regarding possible cause, treatment and prognosis, even when the underlying etiology
is unknown (especially common with veterinary patients and surprisingly common in
human patients). The basis or foundation of the veterinary classification scheme of
seizures should be modeled to and closely resemble that of human classification
schemes. The categorization or classification of epileptic seizures and epilepsies is an
essential component to the successful diagnosis and treatment of the epileptic disorders
because it allows us to communicate with a common "language".
Veterinary classification schemes are based on those developed for humans by the
International League Against Epilepsy (ILAE). The current definition of an epileptic
seizure by the ILAE is:
“a transient occurrence of signs and/or symptoms due to abnormal excessive or
synchronous neuronal activity in the brain.” (Fisher, 2005)
An operational definition of an epileptic seizure would describe the incident in question
based on specific, observable events or conditions that must be present, from which
any observer (layperson, clinician or researcher) can independently use to come to the
same conclusion. An operation definition for an epileptic seizure may be:
“A paroxysmal, transient, stereotypic, electrical discharge of neurons within the brain,
associated with either lack of voluntary control of movement or dyscognition.” (adapted
from de Lahunta, 2009)
Epilepsy is not a disease but rather a disorder of aberrant neural connections (Engel,
2013). Furthermore, Epilepsy is not a single disorder but rather a collection of disorders,
which may be referred to as the epilepsies (Engel, 2012). The contemporary accepted
definition of epilepsy is somewhat different from previous definitions. The most recent
iteration does not specify more than one epileptic seizure over any particular unit of time
(for instance at least two epileptic seizures, at least 24 hours apart) but rather a single
epileptic seizure along with an alteration in the brain that sustains and increases the
likelihood of future epileptic seizures. For practical purposes an operational definition of
epileptic disorders may simply include;
“A history of at least one epileptic seizure, an enduring alteration of the brain that
increases the likelihood of another seizure and any neurobiological or behavioral
disturbances secondary to the epileptic seizure.”
The definition of an epileptic syndrome may help in selecting diagnostic tests,
medications and prognosis. An epileptic syndrome would be defined as:
“A collection of clinical signs, including one or more seizure types, along with
characteristic EEG patterns (if applicable), genetic defects, pathological abnormalities,
etiologies, response to medications and prognostic factors considered together with the
signalment of the patient.”
However, unlike a specific disease there may not be a consistent etiology, treatment or
prognosis due to the multivariate nature of epilepsy. When an underlying cause is not
determined, the syndromic classification provides the clinician with important insights
into management and prognosis of epilepsy and epileptic seizures.
Being able to place a patient in a syndromic classification is the most important element
of managing epilepsy, second only to stopping the seizures. Being able to describe the
type of seizure based on a phenomenological approach is important for communication
and further measurement, but it has little bearing on the cause of epilepsy (see table 1).
a
Table 1 Classification of Seizure Type (Phenomenological)
Generalized (previously Grand Mal)
•
•
•
•
•
•
Tonic: sustained increase in muscle contraction lasting a few seconds to minutes. Extensor or flexor
rigidity.
Clonic: Myoclonus, which is regularly repetitive involving the same muscle groups usually prolonged at
a frequency of 2–3 cycles/second.
Tonic/Clonic: A sequence consisting of a tonic followed by a clonic phase.
Atonic: sudden loss or attenuation of muscle tone without an apparent preceding myoclonic or tonic
event lasting ≥ 1-2 seconds involving head, trunk or limb musculature.
Myoclonic: Myoclonus (sudden brief, single or multiple contraction(s) of muscle(s) or muscle groups.
Can be of variable areas (i.e. axial, proximal or distal limb).
o
Myoclonic
o
Myoclonic atonic
o
Myoclonic tonic
Absence: Recognized as a brief (usually less than 20 sec.) generalized seizure with impaired
consciousness and specific EEG changes characterized by spike-and-slow-wave complexes, which
are bilaterally represented in the cerebral hemispheres. (Previously Petit Mal).
o
Typical
o
Atypical: More pronounced changes in tone. An onset or cessation that is not as abrupt and
more heterogeneous EEG changes
o
Absence with special features: Typically a component of myoclonia and in humans may
involve myoclonia of the eyelids with photosensitivity
Focal (previously Partial)
•
•
With cognition: implies an “awareness” of surroundings
o
Typically, responsive to verbal cues but may have an “affective” state described as
panicked, fearful or anxious. Previously, Simple Partial)
With dyscognition: implies an “unawareness” of surroundings
o
Typically, “unresponsive” to verbal cues. Previously, Complex Partial)
Unknown
•
Not enough evidence to characterize as Generalized, focal or both
a
Modified from Blume, W T., Lüders, H O., Mizrahi, E., Tassinari, C., van Emde Boas, W., and Engel, J, Jr.
2001. Glossary of Descriptive Terminology for Ictal Semiology: Report of the ILAE Task Force on Classification
and Terminology. Epilepsia. 42(9):1212–1218.
!
Epileptic Syndrome
A syndrome is a collection of clinical signs or symptoms, when considered together
constitute a distinctive disorder based on a specific lesion or other causes. By itself, a
syndrome is not a disease entity. A condition that has a specific pathological cause
(underlying substrate) is a disease. The disease may be associated with epileptic
seizures, but seizures themselves are not a disease, they are only an indication of brain
dysfunction. If an epileptic syndrome can be empirically identified or implied through
history and symptomology, the lack of a distinct pathological cause (i.e. the cause) of
the epileptic seizures via diagnostic testing (whether due to inability to perform tests or
normal test results) will still allow the clinician to provide insights into prognosis and
management of the seizures. This is a key point. Identifying a syndrome may also help
to narrow down a diagnostic plan, thereby avoiding unnecessary or risky tests (those
requiring anesthesia) and focusing on those tests, which will have the greatest
diagnostic yield with the lowest risk to the patient and cost to the pet owner.
Furthermore, the clinician may be aided in providing information as to the probability of
more seizures occurring and preparing pet owners for possible future implications
associated with the brain dysfunction causing the seizures. By knowing what to watch
for and understanding the progression of certain diseases over time, the pet owner may
elect to perform diagnostic testing at an earlier date before clinical signs associated with
the underlying disease process are irreversible. Classifying a patient within an epileptic
syndrome does not imply cause or a common etiology. Early diagnosis usually leads to
more successful and more complete treatment. Understanding progression aids in
intervention. Classifying an epileptic syndrome may also help researchers investigate
specific genetic etiologies of epileptic seizures, collation of data leading to better
predictability in regards to prognosis, treatment and outcome, as well as, development
of diagnostic modalities, which may aid in earlier or more complete identification of the
underlying pathology.
Remember that the goals of classification are to aid in choosing diagnostic testing,
treatment choices and prognosis. The current classification scheme of Genetic,
Metabolic-reactive, Structural and Unknown is intended to serve as a foundation for
continued updating as scientific knowledge advances. To aid the clinician in syndromic
classification, modifiers particular to the observational nuances of veterinary medicine
can be applied (e.g. static vs. progressive disease). This scheme replaces Idiopathic or
Primary for Genetic, Symptomatic is replaced by Metabolic/Reactive and Structural.
Cryptogenic
has
been
replaced
by
Unknown
(see
table
2).
Table 2 Underlying Syndrome (type or cause) of Seizure
New Classification
Old Classification
Genetic
Idiopathic or Primary
Metabolic or Reactive
Secondary
Symptomatic / Metabolic
Structural
Static
Secondary
Symptomatic / Structural
Progressive
Unknown
Cryptogenic
When considering a presumptive syndromic diagnosis it is important to critically review
all aspects of history, signalment and response to previous therapies. Pattern
recognition is equally important as recognizing circumstances, which tend to (generally)
increase either the frequency or intensity of seizures and may provide useful information
to the clinician. That same information can be helpful to the pet owner. However, one of
the primary roles of the veterinary caregiver will be to help the pet owner distinguish
between important and relevant details from those that only serve to confuse the
picture.
Ideally, identifying the underlying substrate responsible for the epileptic seizures should
be the clinician’s primary goal. This is diagnostic testing. The two benefits of diagnostic
testing are:
1. The “peace of mind” knowledge may provide to the pet owner. For example, the
prognosis associated with epileptic seizures secondary to a stroke is significantly
different from those that occur secondary to a brain tumor. Knowing this may help
an owner cope better with their pet’s epileptic seizure disorder.
2. The ability to focus treatment more specifically on a particular brain disease or
dysfunction. For example, treatment options and recommendations for
encephalitis are significantly different than those of the genetic form of epilepsy.
This knowledge may lead to more complete and successful treatment of the
condition by more specific and early-targeted treatment of the cause.
Disease identification is the most important aspect and the end goal of a diagnostic
algorithm. However, when identification of a disease substrate is not possible (the client
does not want to do diagnostics, or the results of diagnostics are inconclusive), being
able to classify the epileptic condition within a syndrome will allow the clinician and the
pet owner to consider important aspects of management and prognosis from a
syndromic perspective.
Because most epileptic conditions have multifactorial features, which may be present in
both idiopathic and symptomatic causes of epilepsy, the old classification system of
idiopathic or symptomatic is no longer used in human medicine. Epileptic seizure types
are classified as generalized, focal and unknown. Within each category are more
specific subcategories based on the phenomenology and symptomology of the epileptic
seizure event. Syndromic etiologies are classified as genetic, metabolic/reactive and
structural. We may also gain useful information in being able to determine if a condition
is static or progressive as a modifier applied to the syndrome of structural epilepsy (e.g.
either structural-static or structural-progressive). In general, we consider the age–
related or genetic forms of epilepsy, which do not demonstrate progression to be
benign, the reactive or metabolic causes of seizures to be limited to the underlying
disease process (and therefore not true epilepsy) and the structural causes to be more
pharmacologically resistant to therapy and in the case where progressive brain
dysfunction is present, a more guarded prognosis. These unnatural divisions are
necessary in order to begin the diagnostic and management process but should not be
looked at as all-inclusive. They are artificial distinctions to a multifactorial condition and
therefore, possess an inherent, built–in flaw or bias. However, as long as we consider
them to be more of a “guiding principle” of which, will continue to be built upon and
developed, they will serve a functional and beneficial purpose.
NEW THOUGHTS ON THE ETIOLOGY OF EPILEPSY
Previous definitions focused on the notion an epileptic seizure was due to an imbalance
of electrical activity in the brain resulting in an excessive degree of excitation either as
the primary source or secondary to a lack of inhibition of brain activity. The analogy of
“too much gas and not enough brakes” in the brain, could be used to simplify neuronal
activity to the layperson. The new definition reflects current advances in the
understanding of neuronal networks and focuses on synchronous activity of neurons in
addition to excessive activity and lack of inhibition. Following are a few new thoughts on
the generation of seizure activity from a biological reference in the brain, focusing on
synchronicity.
Gap Junctions
Electrical synapses are formed by gap junctions. Gap junctions are low frequency filter,
bi-directional, rapidly transmitting, passive pores formed between two adjacent cells.
Gap junctions provide a direct cell-to-cell continuity. Connexins are the transmembrane
proteins, which form gap junction pores. These pores are formed from two
hemichannels, known as connexons, each comprised of six connexin subunits. The
channels of one pore will connect to an adjacent pore in another cell membrane to
create a gap junction or connecting conduit between the cytoplasm of two adjacent
cells. Gap junctions allow free passage of ions and molecules up to 1 kDa in size
between cells due to a diameter of approximately 16-20 Å. Connexons are expressed in
different cells, at different times of development and maturity, and are thought to play a
very important role in the developing brain and especially in the development and
maintenance of neural supernetworks (Hormuzdi, 2004). Gap junctions occur in all cells
of the nervous system and allow direct communication between cells of similar function
(glial to glial) and of dissimilar function (neuron to glial or astrocyte to oligodendrocyte).
The interconnectivity of one glial cell to another creates the ability to send signals over
vast distances of the nervous system. Because the coupling of two cells allows for very
rapid communication, gap junctions allow for a very precise, temporally synchronized,
signal transmission. This characteristic has been identified in several areas of the brain
as the ability to generate very rhythmic activity. Neural networks, which contain large
numbers of gap junctions transmitting electrical signals will fire in a more temporal,
homogenously, synchronized manner (White, 1998).
The maintenance or propagation, through failure of disassociation of gap junction
connections in the mature brain, may be one of the underlying causes for enhanced
synchronous activity associated with epilepsy. Non-synaptic epileptiform activity is more
common in the immature brain and gap junction connections are more common in the
immature brain, as well (Roper, 1993). Experimental models which block gap junction
communication show suppression of spontaneous, synchronous events in the C1A
region of the rat hippocampus and conversely, models, which enhance gap junction
communication result in enhanced spontaneous activity (Perez-Velazquez, 1994). Gap
junction communication can be augmented through intracellular alkalization and
suppressed through intracellular acidosis. This mechanism may explain why
hyperventilation, which results in systemic alkalosis, is used clinically to induce seizures
and why certain systemic acidifiers, such as the ketogenic diet are recognized as
anticonvulsant - in humans (Perez-Vasquez, 2000). Although, changing systemic pH,
intracellular pH and the microenvironment of neurons are likely to have a wide variety of
possible effects on epileptogenesis. Carbenoxalone, a drug used to treat gastric ulcers
is a gap junction blocker at high concentrations and may provide future use as an antiseizure medication. A gap junction could represent the form of communication between
friends in a stadium who are physically close to one another (gap junction). When one
friend (neuron) starts to chant (fire spontaneously), the nearby “familiar” friend is more
likely and quicker to join in the chant (temporal synchronization) than a complete
stranger (chemical synapse). The gap junction communication would not only be
stronger but also more likely to be temporally synchronized. Cells connected through
gap junctions, firing in synchrony, will also change the microenvironment through
temporally enhanced extracellular potassium accumulation further leading to increased
excitability and local increases in pH (alkalosis). This depolarization shift, beginning at
the level of connected, gap junction communicating neurons, can lead to increased
neuronal firing through more distant chemical synapses.
Glia
About half of the brain matter is comprised of glial cells. The two main types of glial cells
in the central nervous system are astrocytes, which contain radiating processes
allowing them to interweave between neuronal cells bodies and oligodendrocytes,
responsible for forming the myelin sheath, which wraps around neuronal axons allowing
for the rapid transmission of the action potential. In addition, microglia are present as a
representative of the immune system (Jessen, 2004). Microglia do not originate from the
brain but are derived from blood macrophages. These macrophage-like cells aid in
regulation of the immune system. If neurons are the rock stars of the brain, glial cells
are the roadies. Glial cells have a highly developed control mechanism in place to
regulate neural activity and synchronization. They provide an integral supporting role to
the neurons and their local environment including (but certainly not limited to):
•
•
•
•
•
•
•
Provide elements for the synthesis of neurotransmitters (glutamate, glutamine, Dserine, ATP).
Act as a buffer for neurotransmitters, with active transport of glutamate and
GABA from the extracellular space.
Regulate interstitial (extracellular) homeostasis through the expression of inward
rectifying potassium channels and aquaporin-4, the water channel.
Modulation of the immune system through expression of cell surface molecules
and anti-inflammatory factors (Carson, 2006).
Maintenance of the blood-brain-barrier.
Regulation of neuronal development.
Myelination. A single oligodendrocyte can myelinate between 30-40 axons in the
central nervous system.
The density of potassium channels on glial cells is much greater than sodium channels,
which prevents glial cells from being able to generate an action potential. However, their
lack of ability to generate an action potential does not prevent them from cell signaling
and communication. Glial cells create a vast network through gap junctions. Their
membranes contain neurotransmitter and other chemical receptors. At the synapse,
neurotransmitter activity releases glutamate from nearby astrocytes, which has an
inhibitory effect on neuronal excitability (Haydon, 2001). This occurs with an increase of
intracellular calcium. Intracellular calcium can form a sort of long-range signaling
system, as waves of calcium will spread from one astrocyte to another, through
electronic gap junctions, in response to synaptic activity. This allows one astrocyte to
influence synaptic activity at distant sites (Cornell-Bell, 1990), (Guthrie, 1999).
Furthermore, the release of ATP by astrocytes (as an extracellular messenger) allows
the calcium waves to “jump” over cell-free regions (less than 120 μm), creating the
brain’s own “wireless network” (Hassinger, 1996), (Stamatakis, 2007).
The inhibitory influence of glial cells may also contribute to hypersynchronization as
regulation of action potential may create a situation whereby multiple neurons are
inhibited at the same time allowing for a greater recruitment of primed and ready to fire
neurons.
Organization of Brain Connections
If excitability is considered at the level of the neuron, the synchronization of neurons
(the functional form or excitability) must involve neural networks. Synchronization and
excitation may be enhanced through propagation. The propagation of neuronal signals
occurs through recruitment, augmentation and anatomical connections of various areas
of the brain. The notion that epileptic seizures are exclusively a forebrain mediated
event or result only from forebrain dysfunction is incorrect. Generally speaking, the
telencephalon (cerebral cortex and hippocampus) is the location of epileptic excitable
tissue, however, epileptic seizures may generate from subcortical structures, such as
the amygdala. Diencephalic structures and brainstem projections, such as the pontine
reticular formation, also influence cortical excitability. Connections between the various
structures of the brain (i.e. the brain’s own highways) allow a focal, potentially controlled
disturbance to be propagated to distant sites, recruiting other neural networks to fire
spontaneously and in synchrony.
There are inherent properties of certain local anatomical connections between brain
structures, which lend to ictogenesis. The two main epileptogenic networks of the brain
involve the neocortex and the limbic system.
Neocortical Connections
Generally speaking, the neocortex receives information from the thalamus and other
cortical structures (e.g. the primary olfactory cortex, which bypasses the thalamus).
Feedforward and feedback inhibition are the most common electrical interactions of the
central nervous system. When large pools of neurons are all inhibited at the same time
or with the same frequency, they become “primed” to fire simultaneously with the right
excitatory input, leading to the potential for synchronization. It seems counterintuitive
that inhibition can result in excitation (Trevelyn, 2013). A naturally occurring, post
excitation inhibition due to rebound depolarization of neurons coupled with inhibitory
input further increases the chance for synchronization of neuronal pools to develop. If
these neurons are subjected to an excitatory input at the right time and right frequency,
they will contribute to the collective pool of a synchronous excitatory discharge, which
may propagate to other areas of the brain. GABAergic interneurons are important
elements providing feedforward and feedback inhibition in both the neocortex and the
hippocampus. This inhibition is what strengthens an individual neuron’s response to
afferent, synchronizing input. By being continually suppressed, more neurons are ready
to “step up to the plate”, often collectively at the same time.
Neurons, which have the ability to spontaneously fire in bursts, are present in layers IV
and V of the neocortex. These neurons may operate as neocortical pacemakers if the
burst firing becomes synchronous. Burst firing is possible because of dendritic T-type
calcium currents present in the vicinity of the axon hillock. Repetitive action potentials
are created as a result of continuous depolarization at the axon hillock. Local inhibitory
interneurons and calcium dependent potassium currents eventually suppress the firing
of these neurons. Burst firing of neurons is normally random, however, if they become
synchronous, they have the potential to create high frequency oscillations (HFO). These
HFOs may be normal (referred to as ripples) at frequencies between 100-200 Hz but
can be indicative of epileptogenic tissue at frequencies between 200-600 Hz
(pathological HFOs). The ability to form synchronized discharges and HFOs may lead to
recruiting and augmenting responses from subcortical input to the neocortex. This
normal, afferent input has the potential to induce epileptiform activity if acted on an
abnormal, epileptogenic area of the neocortex, as opposed to being propagated from
abnormal thalamic relay tissue (Gloor, 1977). HFOs may spread throughout the brain
through gap junction mediated calcium waves (Traub, 2001). Gap junction blockers,
such as carbenoxolone, may have a future role in stopping seizures (Sefil, 2012).
Kindling, is the subconvulsive stimulation of neuronal populations leading to progressive
intensification of neuronal firing and culminating in generalized seizures. Kindling is
suspected to be one of the primary means subcortical neurons can spread their epileptic
potential to distant sites through normal anatomical connections. Some of these
anatomical connections are through normal central nervous system “highways” such as
association fibers (connections between different areas of the cerebral cortex within the
same hemisphere), commissural fibers (connections between cerebral hemispheres)
and projection fibers (connecting subcortical and spinal cord areas with the cerebral
cortex). Epileptic seizure propagation may also be made through aberrant neural
connections.
Subcortical Connections
The amygdala is anatomically related to the basal nuclei. It is a poorly organized
collection of neurons and axons, which “pass through” the amygdala to other areas of
the brain. It is a "truck stop". Experimentally kindled seizures have long been generated
through stimulation of the amygdala. The amygdala has efferent and afferent
connections to the hypothalamus, septal area, forebrain olfactory areas and the
brainstem. If the amygdala is stimulated rhythmically, a recruitment response will be
elicited in the hippocampus resulting in status epilepticus, which persists, even after the
stimulus has ceased (McIntyre, 1982). Kindling is classically demonstrated in the
hippocampus through the stimulation of the amygdala to create subthreshold focal
seizures which eventually lead to a progressive, reliable, permanent increase in
epileptic response to a given stimulus (Goddard, 1969). Destruction of cell bodies in the
amygdala by kainic acid, which preserves fibers that pass through the structure, does
not prevent kindling. It is therefore suspected the epileptogenic effects of the amygdala
are due to the fibers transiting through it to the hippocampus as opposed to the intrinsic
cells present within the amygdala (Kaneko, 1981).
The neocortex also receives input from other subcortical structures, organized by the
primary neurotransmitter involved such as dopamine, serotonin, epinephrine and
acetylcholine.
Excitatory amino acids are involved in reciprocal connections from the neocortex to the
brainstem. GABAergic connections predominate from the neocortex to the subcortical
structures. Subcortical and brainstem connections to the neocortex have different
potential to either induce or suppress epileptiform activity. For instance, non-cholinergic
projections from the brainstem and diencephalic nuclei will increase cortical
synchronization similar to their ability to influence slow-wave sleep patterns.
Epileptogenicity is more likely to happen during slow-wave sleep when synchronicity
predominates in the brain. On the other hand, cholinergic input to the neocortex has an
effect on arousal, desynchronization and REM sleep (i.e. less epileptogenic). While
generally true, serotonergic input from the brainstem will suppress epileptic activity,
even though it helps to initiate slow-wave sleep. Noradrenergic and dopaminergic input
to the cortex will also suppress epileptogenicity.
The cerebellar output to the deep cerebellar nuclei is inhibitory. The deep cerebellar
nuclei have connections to the neocortex and the hippocampus. Stimulation of the
cerebellum, experimentally has produced mixed results with some studies showing
suppression of seizures, others having no effect and still others potentiating
epileptogenic activity (Graber, 2012).
Connections Between Hemisphere
A mirror focus is a point of epileptogenic tissue in a homotopic location in the
contralateral hemisphere. Interictal spikes first show up in the area of the brain where
the primary lesion is located (McCarthy, 1997). If allowed to continue, a secondary
location of interictal spikes appears in the contralateral cerebral hemisphere in a mirror
location to the primary side of epileptogenic tissue. The development of mirror foci is
thought to arise from continuous epileptic activity crossing interhemispheric connections
such as the corpus callosum. If the primary site in one hemisphere is allowed to
continuously be active, a mirror focus may develop in the opposite hemisphere, which
matures to the point where it can generate its own, asynchronous (relative to discharge
relating to the progenitor site), epileptic activity, independent of triggering from the
progenitor site. Transection of the corpus callosum has been used to prevent the
development of mirror foci experimentally in animals and to help treat severe forms of
human epilepsy, although there are some reports where callosectomy resulted in
worsening of seizures in patients with independent foci of epileptogenic activity on EEG,
suggesting in certain circumstances the corpus callosum may play a part in contralateral
inhibition of seizure activity (Spencer, 1984).
Brainstem Connections
Penfield and Jasper originally proposed the centrencephalic system of brainstem
involvement in the ictogenesis of generalized seizures (Penfield, 1954). The notion a
generalized seizure may be propagated from a location in the brainstem reticular
formation has since been demonstrated, primarily utilizing genetically epilepsy prone
rats (GEPR-9). The GEPR-9 rats are susceptible to audiogenic, generalized seizures.
Audiogenic, generalized seizures may be confined to brainstem and subcortical
structures prior to kindling (Faingold, 2012). In this model, a sound stimulus propagated
through the cochlear nucleus and superior olivary complex reaches the inferior colliculus
where a deficiency of GABA mediated inhibition leads to excessive auditory evoked
inferior colliculus neuronal firing, subsequently leading to the audiogenic generalized
seizure. The excessive neuronal firing is thought to result in activation of the regional,
brainstem locomotor network, which is located in the brainstem and spinal cord (Grillner,
2009). The physical characteristics of generalized, tonic-clonic seizures are a
manifestation of excessive neuronal activity involving the locomotor apparatus in the
brainstem. As previously discussed there are multiple reciprocal connections from the
neocortex and the hippocampus to the brainstem.
Limbic Connections
The limbic system (from Latin, limbicus meaning “border” or “margin”) is comprised of
two incomplete ring structures in the shape of a “C” located opposite one another
bordering the lateral ventricles. An excellent description of its anatomical development
can be found in de Lahunta (de Lahunta, 2009). The limbic system is generally
considered to be involved with the sense of smell, learning and emotional behavior.
However it has other influences over memory formation, autonomic functions such as
blood pressure and heart rate, reward, pleasure, addiction and the decision making
process, to name a few. It has significant influence over neocortical and brainstem
function, as well as, being influenced by those same structures. Many of its intrinsic
characteristics, both structurally and functionally make it a common site of
epileptogenesis.
The hippocampus is a gyrus of the telencephalon, which is “rolled” under the brain,
adjacent to the lateral ventricles and diencephalon and medial to the temporal lobe. The
hippocampus proper is often referred to as “Ammon’s Horn” because of its appearance
to the coiled ram’s horns of the ancient god Amun (meaning “the hidden one”). The
name hippocampus comes from the Greek words, hippos (meaning “horse”) and
kampos (meaning “sea monster”). When dissected from the brain, the structure
resembles a seahorse. The primary output of the hippocampus is to the hypothalamus,
medial prefrontal cortex and caudal brainstem nuclei. The limbic system is a complex
aggregate of structural and functional elements, which collectively influence most brain
activity. Signals flowing through the hippocampus form a loop or “circuit”. This circuit is
further connected to other parts of the brain forming neural networks. Structurally, the
limbic system is comprised of an inner cortical ring consisting of the amygdala, the
hippocampus and the hippocampal fornix. An outer cortical ring consists of the cingulate
gyrus, cingulum (axons projecting from the cingulate gyrus to the entorhinal cortex), the
septal area, the median forebrain bundle and hypothalamus. The parahippocampal
gyrus, the corpus callosum and the lateral ventricles border the hippocampus. It wraps
around the thalamus.
Hippocampal interneurons play a major role in the feedforward and feedback
mechanisms of synchronization. With repeated stimulation, the inhibitory neurons of the
hippocampus (GABAergic) have a reduced effect, leading to greater excitation of CA1
pyramidal neurons.
Similar to the neocortex, simultaneous inhibition of large pools of pyramidal neurons of
the hippocampus creates a “primed” state where larger numbers are available to fire in
synchrony with the right excitatory input to the hippocampus. Neurons in the CA3 area
of the hippocampus and the subiculum are also capable of burst firing, further adding to
the potential of the hippocampus to result in epileptogenicity. Normal burst firing in the
CA3 area is asynchronous. However, if the burst firing in the CA3 area becomes
synchronous (due to feedback or feedforward inhibition), it can induce CA1 neurons to
burst fire. Oscillatory patterns are favorably created by neurons in the CA3, CA1,
dentate gyrus and subiculum during states of arousal, active motor movement and REM
sleep. Cholinergic input from the septum is responsible for these 4-6 Hz oscillations,
known as the theta rhythm on EEG recordings. Buried within the EEG (sample rates
greater than 2000 Hz), high frequency oscillations (HFOs) have been identified as
potential biomarkers of epilepsy (Zijlmans, 2012). HFOs probably originate from
populations of neurons firing in synchrony and spread through calcium waves, mediated
by electronic gap junction connections. As previously mentioned, HFO’s can be normal
electrical activity of the brain. This activity is referred to as ripples when frequencies are
between 80-250 Hz. When they occur in the mesiotemporal area, they are thought to be
associated with memory. When they arise from the extratemporal neocortex, they are
thought to be associated with information processing. Pathological HFOs (pHFO’s) are
associated with frequencies of 250-600 Hz and are referred to as fast ripples. HFOs
have caught investigators’ attention as they are observed before seizures, during
seizures and in between seizures. They require special EEG recording techniques to
detect. It is thought, HFOs represent small groups of principle cells (i.e. projecting
neurons), which have become synchronized and are pathologically interconnected. If
brain tissue is damaged or alterations in the cell population or local environment occur,
neurons may be more likely to fire in response to subthreshold stimuli. Recruitment and
augmentation secondary to the propensity for inhibition in these areas also contributes
to the ability of this abnormal tissue to become spontaneously active and recruit
interconnected cells in the local vicinity. HFOs have been shown to be a reliable marker
of the future development of seizures in rats (Bragin, 2004). These inherent
characteristics of the hippopcampus (e.g. burst firing, oscillatory patters, large amounts
of potential inhibition and extreme interconnectivity with other areas of the brain) allow
the structure to have a profound influence over epileptogenicity. It is no wonder;
hippocampal sclerosis is the most common pathological substrate of epilepsy in
humans (Engel, 1996).
New methods of determining structural and functional relationships in the brain are
aiding in the understanding of aberrant neuronal connections, their role in the ability of
neurons to spontaneously fire (i.e. epileptogenicity) and the spread and progression of
epilepsy (i.e. epileptogenesis). These new techniques hold a significant promise in
furthering our understanding regarding the underlying pathophysiology of epilepsy. MRI
diffusion imaging (diffusion tensor imaging) allows the delineation of whole brain, threedimensional, maps of fiber pathways throughout the brain. Functional MRI looks at
areas of the brain, which are functionally related either through influences by each
other, on the other or through another site influencing both regions. The metabolism
based, structural information can be very helpful especially when combined with
structural MRI and EEG recordings of brain activity.
Non Brain influences of Epileptic Seizures
If the maintenance of the electrochemical gradient is dependent on the
sodium/potassium ATPase pump, then any systemic alteration of normal cerebral
oxygen or glucose metabolism may lead to membrane instability. Potassium has a
strong conductance through the neuronal membrane. Failure of the sodium/potassium
ATPase pump leads to the membrane potential approaching threshold and subsequent
hyperexcitability.
Electrolyte disturbances such as hypocalcemia, hyperkalemia, hypernatemia,
hypochloridemia and hypomagnesemia have the potential to induce epileptic activity.
Increases in toxic byproducts of metabolism not cleared from the body through normal
mechanisms (hepatic or renal) also have the ability to disrupt the neurons
microenvironment. Imbalances in systemic acid-base status can lead to disruptions of
the highly regulated cellular microenvironment. Glial cells act to buffer changes in the
acid-base status through the use of carbonic anhydrase, which acts to catalyze the
hydration and dehydration of carbon dioxide (Silverman, 1988).
In this simple reaction, carbon dioxide is combined with water to form the bicarbonate
ion and a hydrogen ion. Carbonic anhydrase inhibitors, such as acetazolamide will
cause retention of carbon dioxide (alkalosis) and subsequent reduction in neuronal
excitability. Changes in cerebral circulation, renal disease, hepatic disease,
polycythemia and hypertriglyceridemia all have the ability to create a more epileptogenic
carbonic anhydrase
CO2 + H 2O " ---------------------# HCO3- + H+!
environment in the central nervous system. Alkalosis causes neuronal hyperexcitability
and acidosis is inhibitory to neurons (Ruusuvuori, 2010), (Casey, 2010).
Most mechanisms thought to contribute to the generation of seizures are concentrated
around the idea of either alterations in the inhibitory/excitatory homeostasis of the brain,
changes in transmembrane ion concentrations, alterations in neuronal homeostasis,
alterations in the function of neurotransmitters, factors that cause a large group of
neurons to fire spontaneously and alterations in either glucose or oxygen metabolism. In
the end, epileptic seizures are likely due to a multifactorial alteration in normal brain
homeostasis and unfortunately at this time, the majority of therapies are directed at the
prevention of seizures, not necessarily the cause.
NEW AND FUTURE DIAGNOSTICS
Electroencephalogram (EEG)
Perhaps the greatest difference between the diagnostic evaluation of epileptic seizures
in humans compared to veterinary patients is the use of the electroencephalogram
(EEG). For veterinary neurologists, the MRI is the single most valuable diagnostic tool
for the evaluation of epileptic patients and as advanced neuroimaging became more
commonplace in the veterinary neurodiagnostics, the use of the EEG had declined. The
trend is shifting, however, thanks to the work of some very persistent veterinary
neurologists. For human neurologists, the EEG assumes the role of most useful
diagnostic tool (Engel, 2013). The sensitivity of EEG in veterinary medicine in detecting
abnormal electrical activity is variable and reported to be anywhere from 0-100% in
detection of epileptic discharges (Pakozdy, 2012). Variations in sedative and anesthesia
techniques, as well as, activation procedures (e.g. hyperventilation, photic stimulation)
may increase the sensitivity of the EEG (Brauer, 2012), (Engel, 2013). The difficulty in
evaluating the benefit of the use of EEG in a clinical setting, may be due to the
variability of the application, including the form of sedation or anesthesia used and the
purpose of the EEG study and the patient population (i.e. genetic vs. structural
epilepsy). A strong correlation exists between the clinical seizure type observed and
changes observed on an EEG recording in dogs (Holliday, 1970), (Jaggy, 1998),
(Berendt, 1999).
The EEG is a recording of spontaneous electrical activity of the brain. Abnormal
electrical activity may confirm and help to localize a seizure disorder. In veterinary
medicine, advanced imaging techniques, such as MRI have largely supplanted the use
of EEG as a diagnostic tool. The EEG may help determine if the patient has epilepsy
(especially in cases of focal epilepsy vs. behavioral disorder), what kind of epilepsy the
patient has (absence as opposed to focal) and the location of the lesion, especially in
cases where epileptic seizures are focal and cannot be identified with advanced imaging
techniques. The EEG may be especially useful in confirming the diagnosis of epileptic
seizures when the “events” have not been observed by the clinician and the description
of the “events” by the owner do not exactly correspond with the definition of an epileptic
event (Berendt, 1999). In human medicine, the EEG may also be useful in determining
the efficacy of medical management. Particular attention is made to the location of an
epileptogenic site in human medicine, as surgical resection of abnormal tissue may be a
treatment option in certain cases. In dogs and cats, the EEG is performed by inserting
small, fine, scalp needle electrodes in the skin overlying specific areas of the brain. The
EEG electrode will record the electrical potential between two locations (an individual
channel or derivation). The combination of multiple locations is referred to as a
montage. Multiple locations are recorded at once creating a temporal sequence of brain
electrical activity. The normal brain electrical activity will change depending on the state
of awareness of the patient and external stimulation. Abnormal activity is typically
characterized by either depressed electrical activity relative to the state of the patient
(e.g. an awake patient with depressed activity may be abnormal) or excessive activity
(i.e. spike-and-wave activity in a patient having seizures). There are many practical
limitations to the everyday use of EEG in veterinary patients, which creates a highly
specialized diagnostic test with a low diagnostic yield when compared to MRI, however
the type of data one can access is not comparable to MRI. Some of the practical
limitations in veterinary medicine include:
•
•
•
•
•
•
•
•
•
•
•
Patients are typically intolerant of skin electrodes.
The muscle mass and relatively thick skull of veterinary patients overlying the
brain may attenuate the electrical signals by the time they reach the surface
electrodes.
The muscle mass of veterinary patients may create excessive movement artifacts
(e.g. eye blinking or facial twitching).
Sedation or anesthesia must often be used, which can alter the normal or
abnormal EEG recordings.
Alterations in electrical activity of a diseased brain are not pathognomonic for any
particular disease (low specificity).
Complete recordings need to be made in the awake and sleeping patient. It is
difficult to obtain artifact free recordings in awake patients (Holliday, 1998)
Small lesions or alterations in electrical activity, indicative of disease, may be
overlooked, as the EEG is a summation of cortical electrical activity.
No specific, generally accepted operating parameters (i.e. montage, anesthetic or
sedative use etc.) has been developed and adopted in veterinary medicine
(Brauer, 2012).
The ability to detect abnormal activity is related to time of the epileptic seizure to
the EEG recording, as well as, the severity of the seizure (Berendt, 1999a).
A single period of EEG recording may not be adequate to detect an ictus (Cuff,
2014).
Interpretation required specialized training and experienced interpreters of EEG
data in veterinary patients are few.
While there are many controversial limitations to the practical and justifiable diagnostic
yield of EEG recording in a clinical situation (as opposed to research or teaching) an
EEG recording may be useful in the following situations:
•
Determining if the patient is actually having seizures (focal or absence) or
simply displaying abnormal behavior or syncope (Penning, 2009), (Poma,
2010).
•
•
•
•
•
•
Determining if a post ictal patient is actively having seizures or a stereotypic
movement disorder (Kube, 2006).
Determining if the patient is “brain dead” and helping to determine prognosis
in critical patients (Firosh, 2005), (Scozzafava, 2010).
Classification of epileptic syndromes amongst veterinary patients (Srenk,
1996), (Jaggy, 1998), (Poma, 2010).
Identification of non-convulsive status epilepticus (Bush, 2013), (Cuff, 2014).
Evaluate the effectiveness of chronic and pulse anti-seizure medications
(Frost, 1986), (Cuff, 2014).
Determine the localization of an epileptogenic focus for possible surgical
removal (Bagley, 1996), (Jaggy, 1998).
EEG is commonly used in the study of human epilepsy to help classify epileptic seizures
based on electroclinical syndromes (Engel, 2001), (Berg, 2010). Not all patients will fit
into “standard” classification schemes based on symptomology and semiology.
Electroclinical syndromes provide an alternative classification system (Parisi, 2011),
(Seneviratne, 2012). The practical use of EEG in veterinary medicine may allow for the
recognition of electroclinical syndromes which may help clinicians further recognize
those epileptics without typical semiology, characterize the underlying etiology and
apply the most efficacious treatments (i.e. targeted therapy) for a particular identified
epileptic syndrome (Srenk, 1996), (Jaggy, 1998), (Poma, 2010). For example, when
children are diagnosed with childhood absence epilepsy (i.e. petite mal epilepsy) or
juvenile absence epilepsy, by demonstrating typical absence seizures with or without
myoclonia and a classic EEG pattern characterized by 2.5-4 Hz generalized spike-andslow-wave discharges, treatment with drugs such as sodium valproate and
ethosuximide are specifically chosen. Furthermore, the syndromic classification may
also correspond with classic MRI changes including thalamic atrophy and changes in
cortical gray matter (microdysgenesis) (Engel, 2013). By realizing the similarities
between veterinary and human patients (either through EEG or MRI), we may be able to
apply more effective treatment. After all, animal models of epileptic seizures are used in
order to determine therapeutic drug efficacy in humans. It makes sense we would be
able to “reverse engineer” the successful application of a treatment corresponding to a
human epileptic syndrome, if the same syndrome could be identified in a veterinary
patient and the corresponding therapy is tolerated. As investigators continue to unravel
the often nebulous causes of epileptic seizures, EEG may be a useful tool to suggest
further diagnostic testing, treatment options and prognosis associated with the cause.
For example, cats presenting with orofacial seizures may fit into a syndromic
classification of, as of yet, poorly understood hippocampal sclerosis (Fatzer, 2000),
(Pakozdy, 2014).
The EEG can be very useful in cases where the determination of actual epileptic
seizures cannot be made by visual observation alone. In a clinical setting the patient
who is actively having seizures, may physically stop having tonic clonic convulsions,
however, repetitive movements such as paddling or facial twitching may be present in
the unconscious and “relaxed” patient. Using an EEG can help the clinician determine if
abnormal brain electrical activity is continuing; allowing for possible alterations in
therapy in order to stop sub-clinical epileptic activity (Poma, 2010), (Kube, 2006), (Bush,
2013). Non-convulsive status epilepticus may also be diagnosed, although it is stressed,
interpretation of an EEG to diagnose non-convulsive status epilepticus is user
dependent and quite subjective (Cuff, 2014). Making this determination with EEG may
help prevent brain damage associated with continuous abnormal electrical activity (e.g.
glutamate mediated excitotoxicity, kindling, development of mirror focus etc.) associated
with refractory convulsive status epilepticus, non-convulsive status epilepticus or
subclinical status epilepticus (Majores, 2007). EEG may also be helpful when monitoring
the effect of a medically induced coma. Medically induced comas may be employed as
a treatment following severe brain injury or intractable epileptic seizures. An EEG
indication of the coma being generated is the presence of burst suppression of electrical
activity. A burst suppression pattern appears as reduced to quiet electrical activity
following bursts of electrical activity (Cuff, 2014). Drugs used to induce a medical coma
(e.g. propofol, pentobarbital, ketamine) can be titrated to achieve this effect through
EEG monitoring (Rossetti, 2004), (Raith, 2010). The burst suppression pattern is
indicative of deep sedation as an effect of the anesthetic agent and commonly regarded
as an artificially induced end point of status epilepticus.
The application of wireless transmitted EEG data to alert pet owners of potential
epileptic activity is being explored and promises to provide for earlier treatment, as well
as, reduced incidences of status epilepticus, visits to emergency rooms, identification of
subconvulsive states and complications associated with untreated epileptic seizures
when used in conjunction with seizure prediction algorithms (Lehnertz, 2007), (Davis,
2011), (Coles, 2013).
The interpretation of EEG data is often regarded as more of an art than a science. A
significant amount of over interpretation exists. Computer-enhanced EEG and videomonitoring EEG have the potential to greatly improve the diagnostic yield of the EEG
recording in veterinary medicine as it has in human medicine. Brain mapping software is
available and routinely used in human medicine to provide a topographic representation
of EEG activity (Nuwer, 1988). The combination of EEG data, MRI and topographical
mapping utilized together to provide a comprehensive study of the abnormal brain
promises to advance the diagnosis and treatment of epilepsy whether through early
intervention and prevention or treatment utilizing medical or surgical modalities.
Technology is starting to catch up. Several ambulatory EEG systems are currently
available which allow awake recordings in veterinary patients, thereby eliminating the
problems associated with anesthesia or heavy sedation. Furthermore, recordings can
occur for hours or days to capture an "event" which is simultaneously recorded on video.
This has greatly expanded our ability to recognize seizures in cases where the
vagueness of the event may prevent the use of anti-seizure medications.
Functional MRI (fMRI)
The use of MRI is most well known for the anatomical and structural evaluation of the
brain. Functional MRI (fMRI) utilizes the fact that oxyhemoglobin is paramagnetic while
deoxyhemoglobin is diamagnetic. Paramagnetic substances produce an increased MRI
signal. Neuronal activity results in increased blood flow to active areas of the brain,
resulting in local increases in oxyhemoglobin and a subsequent increased signal. The
Blood oxygen level-dependent (BOLD) fMRI utilizes this concept to evaluate patterns of
blood flow in different anatomical areas of the brain and through averaged, repeated
acquisitions and subtracting baseline studies from EEG - triggered studies (Krakow,
1999). Using this methodology with MRI has the advantage of superior temporal
resolution over functional PET studies, which require up to an hour following injection of
radiolabeled ligand to evaluate metabolism. Functional MRI allows near immediate
image acquisition following an epileptiform discharge. The BOLD image identifies the
anatomical substrate where the epileptiform discharge originated. Additionally, fMRI
may identify hemodynamic changes associated with underlying networks which help to
classify certain epilepsies related to a specific syndrome by way of an imaging
fingerprint (Gotman, 2008), (Moeller, 2013). Another role of fMRI is to identify an
epileptogenic zone as part of pre-surgical evaluation. The area of the brain where the
EEG associated epileptiform discharges occur, is referred to as the irritative zone and is
often a closely related but distinct site to the cortical area where epileptic seizures are
initiated, known as the ictal onset zone (Engel, 2013). The purpose of multiple
sophisticated diagnostics is to identify the epileptogenic zone with the ultimate goal of
surgical resection for medically intractable epilepsy and preserving eloquent brain tissue
(e.g. speech centers) (Moeller, 2009). Even with extensive diagnostics workups, lesion
identification is not possible, particularly in frontal lobe epilepsy (FLE) of humans. These
patients are often pharmacoresistant and surgical treatment may be an option, however,
approximately 15% of the patients are rejected as surgical candidates due to the
inability to identify the epileptogenic zone with standard diagnostics. The combination of
EEG and fMRI helps to identify occult lesions for surgical resection in many of these
patients (Zijlmans, 2007). Surgical treatment of epilepsy in veterinary patients has been
reported, although the cause of the epileptic seizures was a mass effect from a fungal
lesion (Parker, 1971). While generally not expected, epileptic seizure cessation
occasionally occurs following the removal of discrete brain lesions (i.e. neoplasia or
developmental malformation), in the author’s experience. Even with reported cessation
of seizures, unless the patient cannot tolerate antiseizure medications, they should be
maintained on chronic, maintenance therapy. The use of fMRI has been employed
experimentally in dogs and cats to evaluate the auditory and visual pathways (Willis,
2001a), (Willis, 2001b), (Aguirre, 2007), (Bach, 2013), (Brown, 2013). Despite requiring
anesthesia and the concerns naturally revolving around decreased cerebral metabolism,
BOLD fMRI has demonstrated to be effectively utilized, in a research setting, with
anesthetized animals and in a single report of highly trained canines, without anesthesia
(Berns, 2012). Functional MRI remains a research tool at this time in regards to
veterinary medicine. As high field strength MRI units become more available, the use of
this technology holds promise to provide improved classification of epileptic syndromes
in veterinary patients, identification of lesions not visible with conventional imaging and
potential targeted surgical resection of epileptogenic zones.
ENHANCING TREATMENT SUCCESS
The focus of treatment is usually drugs. Determining the success of a drug protocol, in
all but the easiest cases, is dependent on accurate reporting of seizure activity by the
owner. Being able to identify triggers of epileptic seizures, patterns of seizure activity
and track side effects, as well as, effectiveness of medications can be challenging to pet
owners and clinicians. A potential area that can be used to enhance treatment success
is the use of online tracking software, designed to allow the owners of the pet to input
relative variables regarding seizure activity and response to treatment. A common or
"universal" platform will allow owners of pets and clinicians to communicate in a similar
manner. Being able to view a patient's history and seizure activity in a highly organized
and customizable platform will greatly enhance treatment decisions.
Seizure Log
If an owner keeps a seizure log of their pet, a quick scan may reveal a change in
seizure pattern. Seizure logs should contain information such as time of seizure (day or
hour), intensity of the seizure, current medications at the time of the seizure, therapeutic
drug levels, changes to medications and any particular stressors or triggers, which may
have occurred prior to the onset of the seizure. A seizure log can be as detailed as an
owner wants but it is important to be able to recognize patterns. A diary form may
provide detailed information of the actual seizure but can be difficult to interpret over
time. Plotting the information in a linear format allows for easier pattern recognition.
Anti-Seizure Medication History
Our selection of anti-seizure medications is limited in veterinary patients. There are only
a few “tools in the toolbox”, therefore it is essential to know what experience, if any, the
patient has had with anti-seizure medications. If negative side effects prevented the
continued use of a medication, it should be failed and removed from the management
array (i.e. the toolbox). Knowing which medication the patient has failed is made easier
by following the rule: “treat to effect or to side effect”. If a medication is failed there is no
need to revisit it. A common mistake in treatment is the premature failure of a drug,
either due to perceived ineffectiveness (usually at sub-therapeutic doses) or intolerance
of often temporary side effects. If the clinician is going to fail a medication, they need to
be certain it will not be revisited in the future. Avoiding the “see-saw” effect of
medicating is best done through the use of one medication at a time. There is no way to
predict which medication may work or not, which medication may create intolerable side
effects or which medication(s) may be a complete success. Choosing an anti-seizure
medication is like picking an antibiotic, when you do not know what the source of the
infection is. You hope to choose a drug with broad-spectrum activity and minimal side
effects. Knowing which medications the patient has been on in the past, why they are
not on them now, or what side effects they experienced, may help piece together a
more appropriate management plan. For example, if I suggest phenobarbital to a client
and they mention, intolerable side effects such as sedation, polydipsia and polyphagia, I
will then ask when those side effects occurred. Since the side effects of phenobarbital
often resolve within a few weeks of beginning treatment, it may be a medication, which
can be revisited, if in fact the medication was discontinued prematurely. Specific
questions, which should be answered include:
•
•
•
•
•
A complete list of any medications tried, the maximum doses, the length of time
on each medication and any combination with other medications.
Any negative side effects associated with a particular medication or combination
of medications.
Any benefits of any medication or combination of medications. This should
include reduced frequency or intensity of seizures, as well as, reduction of side
effects.
If any drug was discontinued, why was it discontinued?
Any other modalities used to treat epilepsy (integrative medicine, diet changes
etc.)?
Question the owner about lifestyle. Are they able to monitor the pet? Are they able to
give a medication every 12 hours? What about every 8 hours? Knowing a little about the
client’s lifestyle may help the clinician formulate a therapy plan. For example, a person
who works 8-10 hours a day may not be able to dose levetiracetam every 8 hours to
their toy poodle. In this situation, zonisamide might be a better choice simply because of
dose schedule. As veterinarians we often run in to the economic realities of diagnosis
and treatment of disease. A client’s financial ability to diagnose or treat the condition
may warrant which medication is considered, how aggressive to be with medication
choices and which diagnostic tests have the best cost/benefit ratio. Oftentimes, antiseizure medications are discontinued prematurely either due to perceived toxic side
effects, worry or suspicion of potential toxic effects. The veterinarian needs to be a
source of empathy, as well as factual knowledge regarding the use of anti-seizure
medications, progression of disease, treatment and prognosis. Many side effects will
resolve spontaneously with time or slight alterations in dose, while still maintaining
adequate seizure control.
Taking an active role in the management of your patient's epilepsy can be facilitated
and enhanced through the use of a tracking program. This strengthens the triangular
relationship between pet owner, veterinarian and specialist.
REFERENCES
Aguirre, Geoffrey K., Komáromy, András M., Cideciyan, Artur V., Brainard, David H., Aleman, Tomas S.,
Roman, Alejandro J., Avants, Brian B., Gee, James C., Korczykowski, Marc., Hauswirth, William
W., Acland, Gregory M., Aguirre, Gustavo D., and Jacobson, Samuel G. 2007. Canine and
Human Visual Cortex Intact and Responsive Despite Early Retinal Blindness from RPE65
Mutation. PLoS Medicine. 4(6):e230.
Bach, Jan-Peter., Lüpke, Matthias., Dziallas, Peter., Wefstaedt, Patrick., Uppenkamp, Stefan., Seifert,
Hermann., and Nolte, Ingo. 2013. Functional Magnetic Resonance Imaging of the Ascending
Stages of the Auditory System in Dogs. BMC Veterinary Research. 9(1):210.
Bagley, R S., Harrington, M L., and Moore, M P. 1996. Surgical Treatments for Seizure. Adaptability for
Dogs. The Veterinary Clinics of North America. Small Animal Practice. 26(4):827–842.
Berendt, M., Høgenhaven, H., Flagstad, A., and Dam, M. 1999. Electroencephalography in Dogs with
Epilepsy: Similarities Between Human and Canine Findings. Acta Neurologica Scandinavica.
99(5):276–283.
Berg, Anne T., Berkovic, Samuel F., Brodie, Martin J., Buchhalter, Jeffrey., Cross, J Helen., van Emde
Boas, Walter., Engel, Jerome., French, Jacqueline., Glauser, Tracy A., Mathern, Gary W., Moshé,
Solomon L., Nordli, Douglas., Plouin, Perrine., and Scheffer, Ingrid E. 2010. Revised Terminology
and Concepts for Organization of Seizures and Epilepsies: Report of the ILAE Commission on
Classification and Terminology, 2005-2009. Epilepsia. 51(4):676–685.
Berns, Gregory S., Brooks, Andrew M., and Spivak, Mark. 2012. Functional MRI in Awake Unrestrained
Dogs. PloS One. 7(5):e38027.
Blume, W T., Lüders, H O., Mizrahi, E., Tassinari, C., van Emde Boas, W., and Engel, J, Jr. 2001.
Glossary of Descriptive Terminology for Ictal Semiology: Report of the ILAE Task Force on
Classification and Terminology. Epilepsia. 42(9):1212–1218.
Bragin, Anatol., Wilson, Charles L., Almajano, Joyel., Mody, Istvan., and Engel, Jerome, Jr. 2004. Highfrequency Oscillations After Status Epilepticus: Epileptogenesis and Seizure Genesis. Epilepsia.
45(9):1017–1023.
Brauer, Christina., Kästner, Sabine B R., Rohn, Karl., Schenk, Henning C., Tünsmeyer, Julia., and Tipold,
Andrea. 2012. Electroencephalographic Recordings in Dogs Suffering from Idiopathic and
Symptomatic Epilepsy: Diagnostic Value of Interictal Short Time EEG Protocols Supplemented by
Two Activation Techniques. Veterinary Journal (London, England: 1997). 193(1):185–192.
Brown, Trecia A., Joanisse, Marc F., Gati, Joseph S., Hughes, Sarah M., Nixon, Pam L., Menon, Ravi S.,
and Lomber, Stephen G. 2013. Characterization of the Blood-oxygen Level-dependent (BOLD)
Response in Cat Auditory Cortex Using High-field fMRI. NeuroImage. 64:458–465.
Bush, WW., Garcia, GA., Weaver, CE., Young, MG., Cuff, DE., Williams, D C., and Stecker, MM. 2013.
Electroencephalography and Clinical Findings in 37 Dogs and 4 Cats. In Proceedings of the
American College of Veterinary Internal Medicine 31st Annual Veterinary Medical Forum. Seattle,
Wa.
Carson, Monica J., Doose, Jonathan M., Melchior, Benoit., Schmid, Christoph D., and Ploix, Corinne C.
2006. CNS Immune Privilege: Hiding in Plain Sight. Immunological Reviews. 213:48–65.
Casey, Joseph R., Grinstein, Sergio., and Orlowski, John. 2010. Sensors and Regulators of Intracellular
pH. Nature Reviews. Molecular Cell Biology. 11(1):50–61.
Coles, Lisa D., Patterson, Edward E., Sheffield, W Douglas., Mavoori, Jaideep., Higgins, Jason., Michael,
Bland., Leyde, Kent., Cloyd, James C., Litt, Brian., Vite, Charles., and Worrell, Gregory A. 2013.
Feasibility Study of a Caregiver Seizure Alert System in Canine Epilepsy. Epilepsy Research.
106(3):456–460.
Cornell-Bell, A H., Finkbeiner, S M., Cooper, M S., and Smith, S J. 1990. Glutamate Induces Calcium
Waves in Cultured Astrocytes: Long-range Glial Signaling. Science (New York, N.Y.).
247(4941):470–473.
Cuff, Daniel E., Bush, William W., Stecker, Mark M., and Williams, D Colette. 2014. Use of Continuous
Electroencephalography for Diagnosis and Monitoring of Treatment of Nonconvulsive Status
Epilepticus in a Cat. Journal of the American Veterinary Medical Association. 244(6):708–714.
Davis, Kathryn A., Sturges, Beverly K., Vite, Charles H., Ruedebusch, Vanessa., Worrell, Gregory.,
Gardner, Andrew B., Leyde, Kent., Sheffield, W Douglas., and Litt, Brian. 2011. A Novel
Implanted Device to Wirelessly Record and Analyze Continuous Intracranial Canine EEG.
Epilepsy Research. 96(1–2):116–122.
de Lahunta, Alexander., and Glass, Eric. 2009. Veterinary Neuroanatomy and Clinical Neurology. St.
Louis, Mo.: Saunders Elsevier. http://www.sciencedirect.com/science/book/9780721667065.
Engel, J, Jr. 1996. Introduction to Temporal Lobe Epilepsy. Epilepsy Research. 26(1):141–150.
Engel, J, Jr. 2001. Intractable Epilepsy: Definition and Neurobiology. Epilepsia. 42 Suppl 6:3.
Engel, Jerome, Jr., and Wiebe, Samuel. 2012. Who Is a Surgical Candidate? Handbook of Clinical
Neurology. 108:821–828.
Engel, Jerome. 2013. Seizures and Epilepsy. New York: Oxford University Press.
Faingold, Carl L. 2012. Brainstem Networks: Reticulo-Cortical Synchronization in Generalized Convulsive
Seizures. In Jasper’s Basic Mechanisms of the Epilepsies., edited by Jeffrey L Noebels, Massimo
Avoli, Michael A Rogawski, Richard W Olsen, and Antonio V Delgado-Escueta. 4th ed. Bethesda
(MD): National Center for Biotechnology Information (US).
http://www.ncbi.nlm.nih.gov/books/NBK98187/.
Fatzer, R., Gandini, G., Jaggy, A., Doherr, M., and Vandevelde, M. 2000. Necrosis of Hippocampus and
Piriform Lobe in 38 Domestic Cats with Seizures: a Retrospective Study on Clinical and
Pathologic Findings. Journal of Veterinary Internal Medicine / American College of Veterinary
Internal Medicine. 14(1):100–104.
Firosh Khan, S., Ashalatha, R., Thomas, S V., and Sarma, P S. 2005. Emergent EEG Is Helpful in
Neurology Critical Care Practice. Clinical Neurophysiology: Official Journal of the International
Federation of Clinical Neurophysiology. 116(10):2454–2459.
Fisher, Robert S., van Emde Boas, Walter., Blume, Warren., Elger, Christian., Genton, Pierre., Lee,
Phillip., and Engel, Jerome, Jr. 2005. Epileptic Seizures and Epilepsy: Definitions Proposed by
the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE).
Epilepsia. 46(4):470–472.
Frost, J D, Jr., Kellaway, P., Hrachovy, R A., Glaze, D G., and Mizrahi, E M. 1986. Changes in Epileptic
Spike Configuration Associated with Attainment of Seizure Control. Annals of Neurology.
20(6):723–726.
Gloor, P., Quesney, L F., and Zumstein, H. 1977. Pathophysiology of Generalized Penicillin Epilepsy in
the Cat: The Role of Cortical and Subcortical Structures. II. Topical Application of Penicillin to the
Cerebral Cortex and to Subcortical Structures. Electroencephalography and Clinical
Neurophysiology. 43(1):79–94.
Goddard, G V., McIntyre, D C., and Leech, C K. 1969. A Permanent Change in Brain Function Resulting
from Daily Electrical Stimulation. Experimental Neurology. 25(3):295–330.
Gotman, Jean. 2008. Epileptic Networks Studied with EEG-fMRI. Epilepsia. 49 Suppl 3:42–51.
Graber, Kevin D., and Fisher, Robert S. 2012. Deep Brain Stimulation for Epilepsy: Animal Models. In
Jasper’s Basic Mechanisms of the Epilepsies., edited by Jeffrey L Noebels, Massimo Avoli,
Michael A Rogawski, Richard W Olsen, and Antonio V Delgado-Escueta. 4th ed. Bethesda (MD):
National Center for Biotechnology Information (US).
http://www.ncbi.nlm.nih.gov/books/NBK98160/.
Grillner, Sten., and Jessell, Thomas M. 2009. Measured Motion: Searching for Simplicity in Spinal
Locomotor Networks. Current Opinion in Neurobiology. 19(6):572–586.
Guthrie, P B., Knappenberger, J., Segal, M., Bennett, M V., Charles, A C., and Kater, S B. 1999. ATP
Released from Astrocytes Mediates Glial Calcium Waves. The Journal of Neuroscience: The
Official Journal of the Society for Neuroscience. 19(2):520–528.
Hassinger, T D., Guthrie, P B., Atkinson, P B., Bennett, M V., and Kater, S B. 1996. An Extracellular
Signaling Component in Propagation of Astrocytic Calcium Waves. Proceedings of the National
Academy of Sciences of the United States of America. 93(23):13268–13273.
Haydon, P G. 2001. GLIA: Listening and Talking to the Synapse. Nature Reviews. Neuroscience.
2(3):185–193.
Holliday, T A., Cunningham, J G., and Gutnick, M J. 1970. Comparative Clinical and
Electroencephalographic Studies of Canine Epilepsy. Epilepsia. 11(3):281–292.
Hormuzdi, Sheriar G., Filippov, Mikhail A., Mitropoulou, Georgia., Monyer, Hannah., and Bruzzone,
Roberto. 2004. Electrical Synapses: a Dynamic Signaling System That Shapes the Activity of
Neuronal Networks. Biochimica Et Biophysica Acta. 1662(1–2):113–137.
Jaggy, A., and Bernardini, M. 1998. Idiopathic Epilepsy in 125 Dogs: a Long-term Study. Clinical and
Electroencephalographic Findings. The Journal of Small Animal Practice. 39(1):23–29.
Jessen, Kristjan R. 2004. Glial Cells. The International Journal of Biochemistry & Cell Biology.
36(10):1861–1867.
Kaneko, Y., Wada, JA., and Kimura, H. Is the Amygdaloid Neuron Necessary for Amygdaloid Kindling? In
Kindling 2., edited by Juhn A Wada, 249–264. New York: Raven Press, n.d.
Krakow, K., Woermann, F G., Symms, M R., Allen, P J., Lemieux, L., Barker, G J., Duncan, J S., and
Fish, D R. 1999. EEG-triggered Functional MRI of Interictal Epileptiform Activity in Patients with
Partial Seizures. Brain: a Journal of Neurology. 122 ( Pt 9):1679–1688.
Kube, Stephanie A., Vernau, Karen M., and LeCouteur, Richard A. 2006. Dyskinesia Associated with Oral
Phenobarbital Administration in a Dog. Journal of Veterinary Internal Medicine / American College
of Veterinary Internal Medicine. 20(5):1238–1240.
Lehnertz, Klaus., Mormann, Florian., Osterhage, Hannes., Müller, Andy., Prusseit, Jens., Chernihovskyi,
Anton., Staniek, Matthäus., Krug, Dieter., Bialonski, Stephan., and Elger, Christian E. 2007.
State-of-the-art of Seizure Prediction. Journal of Clinical Neurophysiology: Official Publication of
the American Electroencephalographic Society. 24(2):147–153.
Majores, Michael., Schoch, Susanne., Lie, Ailing., and Becker, Albert J. 2007. Molecular Neuropathology
of Temporal Lobe Epilepsy: Complementary Approaches in Animal Models and Human Disease
Tissue. Epilepsia. 48 Suppl 2:4–12.
McCarthy, Richard J., O’Connor, Michael J., and Sperling, Micahel R. 1997. The Mirror Focus
Phenomenon and Secondary Epileptogenesis in Human Epilepsy. Journal of Epilepsy. 10(2):78–
85.
McIntyre, D C., Nathanson, D., and Edson, N. 1982. A New Model of Partial Status Epilepticus Based on
Kindling. Brain Research. 250(1):53–63.
Moeller, F., Tyvaert, L., Nguyen, D K., LeVan, P., Bouthillier, A., Kobayashi, E., Tampieri, D., Dubeau, F.,
and Gotman, J. 2009. EEG-fMRI: Adding to Standard Evaluations of Patients with Nonlesional
Frontal Lobe Epilepsy. Neurology. 73(23):2023–2030.
Moeller, Friederike., Stephani, Ulrich., and Siniatchkin, Michael. 2013. Simultaneous EEG and fMRI
Recordings (EEG-fMRI) in Children with Epilepsy. Epilepsia. 54(6):971–982.
Nuwer, M R. 1988. Frequency Analysis and Topographic Mapping of EEG and Evoked Potentials in
Epilepsy. Electroencephalography and Clinical Neurophysiology. 69(2):118–126.
Pakozdy, Akos., Glantschnigg, Ursula., Leschnik, Michael., Hechinger, Harald., Moloney, Teresa., Lang,
Bethan., Halasz, Peter., and Vincent, Angela. 2014. EEG-confirmed Epileptic Activity in a Cat with
VGKC-complex/LGI1 Antibody-associated Limbic Encephalitis. Epileptic Disorders: International
Epilepsy Journal with Videotape. 16(1):116–120.
Pakozdy, Akos., Thalhammer, Johan., Leschnik, Michael., and Halasz, Peter. 2012.
Electroencephalographic Examination of Epileptic Dogs Under Propofol Restraint. Acta
Veterinaria Hungarica. 60(3):309–324.
Parisi, Pasquale., Verrotti, Alberto., Paolino, Maria Chiara., Castaldo, Rosa., Ianniello, Filomena., Ferretti,
Alessandro., Chiarelli, Francesco., and Villa, Maria Pia. 2011. “Electro-clinical Syndromes” with
Onset in Paediatric Age: The Highlights of the clinical-EEG, Genetic and Therapeutic Advances.
Italian Journal of Pediatrics. 37:58.
Parker, A J., and Cunningham, J G. 1971. Successful Surgical Removal of an Epileptogenic Focus in a
Dog. The Journal of Small Animal Practice. 12(9):513–521.
Penfiled, Wilder., and Jasper, Herbert. 1954. Epilepsy and the Functional Anatomy of the Human Brain.
First. Little, Brown and Co., n.d.
Penning, V A., Connolly, D J., Gajanayake, I., McMahon, L A., Luis Fuentes, V., Chandler, K E., and Volk,
H A. 2009. Seizure-like Episodes in 3 Cats with Intermittent High-grade Atrioventricular
Dysfunction. Journal of Veterinary Internal Medicine / American College of Veterinary Internal
Medicine. 23(1):200–205.
Perez Velazquez, J L., and Carlen, P L. 2000. Gap Junctions, Synchrony and Seizures. Trends in
Neurosciences. 23(2):68–74.
Perez-Velazquez, J L., Valiante, T A., and Carlen, P L. 1994. Modulation of Gap Junctional Mechanisms
During Calcium-free Induced Field Burst Activity: a Possible Role for Electrotonic Coupling in
Epileptogenesis. The Journal of Neuroscience: The Official Journal of the Society for
Neuroscience. 14(7):4308–4317.
Poma, Roberto., Ochi, Ayako., and Cortez, Miguel A. 2010. Absence Seizures with Myoclonic Features in
a Juvenile Chihuahua Dog. Epileptic Disorders: International Epilepsy Journal with Videotape.
12(2):138–141.
Raith, Karina., Steinberg, Tanja., and Fischer, Andrea. 2010. Continuous Electroencephalographic
Monitoring of Status Epilepticus in Dogs and Cats: 10 Patients (2004-2005). Journal of Veterinary
Emergency and Critical Care (San Antonio, Tex.: 2001). 20(4):446–455.
Roper, S N., Obenaus, A., and Dudek, F E. 1993. Increased Propensity for Nonsynaptic Epileptiform
Activity in Immature Rat Hippocampus and Dentate Gyrus. Journal of Neurophysiology.
70(2):857–862.
Rossetti, Andrea O., Reichhart, Marc D., Schaller, Marie-Denise., Despland, Paul-André., and
Bogousslavsky, Julien. 2004. Propofol Treatment of Refractory Status Epilepticus: a Study of 31
Episodes. Epilepsia. 45(7):757–763.
Ruusuvuori, Eva., Kirilkin, Ilya., Pandya, Nikhil., and Kaila, Kai. 2010. Spontaneous Network Events
Driven by Depolarizing GABA Action in Neonatal Hippocampal Slices Are Not Attributable to
Deficient Mitochondrial Energy Metabolism. The Journal of Neuroscience: The Official Journal of
the Society for Neuroscience. 30(46):15638–15642.
Scozzafava, James., Hussain, Muhammad S., Brindley, Peter G., Jacka, Michael J., and Gross, Donald
W. 2010. The Role of the Standard 20 Minute EEG Recording in the Comatose Patient. Journal of
Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia. 17(1):64–68.
Sefil, Fatih., Bagirici, Faruk., Acar, M Dilek., and Marangoz, Cafer. 2012. Influence of Carbenoxolone on
the Anticonvulsant Efficacy of Phenytoin in Pentylenetetrazole Kindled Rats. Acta Neurobiologiae
Experimentalis. 72(2):177–184.
Seneviratne, Udaya., Cook, Mark., and D’Souza, Wendyl. 2012. The Electroencephalogram of Idiopathic
Generalized Epilepsy. Epilepsia. 53(2):234–248.
Silverman, David., and Lindskog, Sven. 1988. The Catalytic Mechanisms of Carbonic Anydrase:
Implications of a Rate-Limiting Proteolysis of Water. Acc. Chem. Res. 21:30–36.
Spencer, S S., Spencer, D D., Glaser, G H., Williamson, P D., and Mattson, R H. 1984. More Intense
Focal Seizure Types After Callosal Section: The Role of Inhibition. Annals of Neurology.
16(6):686–693.
Srenk, P., and Jaggy, A. 1996. Interictal Electroencephalographic Findings in a Family of Golden
Retrievers with Idiopathic Epilepsy. The Journal of Small Animal Practice. 37(7):317–321.
Stamatakis, Michail., and Mantzaris, Nikos V. 2007. Astrocyte Signaling in the Presence of Spatial
Inhomogeneities. Chaos (Woodbury, N.Y.). 17(3):033123.
Traub, R D., Whittington, M A., Buhl, E H., LeBeau, F E., Bibbig, A., Boyd, S., Cross, H., and Baldeweg,
T. 2001. A Possible Role for Gap Junctions in Generation of Very Fast EEG Oscillations
Preceding the Onset of, and Perhaps Initiating, Seizures. Epilepsia. 42(2):153–170.
Trevelyan, Andrew J., and Schevon, Catherine A. 2013. How Inhibition Influences Seizure Propagation.
Neuropharmacology. 69:45–54.
White, J A., Chow, C C., Ritt, J., Soto-Treviño, C., and Kopell, N. 1998. Synchronization and Oscillatory
Dynamics in Heterogeneous, Mutually Inhibited Neurons. Journal of Computational
Neuroscience. 5(1):5–16.
Willis, C K., Quinn, R P., McDonell, W M., Gati, J., Partlow, G., and Vilis, T. Jul 2001a. Functional MRI
Activity in the Thalamus and Occipital Cortex of Anesthetized Dogs Induced by Monocular and
Binocular Stimulation. Canadian Journal of Veterinary Research = Revue Canadienne De
Recherche Vétérinaire. 65(3):188–195.
Willis, C K., Quinn, R P., McDonell, W M., Gati, J., Parent, J., and Nicolle, D. 2001b. Functional MRI as a
Tool to Assess Vision in Dogs: The Optimal Anesthetic. Veterinary Ophthalmology. 4(4):243–253.
Zijlmans, Maeike., Huiskamp, Geertjan., Hersevoort, Maaike., Seppenwoolde, Jan-Henry., van Huffelen,
Alexander C., and Leijten, Frans S S. 2007. EEG-fMRI in the Preoperative Work-up for Epilepsy
Surgery. Brain: a Journal of Neurology. 130(Pt 9):2343–2353.
Zijlmans, Maeike., Jiruska, Premysl., Zelmann, Rina., Leijten, Frans S S., Jefferys, John G R., and
Gotman, Jean. 2012. High-frequency Oscillations as a New Biomarker in Epilepsy. Annals of
Neurology. 71(2):169–178.
Notes
Round cell tumor cytology for the general practitioner
Seung Yoo, MS, MBA, DVM, DACVP (Clinical)
Seattle Veterinary Specialists
Kirkland, WA
Introduction
Cytologic evaluation in veterinary medicine is inexpensive, provides rapid results,
requires minimal anesthesia or sedation, and is of minimal risk to the patient. Utilized
appropriately, cytology can be an important diagnostic cornerstone in many veterinary
practices, often guiding diagnostics and treatment plans, and may provide definitive
diagnoses. While cytologic samples are increasingly submitted to clinical pathologists at
diagnostic laboratories, it is the author’s opinion that all samples should be evaluated
first by the primary practitioner. Some potential interferences to effective cytologic
sampling and examination include poor cellularity or sample preparation, inexperience,
misinterpretation, and incomplete evaluation. With experience and technique, the astute
practitioner can become adept at diagnosing some common lesions on-site while
ensuring an adequate and diagnostic quality sample for potential evaluation by a trained
pathologist. This assists in minimizing preanalytical errors and enables a more efficient
path to guiding therapy and diagnostics. A useful approach to the cytologic evaluation of
cells is given in Figure 1.
There are seven neoplasms with a discrete or round cell appearance that can be
definitively diagnosed using cytology. While the tissue of origin for these neoplasms can
be quite variable, the cells arising from these neoplasms often have a general
characteristic cytologic appearance. These neoplasms often lack or demonstrate weak
cell to cell binding, exfoliate readily, and are often highly cellular thus making them ideal
candidates for cytologic evaluation. While many of these tumors are hematopoietic in
origin, the terms ‘round’ or ‘discrete’ are only used to describe a cytomorphologic
appearance and does not imply specific tissue histogenesis.
Histiocytomas
Canine histiocytomas originate from the Langerhans cell of the epidermis, a type of
dendritic cell. These are benign tumors that often resolve within several weeks. They
are reported to occur commonly in young dogs but this tumor can occur in dogs of all
ages. Grossly, these tumors appear as solitary, red, raised, alopecic and occasionally
ulcerated masses. Cytologically, cells have round to indented nuclei with fine chromatin
and indistinct nucleoli. Multinucleated cells are occasionally present and mitotic figures
may be common. Cells exhibit minimal anisocytosis and anisokaryosis. The cytoplasm
is abundant and clear to lightly basophilic with occasionally indistinct cell borders.
A variable number of small well-differentiated lymphocytes and plasma cells are
common in regressing lesions. The clinical importance of this neoplasm is recognizing
what it is not, as other round cell tumors, especially plasma cell tumors, can display a
similar cytologic appearance.
Histiocytic sarcoma
Histiocytes are a broad category of cells that include Langerhan’s cells and dendritic
cells of various tissues. From this cell lineage, various categories of disease exist and
range from benign (e.g. histiocytoma) to extremely aggressive (e.g. histiocytic sarcoma).
Just as normal histiocytes can demonstrate a broad variety of biologic behavior, it
should not be too surprising that proliferative diseases from this cell lineage can
demonstrate a broad variety of clinical presentations. Other diseases involving
histiocytes include cutaneous histiocytosis, systemic histiocytosis, malignant
histiocytosis, dendritic cell leukemia and feline progressive histiocytosis. A useful
approach to consideration of these diseases is that they fall under a continuum of
dysfunctional immunologic interactions and can vary greatly in both progression and
clinical presentation. The cytologic distinction between many of these diseases is often
difficult, if not impossible; therefore this discussion is beyond the scope of these
proceedings.
Histiocytic sarcomas are uncommon neoplasms that occur with higher incidence in
Bernese Mountain dogs, Flat Coated Retrievers, Rottweilers, and Golden Retrievers.
Several clinical entities have been described and include localized histiocytic sarcoma,
disseminated histiocytic sarcoma, malignant histiocytosis, and periarticular histiocytic
sarcoma. For the purposes of this discussion, these entities will be considered as
progression of the broad category of histiocytic sarcoma, as the cytologic features are
similar.
Histiocytic sarcomas occur most commonly in spleen, lung, bone marrow, lymph nodes,
skin, central nervous system, and within the periarticular and articular tissue of limbs.
Depending upon the tissue involved, the lesions may occur as discrete or multifocal
masses, and may occasionally cause diffuse organ enlargement without displaying a
distinct mass effect lesion. The cells may present as discrete round cells with distinct
cell borders or display a spindloid mesenchymal appearance with indistinct cell borders.
Nuclei are round to clefted and contain coarse to clumped chromatin with one to several
indistinct nucleoli. Cytoplasm is typically abundant, basophilic, and often contains few
to moderate numbers of clear vacuoles. Cells are frequently pleomorphic, with
occasional giant multinucleate cells and frequent atypical mitotic figures. Marked
anisokaryosis and anisocytosis are often observed. Evidence of cytophagia is
occasionally observed but is not characteristic except in the hemophagocytic form of
histiocytic sarcoma. For equivocal cytologic findings, immunochemical stains such as
CD1a, CD3, CD4, CD5, and CD18 can help differentiate histiocytic sarcomas from other
discrete cell neoplasms.
Lymphoma
Lymphoma can arise within any tissue of the body that contains lymphoid tissue and
can demonstrate a clinical presentation that may vary dramatically. Lymphoma can be
solitary or generalized, occur as mass-like lesions or demonstrate diffuse or multifocal
involvement, and even demonstrate a slow, indolent behavior. Cells are monomorphic
and recapitulate the morphology of the lymphocyte; cells are round and contain a round,
finely stippled nucleus with scant and pale to deeply basophilic cytoplasm. One to
several nucleoli may be present. The classic cytologic appearance is lymphoblastic
lymphoma with large lymphoblasts comprising the majority of the sample. Neutrophils
can be a useful internal ‘ruler’ to measure lymphocyte size, measuring approximately
10-12 microns in diameter. Small lymphocytes should be smaller than a neutrophil at 710 microns in diameter. Therefore, in lymphoid tissues, where small lymphocytes
predominate, a disproportionate population of large lymphocytes can offer a definitive
diagnosis of lymphoma. While cytology is the diagnostic technique of choice for the
initial diagnosis of lymphoma, occasionally lymphomas that are comprised of small
mature lymphocytes can present a diagnostic challenge to even the most seasoned
cytologist.
For these cases, with the inconvenience and expense of histopathology, additional
molecular techniques have proven valuable. The PCR for antigen receptor
rearrangement (PARR) assay is often helpful in these scenarios and can determine B or
T cell lineages, providing some prognostic utility. A negative result does not rule out
lymphoma, because the assay has an approximately 25% false negative rate in dogs
and a 35% false negative rate in cats. However a positive result is considered highly
specific and would strongly support the diagnosis of lymphoma. The advantage of this
test is that it can be performed on previously stained slides that have been evaluated
and lymphoma is clinically suspected. The disadvantage of this test is its relatively low
sensitivity (especially for cats) and its relatively limited prognostic utility.
Flow cytometry is another molecular technique that offers much more prognostic
information than PARR and thus is the technique of choice for characterizing lymphoma.
Given an appropriate sample with adequate cellularity, this technique provides very
good sensitivity and specificity for the diagnosis of lymphoma. The disadvantage of this
technique is that it requires a fluid based sample so specific, albeit uncomplicated,
preparation is necessary for analysis. This may require a separate client visit and/or
ultrasonagraphic guidance, thus making PARR a more convenient test for equivocal
samples in some situations.
Mast cell tumors
Mast cell tumors are common cutaneous neoplasms in dogs and cats but can occur in
multiple visceral organs. Grossly, masses are well demarcated and can appear as
raised, alopecic masses or flat, plaque-like lesions with occasional ulceration. They can
appear on any skin surface and are commonly reported on the head, neck, trunk, and
limbs. Samples are typically highly cellular with many discrete cells appearing
individually or in small loose aggregates. Cells are typically heavily granulated with
many metachromatic granules. In dogs, these tumors may be associated with few to
moderate numbers of eosinophils. This does not appear to be the case in cats. Samples
may also contain collagen, fibroblasts, and variable numbers of neutrophils and/or
lymphocytes. In a small percentage of mast cell tumors, water based quick stains
occasionally will fail to stain mast cell granules. If a mast cell tumor is suspected,
Wright’s or Giemsa based stains will often stain the mast cell granules that failed to
stain with the quick stain but this must be performed on previously unstained slides.
Occasionally, mast cell tumors will be pleomorphic with considerable variation in cell
and nuclear size and contain more than one nuclei. These tumors tend to contain no or
few metachromatic granules, thus making interpretation difficult. While this cytologic
appearance may be associated with a more aggressive biologic behavior, it is important
to recognize that complete mast cell tumor grading requires evaluation of mitotic index
and tissue architecture. Thus with these tumors, histopathology is always
recommended.
Melanoma
Melanomas are common canine cutaneous tumors, most which are benign. However,
melanomas that occur on mucocutaneous junctions, within the oral cavity, or nail bed
are associated with a more aggressive behavior. Cells often contain an abundant
amount of melanin pigment that can appear green-blue to brown-black or gray. This is
the single most useful aid in diagnosis. Consequently, poorly pigmented melanomas
can be especially difficult to diagnose. Often designated the great pretender, these cells
can display a variety of cytologic appearances, ranging from discrete to mesenchymal to
epithelial, sometimes within the same sample. This pleomorphic behavior may assist
the observant cytologist in interpretation of undifferentiated melanomas. Poorly
pigmented neoplasms may appear as a discrete cell that often appears in small
aggregates with indistinct cell borders and moderately abundant cytoplasm. The
nucleus is coarsely stippled and may contain a very large single nucleolus. Most poorly
pigmented melanomas have rare to few cells that contain a scant dusting of pigmented
granules thus necessitating a very thorough evaluation of all cells at high oil
magnification.
Plasmacytoma
Plasmacytomas commonly occur on the skin and oral cavity. These tumor cells
classically contain an eccentric nucleus that displays a clumped ‘wagon wheel’
appearance and a deeply basophilic cytoplasm. Perinuclear clear Golgi zones are
common as are binucleate and trinucleate cells. These cells can occasionally be quite
pleomorphic with overlapping characteristics with other discrete cell tumors. While most
cutaneous plasmacytomas are benign with a low rate of metastasis, occasional
aggressive behavior can occur with local recurrence.
Distinct from extramedullary plasmacytomas, solitary osseous plasmacytomas are
rarely clinically diagnosed and occur on the vertebra, zygomatic arch, and ribs. Most of
these tumors are thought to progress to multiple myeloma. Multiple myeloma is a clinical
diagnosis that involves two or more of the following: monoclonal gammopathy, osteolytic
bone lesions, >10-20% of plasma cells in the bone marrow, and Bence Jones
proteinuria. In cats, some have proposed that visceral organ infiltration should be
considered one of these criteria. Most cases of multiple myeloma involve IgG or IgA or a
combination of these two. IgM, and light or heavy chain producing neoplasms are rare.
Transmissible venereal tumors
These unique neoplastic cells contain 59 chromosomes compared to the normal canine
karyotype of 78, indicating that these cells are not likely of canine origin. This tumor is
often associated with mucous membranes of the genitals and occasionally other areas
associated with sexual contact. The gross appearance of this neoplasm is multilobular
and generally poorly demarcated, often ulcerated and hemorrhagic, and frequently
associated with secondary bacterial infections. Cells are fairly uniform and contain a
round coarsely stippled nucleus with one to two distinct nucleoli. Cytoplasm is
moderately abundant and pale basophilic. Mitotic figures are common. One of the
identifying features of this tumor is moderate numbers of clear punctate cytoplasmic
vacuoles. The importance of appropriate clinical history and anatomic location cannot
be emphasized enough for any cytologic sample; this is especially vital for the proper
interpretation of this tumor.
SUGGESTED READINGS
1.
Avery, P.R., Burton, J., Bromberek, J.L., Seelig, D.M., Elmslie, R., Correa, S., Ehrhart, E.J.,
Morley, P.S., and Avery, A.C. (2014). Flow Cytometric Characterization and Clinical Outcome of
CD4+ T-Cell Lymphoma in Dogs: 67 Cases. Journal of Veterinary Internal Medicine 28, 538–546.
2. Burkhard, M.J., and Bienzle, D. (2013). Making Sense of Lymphoma Diagnostics in Small Animal
Patients. Veterinary Clinics of North America: Small Animal Practice 43, 1331–1347.
3. Cowell, R.L., Valenciano, A.C., 2013, Cowell and Tyler’s Diagnostic Cytology and Hematology of
th
the Dog and Cat, 4 ed. St. Louis, Mo: Saunders/Elsevier.
4. Moore, P.F., Rodriguez-Bertos, A., and Kass, P.H. (2012). Feline Gastrointestinal Lymphoma:
Mucosal Architecture, Immunophenotype, and Molecular Clonality. Veterinary Pathology 49, 658–
668.
5. Moore, P.F. (2014). A Review of Histiocytic Diseases of Dogs and Cats. Veterinary Pathology 51,
167–184.
6. Rao, S., Lana, S., Eickhoff, J., Marcus, E., Avery, P.R., Morley, P.S., and Avery, A.C. (2011).
Class II Major Histocompatibility Complex Expression and Cell Size Independently Predict
Survival in Canine B-Cell Lymphoma: Class II Expression Predicts Survival. Journal of Veterinary
Internal Medicine 25, 1097–1105.
7. Raskin, Rose, and Dennis J. Meyer, eds. 2010. Canine and Feline Cytology: A Color Atlas and
Interpretation Guide. 2nd ed. St. Louis, Mo: Saunders/Elsevier.
8. Seelig, D.M., Avery, P., Webb, T., Yoshimoto, J., Bromberek, J., Ehrhart, E.J., and Avery, A.C.
(2014). Canine T-Zone Lymphoma: Unique Immunophenotypic Features, Outcome, and
Population Characteristics. Journal of Veterinary Internal Medicine 28, 878–886.
9. Thalheim, L., Williams, L.E., Borst, L.B., Fogle, J.E., and Suter, S.E. (2013). Lymphoma
Immunophenotype of Dogs Determined by Immunohistochemistry, Flow Cytometry, and
Polymerase Chain Reaction for Antigen Receptor Rearrangements. Journal of Veterinary Internal
Medicine 27, 1509–1516.
10. Valli, V.E., Kass, P.H., Myint, M.S., and Scott, F. (2013). Canine Lymphomas: Association of
Classification Type, Disease Stage, Tumor Subtype, Mitotic Rate, and Treatment With Survival.
Veterinary Pathology 50, 738–748.
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Hypercalcemia in dogs: Diagnostic plan, emergency stabilization,
surgical correction, and post-operative management
Jim Perry, PhD, Diplomate ACVIM (Oncology), Diplomate AVCS
Seattle Veterinary Specialists
Kirkland, WA
Hypercalcemia is a relatively common serum chemistry abnormality in dogs. Clinical
signs associated with hypercalcemia are variable and often non-specific. If present,
clinical signs can include PU/PD, hyporexia, weakness, and gastrointestinal
abnormalities such as vomiting and ileus. Chronic hypercalcemia can lead to aberrant
tissue calcification (metastatic calcification) and an increased incidence of calcium
oxalate urolithiasis; while, severe acute elevations in calcium can result in cardiac
arrhythmias, seizures, and even death.
The three most common causes of hypercalcemia, in order of decreasing frequency in
dogs, are hypercalcemia of malignancy (humeral hypercalcemia), hypoadrenocortism
(often asymptomatic hypercalcemia), and parathyroid dependent hypercalcemia
(primary hyperparathyroidism). Hypercalcemia is also a finding in 10-15 percent of dogs
with multiple myeloma. Other less common but important causes of hypercalcemia that
should be quickly ruled out include spurious/laboratory error, vitamin D toxicosis, and
granulomatous/fungal disease.
The basic work-up for hypercalcemia should first start with a very thorough physical
exam, paying particular attention to thoracic auscultation, peripheral lymph node
palpation, evaluation of both anal sacs and evidence of bone pain. Hypercalcemia of
malignancy is the cause of hypercalcemia in >50% of cases and is often associated with
over production of PTH-related peptide (PTH-rp). T cell lymphoma, anal sac
adenocarcinoma, and thymoma represent the most common malignancies to induce
hypercalcemia. Multiple myeloma and various other tumors are also causes, with or
without elevations in PTHrp, while primary and metastatic bone tumors are very rare
causes of hypercalcemia.
The clinical work-up for hypercalcemia should be systematic. “Shotgun” approaches
often result in unnecessary tests, increased costs, and ultimately a delay in the time to a
definitive diagnosis and treatment. Understanding the basic biology underlying calcium
homeostasis provides a foundation for generating a successful diagnostic and treatment
plan. The “Disorders of Calcium” chapter in Fluid, Electrolyte, and Acid-Base Disorders
by DiBartola provides and excellent review of these pathways. This thorough knowledge
of calcium homeostasis can help rule out the majority of differential diagnoses utilizing
only minimum database diagnostics such as patient signalment, clinical history, physical
exam, and basic blood work with ionized calcium. Additional diagnostic tests should be
utilized only after the large list of differential diagnoses has been narrowed down based
on minimum database findings. In the vast majority of cases of hypercalcemia in dogs, a
definitive treatment plan can be established with as little as a physical exam, thoracic
radiographs, fine needle aspirates and occasionally measure of PTH and PTHrp paired
with ionized calcium. The latter test is performed through the Michigan State Veterinary
diagnostic laboratory. Samples obtained for iCa++/PTHrp/PTH should be taken after
fasting as lipemia can spuriously elevate iCa++.
Fortunately, the majority of causes of hypercalcemia can be treated, at least
temporarily, such that calcium concentrations return to normal during periods of
remission. In cases of primary hyperparathyroidism or humeral hypercalcemia of
malignancy, calcium concentrations often fall to normal within hours following medical
treatment or surgical removal of the inciting PTH or PTHrp source. This includes surgery
in the case of functional parathyroid adenoma, anal sac adenocarcinoma and thymoma
or initiation of chemotherapy in the case of lymphoma, leukemia and myeloma. Failure
of the calcium concentration to return to normal within 2-3 days following initiation of
treatment often indicates incomplete removal of the primary source or failure to detect
and treat functional metastases or missed diagnoses. Return of hypercalcemia after a
period of time suggest recurrent disease and can be used as a biomarker for monitoring
remission status.
In the hypercalcemic patient, it may be necessary to empirically treat the hypercalcemia
pending test results and definitive treatment of the underlying cause of the
hypercalcemia. Asymptomatic patients with a calcium:phosphorus product less than 60
often do not require interim treatment for the hypercalcemia while diagnostics and
definitive management are pending. If immediate treatment is indicated, as in cases with
significant clinical signs, marked Ca:P elevations, or total calcium >18mg/dL, the initial
therapy for hypercalcemia is often non-specific. The most effective and least invasive
initial treatment for hypercalcemia is fluid diuresis. In most cases of hypercalcemia,
simple fluid diuresis can decrease serum calcium to temporarily safe concentrations to
alleviate clinical signs while diagnostics are pursued. Administration of isotonic fluids
such as 0.9% NaCl, Norm-R or Plasmalyte, (even LRS which contains a small amount
of calcium) can be administered at 100-125mL/kg/day. Furosemide at a dose of 24mg/kg IV BID to TID can be added once volume expansion with crystaloids has been
performed and continued until definitive treatment can occur. Electrolytes should be
monitored closely during heavy diuresis, especially with 0.9% NaCl to monitor for
potential hypernatremia or other electrolyte aberrations. Additional medications such as
bisphosphonates, corticosteroids and calcitonin, as discussed later, are often
unnecessary in the initial treatment of hypercalcemia and are reserved for cases in
which the underlying cause of the hypercalcemia cannot be corrected by surgical or
chemotherapeutic means. Steroids in particular should be withheld until a definitive
diagnosis is obtained as these drugs can alter the ability to obtain a diagnosis in some
malignancies (i.e. lymphoma, myeloma and some leukemias). The goal of initial
empirical therapy should not be focused on normalizing the calcium but rather
decreasing the severity of hypercalcemia until a definitive diagnosis and therapeutic
plan can be established.
Once the underlying cause of hypercalcemia is identified and treated, monitoring of
serum calcium concentrations should be performed in the peri-treatment setting with or
without exogenous calcitriol and calcium. As stated above, a rapid normalization of
calcium following treatment should be used to assess completeness of remission
following surgery or initiation of chemotherapy. Induction of a hypocalcemic state can
occur and treatment of such occurrences should be initiated before significant sequelae
result from the hypocalcemia. In the case of PTHrp related disorders, which rarely show
post treatment hypocalcemia, iCa++ or total calcium concentrations (whichever is
available to the clinician) should be measured immediately post-treatment then every
12-24 hours until a plateau is reached (often 1-2 days after surgery or initiation of
chemotherapy). Recheck measure of calcium should then be performed every 6 weeks
in the case of anal sac adenocarcinoma or prior to each dose of chemotherapy in the
case of leukemia, lymphoma, or multiple myeloma. In contrast, serum calcium
concentration should be monitored much more closely, and in some cases longer, in the
perioperative setting following removal of a parathyroid adenoma associated with
primary hyperparathyroidism. This is the case because many of these animals will
develop significant hypocalcemia resulting in variable clinical sign such as pruritus,
tremors, weakness, seizures and occasionally death. Total calcium or iCa++
concentrations are often measured every 4-6 hours initially following surgery while
hospitalized, then once to twice daily until a plateau is reached. Unfortunately, it is
difficult to predict pre-operatively which patients will develop hypocalcemia following
parathyroid adenectomy, and therefore close monitoring is warranted in all patients
following surgery for primary hyperparathyroidism. Additionally, steady decline in
calcium concentrations can occur over a period of days to weeks in the case of primary
hypercalcemia and thus close monitoring after discharge should be included in the
patient’s discharge instructions.
Post-operative calcium and calcitriol supplementation is usually reserved for cases of
primary hyperparathyroidism or in cases where all parathyroid glands are removed (i.e.
following bilateral thyroidectomy). Rarely is such supplementation necessary following
treatment for humeral hypercalcemia of malignancy. Some authors recommended
supplementation for dogs with pre-operative total calcium concentration of >14mg/dL;
however, this “cut-off” value has come into question since several recent studies have
failed to make a correlation between pre-operative calcium concentration and incidence
of post-operative hypocalcemia. Again, calcitriol and calcium supplementation is rarely
necessary following treatment of PTHrp secreting tumors, regardless of the preoperative calcium concentration. In the author’s practice, no patient is started on
calcitriol or calcium unless hypocalcemia is noted post-op or if all 4 parathyroid glands
are removed. The goal of calcitriol and calcium therapy in cases of surgically treated
primary hyperparathyroidism is to prevent clinical hypocalcemia, while maintaining a
low-normal calcium concentration in order to promote endogenous PTH production from
the remaining parathyroid glands. In cases where all 4 parathyroid glands are removed,
life long supplementation with calcitriol and calcium is often required since as few as 6%
of dogs possess ectopic parathyroid tissue.
The recommended initial dosage of calcitriol is 20-30ng/kg/day (note: nanograms).
Additional supplementation of oral calcium carbonate is commonly combined with
calcitriol but may not be required since ample calcium is obtained from most commercial
canine diets. The most important supplement is calcitriol as this is required for the
majority of calcium absorption in the small intestine; without calcitriol, supplemented
calcium is poorly absorbed. Calcitriol is available in 0.25ug (250ng) and 0.50ug (500ng)
tablets but can also be obtained from reputable compounding pharmacies. The time to
effect can take 1-4 days, and thus frequent monitoring during the initial phases of
therapy is important. If acute clinical hypocalcemia occurs, intravenous calcium
gluconate should be utilized until the calcitriol can take effect. Calcium gluconate is
administered IV to effect while monitoring the patient’s ECG, then at 5-15mg/kg/day until
weaning is possible without recurrence of hypocalcemia.
In cases with persistent hypercalcemia and non-operable or chemoresistent PTHrp
secreting tumors, medical management with glucocorticoids, long term diuretics, and
bisphosphonates should be considered. Calcitonin, an additional option for
hypercalcemia, is relatively expensive and short acting and therefore has little clinical
utility in the chronic management of refractory hypercalcemia. Prednisone at 0.52mg/kg/day can be utilized life long for any tumor type to promote increased renal
excretion of calcium. Similarly, Lasix at 1-2mg/kg PO BID-TID can be administered long
term to further promote excretion of calcium through the kidneys. Pamidronate, which is
currently the most commonly used bisphosphonate in veterinary medicine, is
administered at 1-2mg/kg IV over 2 hours diluted in 20mL/kg NaCl q3-4 weeks to inhibit
mobilization of calcium from bone. Zolidronate, a newer generation bisphosphonate is
more potent than Pamidronate is also becoming increasingly available relatively
inexpensively. The time to effect for IV bisphosphonates is often rapid with significant
decreases in serum calcium usually occurring within 48 hours. While caution should be
used in dogs with underlying renal disease, there is little evidence showing clinically
significant nephrotoxicosis when administered at the recommended dose, administration
time, dilution, and dosing interval. Unfortunately, even with aggressive management for
hypercalcemia, many animals become refractory to all treatment modalities. While no
studies have directly assessed the success or duration of palliative medical
management with glucocorticoids, diuretics and bisphosphonates for cases of refractory
hypercalcemia, the majority of these dogs succumb to their disease within 1-3 months.
References:
Arbaugh M, Smeak, D, Monnet E. Evaluation of preoperative serum concentrations of ionized calcium and
parathyroid hormone as predictors of hypocalcemia following parathryoidectomy in dogs with primary
hyperparathyroidism: 17 cases (2001-2009). J Am Vet Med Assoc. 2012: 241(2):233-236
Hostutler RA e al. Uses and effectiveness of pamidronate disodium for treatment of dogs and cats with
hypercalcemia. J Vet Intern Med. 2005: 19(1):29-33
Tuohy JL, Worley DR, Withrow SJ. Outcome following simultaneous bilateral thyroid lobectomy for
treatment of thyroid gland carcinoma in dogs: 15 cases (1994-2010). J Am Vet Med Assoc. 2012:
241(1):95-103
Schenck PA, Chew DJ, Nagode LA, Rosol, TJ. Disorders of Calcium: Hypercalcemia and Hypocalcemia.
rd
In Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice. 3 Edition. Stephen DiBartola
Editor. Elseiver Sauders 2006 pp122-194
Seguin B, Brownlee L. Thyroid and Parathyroid Glands. In Small Animal Veterinary Surgery. Tobias and
Johnson Editors. Elseiver Sauders 2012 pp2043-2058.
Notes
What’s New With Fracture Management?
Kent J. Vince, DVM, MSpVM, DACVS-SA
Seattle Veterinary Specialists
Kirkland, WA
Bone fractures in veterinary patients can be a challenge to diagnose, treat, and return
the patient to normal function. Insufficient stabilization, lack of activity restriction,
inadequate bone purchase, poor nutrition and osteomyelitis are all issues that can lead
to fracture fixation failure.
Veterinary orthopedic companies are continuously
developing new and improved methods and implants to treat fractures.
The
development of carbon fiber external fixator rods, locking screws and plates, angle
stable interlocking nails, extracorporeal shockwave therapy, and antibiotic impregnated
pluronic gel are just a few of the newer items and methods used to treat challenging
fractures in veterinary medicine.
Brilliance in the Basics:
While many things have changed over the years in how we treat fractures, brilliance in
the basics will set you up for success when treating a fracture case. Never under
estimate the importance of a thorough physical exam when you are presented with a
patient that has sustained a traumatic injury. Is the patient ambulating on all four limbs?
What is the neurological status of the patient? Is there sensation and movement to all
of the limbs? Be sure to look “outside the prize” and fully assess all organ systems and
not just the obvious broken bone. While an animal will suffer significant pain due to the
fracture, the other injuries that they often sustain are more likely to have life damaging
effects.
All trauma patients should have baseline diagnostic tests performed to help with your
treatment plan. A complete blood count, serum chemistry and a urinalysis should be
performed to establish if the patient is suffering from any systemic issues. Good quality
orthogonal radiographs are essential in diagnosing fractures. If your patient is painful,
be sure to provide adequate pain relief and sedation to allow your staff to obtain good,
diagnostic films. Placing a measurement marker in the radiograph view at the level of
the bone in question will allow for accurate measurement calibration. This will help with
pre-operative planning on the size of implant that can be used for the fracture repair. In
some cases, such as skull, carpi and tarsi fractures, a CT scan may be useful to identify
all fractures that may not be evident with radiographs. And finally, is your patient stable
enough for anesthesia? The fracture itself probably won’t kill your patient, but the
complications from hypovolemia while under anesthesia due to the significant blood loss
probably will.
Fracture Classification:
Understanding fracture classification will allow you to better discuss a fracture case with
a colleague. When the person on the other end of the phone understands exactly what
you are describing, then advice on fracture fixation can be easily shared. An open
fracture will require surgery ASAP, while a closed fracture can potentially be repaired
within a few days. The main reason to address an open fracture is to thoroughly
decontaminate the fracture site to help minimize the chance of developing osteomyelitis.
When describing the location of the fracture, state whether it is diaphyseal,
metaphyseal, physeal, articular and what bone is fractured. Words to explain fracture
morphology and severity include: transverse, oblique, spiral, incomplete, complete,
multifragmental, extraarticular, partial articular, complete articular, impacted, avulsion.
Displacement describes the distal fragment in relation to the proximal fragment.
Treatment Goals:
The goals of fracture treatment are to provide stable fixation, ensure adequate joint
alignment and limb length, preservation of the blood supply, and early active pain free
movement of the patient. When planning your fracture repair, you must consider all of
the forces that the fixation must resist. Bending, compression and torsion are the big
three forces you must consider. Certain fixation implants resist these forces better than
others. For example, an IM pin resists bending quite well but fails to resist compression
or torsion. While an interlocking nail will counteract bending, compression and torsion.
Some fractures can heal with closed reduction, while others will require open reduction
and internal fixation. Closed reduction optimizes the biology of healing by preserving
the blood supply and providing sufficient stability for callus formation. Casts, bandages
and external fixators are considered closed reduction management. Casts and
bandages, while very useful, are often resorted to because of a lack of resources and
money. Certain fractures may not be amenable to open reduction and thus closed
reduction is the only option. Open reduction involves surgical incisions and uses
internal fixation. During surgery, the fracture site is open to the air and the fragments
are manually handled to aid in reduction. A limited or “open but do not touch” is
commonly used with comminuted fractures. The two major fracture fragments are
manipulated and implants are placed, but the smaller commented pieces are left alone.
And finally, minimally invasive plate osteosynthesis (MIPO) is more frequently used in
treating long bone fractures to minimize any disruption to the blood supply at the
fracture site. Locking plates and screws or interlocking nails are implants used with
MIPO. Small incisions at the proximal and distal ends of the fractured bone are made to
allow for insertion of the implants. Fluoroscopy is very helpful in ensuring appropriate
fracture reduction, limb alignment, and implant placement.
Options for Fixation:
There are just about as many options and devices to treat fractures, as there are types
of fractures. Options for fixation in veterinary medicine include, but are not limited to:
cast and bandages, bone plates, screws, external fixators, interlocking nails (ILN),
clamp rod internal fixation system (CRIF), lag screws, IM pins, k-wires, and cerclage
wire.
External coaptation is indicated for protecting wounds or devices, immobilizing injuries
primarily below the elbow and stifle to help reduce pain, swelling, and minimize
additional tissue damage. It is important to be aware of different types of bandages,
splints and casts and know the indications for the common types. You need to be able
to explain to a client how to care for a bandage and what to look for if a problem should
arise. Casts can be used to treat stable and minimally displaced fractures in young
animals. We often think that casting fractures will be less expensive than performing
surgery, but that isn’t always the case. Frequent bandage changes and complications
with bandages can be costly. It is imperative that owners and veterinarians examine the
pet’s bandage frequently to minimize the damage that complications can cause, such as
pressure sores. I recommend that casts and bandages used to stabilize fractures are
changed every 5-10 days depending on the age and size of the patient.
An external fixator can be a very good option for stabilizing challenging fractures. There
are several different manufacturers of external fixator systems with Securos and Imex
being two of the more common brands. The construction of a circular or hybrid fixator is
very advantageous when treating an open fracture or one where there is limited bone
stock. Epoxy fixators are a great option for small patients as the epoxy allows for
tremendous freedom with the angle of your pin placement.
The interlocking nail is a newer implant system that can be used to treat diaphyseal
fractures of the humerus, femur and tibia. They are often the only option when treating
highly comminuted long bone fractures. ILNs counteract bending, compression and
torsion very well and provide a very solid and stable construct. ILNs can be placed
through an open approach or minimally invasive with the aid of fluoroscopy.
Bone plates and screws are still the mainstay of most open reduction internal fixation of
fractures. Traditional or non-locking screws compress the plate to the bone via friction.
Locking screws maintain stability via the fixed screw head/plate interface. This creates
a very stiff and stable construct and can be used in poor bone stock. In human patients,
locking plates and screws are the implants of choice for osteoporotic bone. Locking
systems are an “internal” external fixator. They do not require exact precise contouring
and only require engagement of four cortices per segment vs. six cortices per segment
with traditional non-locking screws. The locking head enables locking screws to be
used with monocortical placement. There are numerous veterinary locking screw and
plate manufacturers with Synthes, Securos Pax, Orthomed, New Generation Devices
and Kyon as the most common.
What to do When Fractures Fail to Heal?
Fracture fixation failure is caused by instability, infection, damaged blood supply or poor
nutrition. If a fracture is failing to heal, you must thoroughly evaluate the patient to
identify the cause of failure. Are the implants too small and the patient too active to
provide adequate stability? Is the fracture gap too big for the fracture callus to form? Is
there an infection that is preventing the fracture from healing? Once you identify the
cause of failure, then you can ideally resolve the issue and allow the fracture to heal.
An infection can be a nightmare to treat for a fracture patient. Bone infections cause
inflammation, retard callus formation and healing, and form a biofilm on fixation implants
that limits antibiotics ability to clear the infection and can ultimately lead to implant
loosening and fixation failure. The mainstay of defeating osteomyelitis is to rid the
infection. Start by performing a deep aspirate culture & sensitivity and then hospitalize
the patient and place them on appropriate IV antibiotics. In the past, implantation of
antibiotic impregnated beads was common to provide a high concentration of antibiotics
at the fracture site. These beads would have to be removed 3-4 weeks after
implantation. Thankfully, we now have the ability to inject pluronic gel with antibiotics at
the fracture or osteomyelitis site. Pluronic gel is an absorbable polymer that can be a
carrier for antibiotics. The gel allows high concentrations of antibiotics to elute in the
tissues for 5-7 days. Injections can be performed weekly until the patient no longer
shows any external signs of an infection. Once the fracture has healed, implant removal
is recommended to prevent recurrence of the osteomyelitis.
A lot of research has gone into the stimulation of bone healing. Autogenous bone graft
is one way to help restart the bone healing process. When the opportunity to obtain an
autogenous bone graft is limited or you want to provide additional osteoinductive
properties to fracture, you can do so with several off-the-shelf products.
An
osteoallograft, demineralized bone powder or bone putty are all products that can be
purchased from Veterinary Transplant Services that you can place into the fracture site.
These products provide osteoinductive properties to help stimulate healing. Velosity
and Consil are both synthetic products that are osteostimulative to the fracture site.
Extracorporeal shockwave therapy (ESWT) is performed with a device that emits highenergy waves that stimulate the body’s regeneration process. ESWT is used to help
stimulate bone healing. Energy released leads to a cellular reaction that releases BMP2, eNOS, VEGF and PCNA. ESWT is performed under brief anesthesia. I recommend
performing three treatments spaced three weeks apart.
Recap:
For every fracture case that presents to your hospital, it is vital to perform a good PE,
ortho and neuro exam to ensure you have identified all injuries. Make quality orthogonal
radiographs with a measuring device in view to aid in pre-operative fracture repair
planning. Open fractures require immediate action. There are usually multiple ways to
fix a fracture. Don’t underestimate the pain relieving power of immobilization and
bandaging while waiting for surgery.
References and Recommended Reading:
Veterinary Surgery: Small Animal. Tobias & Johnston, 2nd Ed 2011.
Small Animal Orthopedics and Fracture Repair. Brinker, Piermattei & Flo, 4th Ed 2006.
www.imexvet.com
www.biomedtrix.com
www.securos.com
www.pulsevet.com
www.royerbiomedical.com
www.us.synthesvet.com
www.kyon.ch
www.vtsonline.com
www.orthomed.co.uk
http://www.ngdvet.com
Notes