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IVMA 2017 Caudal Cervical Spondylomyelopathy – did that Great Dane just wobble?! Stephanie Thomovsky, DVM, MS, DACVIM (Neurology), CCRP Clinical Assistant Professor of Neurology and Neurosurgery at Purdue University Director of Physical Rehabilitation at Purdue Caudal Cervical Spondylomyelopathy – Wobbler Disease I. Caudal cervical spondylomyelopathy (CCSM) A. Aka Wobbler’s Disease, acquired vertebral malformation/malarticulation. B. This disease is relatively common; it is definitely one you will diagnose regularly in private practice. C. The equine also suffers from Wobbler’s Disease. The equine version of the disease is referred to as cervical stenotic myelopathy. This condition shares many similarities with the canine form but there are also some differences. D. Patients with CCSM have a C6-T2 spinal cord neurolocalization, the vast majority of the time. They therefore have a proprioceptive ataxia in all four limbs, reflex deficits in the thoracic limbs and normal to hyper-reflexive pelvic limb reflexes. 1. C6-T2 SC neurolocalization review a) All 4 limbs are neurologically abnormal. The pelvic limbs being often more affected neurologically as compared to the thoracic limbs. (1) Tetraparesis (a) Paresis is often a term reserved to describe weakness in an animal secondary to neurologic disease. (b) By definition it means a partial loss of voluntary movement. The patient often has difficulty supporting weight against gravity (2) Ataxia literally means “off axis.” This is a strictly neurologic term, i.e. if you say that an animal is ataxic you are in effect saying that you think it has an abnormality within the nervous system. (a) There are three main forms of ataxia (vestibular, cerebellar and proprioceptive (b) Spinal ataxia is a type of proprioceptive ataxia. The term spinal ataxia is reserved for cases with a proprioceptive ataxia secondary to spinal cord disease. (i) Dragging or scuffing of limbs – these patients traditionally drag their feet and scuff the tops of them. They often have nail or hoof wear. (ii) There are two types of proprioceptive ataxia: upper motor neuron (UMN) and lower motor neuron (LMN). Clinically an UMN ataxia is far more common/more obvious. LMN ataxia can also be observed but usually is not as obvious. (a) UMN – long, loping stride. They look like they are over-reaching with each step. These patients look, to me, like ice skaters. (b) LMN – short, choppy stride. The LMN that innervate the limbs are not functioning appropriately, as a result, you end up with a short stride as normal limb flexion and extension is altered. (c) Two-engine gait is a type of proprioceptive ataxia. Clinically this type of ataxia is most commonly observed in CCSM patients. This gait occurs in patients with an UMN gait in the pelvic limbs (long and lopey) while a LMN gait in the thoracic limbs (short and choppy) E. There are 2 forms of this disease (refer to chart below) 1. Young dog (Stenotic form) a) 2. This form is most common in the young adult Mastiff and Great Dane Old dog (DJD) a) Most commonly affects adult black and tan dogs. b) Disc associated Wobblers is a type of old dog CCSM. This disease is most common in the Doberman Pinscher. It is the descriptive term utilized for CCSM in which a major component of compression is a protruding, type II disc. 3. The diagnosis of CCSM is made via CT/myelogram or more commonly MRI. Dynamic views are sometimes made. In the case of myelography this means taking radiographs while the head and neck are flexed, extended and distracted. Dynamic MR vies usually mean sagittal images taken in neutral, flexion and distraction. a) Dynamic views are performed to help aid in surgical planning. b) Compression of the spinal cord is observed (see chart below) on imaging. 4. Treatment options a) Medical management (1) Cage rest with controlled leash walks for 6-8 weeks to allow inflammation to decrease. (2) Pain medications are prescribed if spinal hyperesthesia is a component of the neurologic exam. (3) Steroids can be effective in these patients to both decrease inflammation. b) Surgical management (1) Many surgical options exist. Options include: ventral slot, spinal stabilization with implants, distraction with PMMA plug or artificial disc implantation, dorsal laminectomy, hemilaminectomy or a combination of any of the above procedures. (2) Surgical planning is based on imaging findings. Type of CCSM Breed Young Form Great Dane, Mastiff (< 1 yr or just about 1 yr old at presentation) Old Form Doberman, Rottweiler (middle-aged at presentation) Onset • Acute onset • Acute on chronic • Chronic progressive • Acute on chronic Pathophysiology • Osteochondrosis of caudal Cspine facet joints malarticulation/malformation • Stenosis of vertebral canal caudal to C2 • Osteochondrosis of caudal C-spine facet joints malarticulation/malformation • DJD in of caudal C-spine facet joints • IVDD type II caudal C-spine • Proliferation • Facet joint capsule+/-synovial cyst • Ligamentum flavum • Dorsal longitudinal ligament Diagnosis • • • • • • • • • Bulbous articular facets on radiographs MRI Myelography CT All imaging +/- dynamic views Treatment Controversial: conservative vs. surgery Miscellaneous May be associated with high energy MRI Myelography CT All imaging +/- dynamic views Controversial: conservative vs. surgery 2+ levels and high Ca levels in feed. References A Practical Guide to Canine and Feline Neurology. Curtis Dewey, 2 nd ed., 2008 Small Animal Spinal Disorders Diagnosis and Surgery. Nicholas Sharp and Simon Wheeler, 2 nd ed. 2005. Veterinary Clinics of North America Small Animal Practice: Spinal Disease. Ronaldo da Costa, 20 (5); 2010. rd Veterinary Neuroanatomy and Clinical Neurology. Alexander de Lahunta and Eric Glass, 3 ed., 2009. IVMA 2017 Cerebrovascular accidents in dogs – not always a stroke in the wrong direction! Stephanie Thomovsky, DVM, MS, DACVIM (Neurology), CCRP Clinical Assistant Professor of Neurology and Neurosurgery at Purdue University Director of Physical Rehabilitation at Purdue The term cerebrovascular accident (CVA) is synonymous with the more commonly used term, stroke. The definition of stroke is a sudden onset of a nonprogressive focal brain signs secondary to cerebrovascular disease. The basis of stroke is a compromise in blood supply. A thrombus or embolus can occlude the lumen of a blood vessel supplying the brain, a vessel can rupture, and underlying disease of the vessel wall can lead to leakage or the propensity for occlusion. Increased blood viscosity can also lead to a compromised blood supply. Neurologic signs are dependent on the location of the occluded vessel and the section of the brain affected by the vasculature compromise. A CVA is by definition, a stroke whose clinical signs last longer than 24 hours in duration. A stroke, the signs of which, resolve within 24 hours is referred to as a transient ischemic attack (TIA). Most human TIA’s last, on average, 1 minute. There is usually no permanent brain damage in the case of TIAs. These “mini-strokes” are considered in human medicine, the warning sign of stroke; 1/3 of humans who experience a TIA will suffer a CVA within 1 year’s time. There are two main categories of CVA: hemorrhagic and ischemic. The former is caused by rupture of a blood vessel within or on the surface of the brain, while the latter is a sequela to occlusion of a vessel. The most common type of stroke in both humans and dogs is the ischemic infarct. There are two main subcategories of ischemic stroke: territorial infarct and lacunar infarct. Territorial infarcts are those in which a large, major brain artery (rostral, middle or caudal cerebral or rostral or caudal cerebellar artery) becomes occluded. The result is ischemia to a large territory of the brain. These more commonly occur in the cerebral cortex or cerebellum. Lacunar infarcts occur secondary to occlusion of a small intraparenchymal brain artery (perforating arteries). More commonly these occur in the thalamus and midbrain. The result of a lacunar infarct is a small region of brain damage. At the cellular level, ischemia to a section of the central nervous system results in depletion of ATP and subsequent dysfunction of the sodium/potassium ATPase pump on the neuronal cell wall. Intra-neuronal sodium concentrations increase and water flows into the neuron resulting in cytotoxic edema. A depletion of oxygen and glucose secondary to ischemia results in a significant increase in extracellular glutamate levels. Glutamate is an excitatory neurotransmitter. The increase in glutamate results in increased calcium transport within the neuron via NMDA and AMPA channels. The increase in intracellular calcium sets off a chain reaction increase in intracellular xanthine oxidase, nitrous oxide, lipid peroxidation and phospholipase A2. These byproducts increase within the neuron and it depolarizes, free radicals are produced and neuron cell apoptosis is the end result. Neuronal healing can take place if oxygen and glucose delivery is reinstated. According to the United States Stroke Association, 795,000 Americans suffer a new or recurrent stroke each year and 129,000 Americans are killed each year by a CVA. Stroke is the number 5 cause of death in America. As stated previously, hemorrhagic strokes are less common than ischemic stokes in humans, with 13% of all strokes being secondary to hemorrhage. Ischemic strokes comprise 87% of all human CVA’s, the leading cause of which is atherosclerosis. Traditionally diagnosis of stroke in humans is via advanced imaging (CT scan +/- MR). Carotid ultrasounds are performed to look for a source of embolic material. Treatment for strokes is dependent on time of arrival post stroke to a hospital. If a human is treated within 3 hours, they are given intravenous tissue plasminogen activator (tPA). Interventional procedures whose goal is to break down a thrombus or embolus are performed following tPA administration. At the core of the neurologic presentation for stroke is the vascular anatomy of the brain. The most common vessel to stroke in the human is the middle cerebral artery; in the dog it is the rostral cerebellar artery. Humans, therefore, more commonly present with forebrain signs while dogs present with central vestibular/cerebellar signs. As a general rule, in both man and the canine, the basilar artery and internal carotid artery are the major vessels that supply the Circle of Willis. The Circle of Willis is a vascular ring that is located ventral to the brain and surrounds the pituitary. From this ring emanate the major cerebral and cerebellar arteries. In cats the only vessel that supplies this vascular ring is the maxillary artery. The basilar artery actually carries blood away from the circle in the cat. The rostral and middle portion of the forebrain are supplied by the internal carotid artery, while the vertebral artery (via the basilar artery) supplies the caudal forebrain and brainstem and cerebellum in both man and dogs. Strokes are thought to be more common in humans as compared to dogs as there are less anastomotic vessels involved in the arterial supply to the brain. Thus, it is easier to disrupt the blood supply to the brain with a single embolism, for example. In dogs, however, there are many more anastomoses of brain vessels whose jobs are to ensure that the brain has an adequate blood supply. In our canine patients CVA’s are diagnosed based on history, neurologic findings and also MRI characteristics. Historically the neurologic signs have an acute onset and are focal signs, neurolocalization is to one specific side and location within the brain. Progressive signs are uncommon occurring only over the first 24 hours following clot formation. Some neurologic improvement is commonly seen in the first 24-72 hours following the onset of signs. A CVA is not a good differential diagnosis for a dog with chronic progressive signs or a dog with multifocal CNS signs. Several veterinary papers suggest that strokes are most commonly diagnosed in Cavalier King Charles Spaniels and Greyhounds. Many veterinary studies would also suggest that Weimaraners may also be overrepresented. Strokes are more common in dogs that are middle aged to older; several reports indicating the median age at the time of neurologic signs to be 8 years. The size of infarct is inversely proportional to the size of the patient; dogs less than 15 kgs more commonly suffer territorial infarcts while those larger than 15 kg suffer lacunar infarcts. MRI reveals clinical evidence of stroke formation within 12-24 hours of the onset of neurologic signs. Stroke lesions typically do not cause an obvious mass effect. The observed lesion is secondary to ischemia, cytotoxic edema and malacia. Hemorrhagic strokes are best imaged with a T2* or gradient echo (GRE) MR scan. Ischemic strokes are best observed using T2-W, fluid attenuated inversion recovery (FLAIR) imaging, diffusion weighted imaging (DWI) and apparent diffusion coefficient (ADC) imaging. Contrast enhancement is observed only after 7-10 days in a typical stroke as enhancement is occurs secondary to regional reperfusion. A cerebrospinal fluid tap can also be performed but often only reveals a mild protein elevation. Following suspected stroke diagnosis on MR imaging, the next step is to determine the cause of stroke formation. Hemorrhagic strokes in dogs are often secondary to trauma. Ischemic strokes are most commonly a sequela to: chronic kidney disease, neoplasia, cardiac disease or endocrine disease such as hyperadrenocorticism, diabetes mellitus, and hypothyroidism. Hypertension can precede stroke formation. Hypertension is most commonly secondary to chronic kidney disease or hyperadrenocorticism. The veterinary literature would indicate that in only 50% of cases is the cause of stroke diagnosed at the time of MR despite extensive metabolic testing and diagnostic imaging. Metabolic testing includes: CBC, chemistry panel, urinalysis, urine protein/creatinine ratio, anti-thrombin 3 levels, test for Cushing disease (low dose dexamethasone suppression test, ACTH stimulation test or UCCR), thyroid testing (TSH/T4 or T4 by equilibrium dialysis), cardiac work-up (echocardiogram and ECG and serial blood pressure measurements). Chest and abdominal imaging is also recommended in order to look for neoplasia. Coagulation testing is also recommended including thromboelastography, platelet aggregation testing, buccal mucosal bleeding time and clotting times (PT/PTT). Treatment for CVA consists of time and physical therapy. Some neurologists also recommend the use of anti-platelet medications such as clopidogrel or low dose aspirin. At this point, there is no proof in the veterinary literature that would support the use of anti-platelet medications to prevent the recurrence of stroke in dogs. The use of tPA in canine patients is not recommended as it carries significant side effects, is expensive and because canine strokes are rarely diagnosed within 3 hours of the onset of clinical signs. The long term outcome and prognosis of canine stroke in 33 dogs was recently studied by Garosi L et al (2005). There was found to be no association between type of infarct or location of infarct and patient outcome. Concurrent medical conditions as the suspected cause of stroke were recorded in 18 of the dogs in this study, the most common conditions were chronic kidney disease and hyperadrenocorticism. A shorter survival time was observed in patients which were diagnosed with a concurrent medical condition. Dogs were followed for a minimum of 3 months post diagnosis of CVA. Twenty three dogs were reported to be alive, 16 of those dogs were described as having a good or excellent prognosis. Seven dogs were alive but reported to have a poor prognosis at a minimum of 3 months follow-up. Ten dogs were dead at the completion of the study period. Five of these dogs were euthanized because of a lack of neurologic improvement and 5 either died or were euthanized because of the severity of their concurrent medical condition. This is the first veterinary report to assess recurrence of stroke in dogs. Five dogs (15%) suffered a second infarct within 5-10 months of the first stroke event in this study. This infarct was diagnosed either via clinical suspicion or repeat brain MR. Dogs suffering recurrence were more likely to have been diagnosed with a concurrent disease at the time of the first CVA (80% of dogs). In the last 15 year there has been a huge rise in the number of peered reviewed literature in veterinary medicine regarding CVA’s. As more time goes on and the use of MR becomes more and more prevalent hopefully more outcome studies will be published with the end goal of improved treatment for canine stroke patients. References: Garosi LS. Cerebrovascular disease in dogs and cats. Vet Clin North Amer Sm Anim Prac 2010; 40: 6579. Garosi LS and McConnell JF J Ischaemic stroke in dogs and humans: a comparative review. Sm Anim Prac 2005; 46: 89-97. Garosi LS, McConnell, Platt SR, et al. Results of diagnostic investigations and long-term outcome in 33 dogs with brain infarction (2000-2004). J Vet Int Med 2005; 19: 725-731. King AS. Arterial supply to the central nervous system. In King AS (ed). Physiological and clinical anatomy of the domestic mammals, volume 1. New York (NY); Oxford Press, 1987. 1-13. www.strokeassociation.org IVMA 2017 Marvelous micturition Stephanie Thomovsky, DVM, MS, DACVIM (Neurology), CCRP Clinical Assistant Professor of Neurology and Neurosurgery at Purdue University Director of Physical Rehabilitation at Purdue A. Review of the CNS 1. Somatic Nervous System a) This portion of the nervous system is involved with skeletal muscle innervation. The term “soma” literally means “body.” 2. Autonomic Nervous System a) The ANS is made up of two separate divisions. Both portions are involved with smooth muscle innervation: they sympathetic and parasympathetic nervous system. b) The ANS is a 2 neuron system. Meaning that there is a nerve cell body within the CNS (preganglionic cell body) and a second cell body that is outside of the PNS (postganglionic cell body). The term cell body means the same thing as neuron (it is the cell body of the neuron). The axon from the preganglionic cell body sends a signal directly to the postganglionic cell body. The axon from the postganglionic cell body acts directly on what is referred to as an effector or target organ. ANS Sympathetic nervous system Parasympathetic nervous system Type of Receptor Adrenergic Cholinergic Type of neurotransmitter Epinephrine or norepinephrine Acetylcholine (Ach) Purpose Fight or flight Rest and digest Location of preganglionic nerve cell bodies Thoracolumbar spine Cranial or sacral Preganglionic cell body location T1-L4(5) Brainstem nuclei for cranial nerves 3, 7, 9, 10, 11 or Sacral SC (S1-S3) Length of the axon between preganglionic cell body and postganglionic cell body Short Long Location of postganglionic nerve cell bodies Sympathetic chain ganglion (this is a structure you guys would have dissected in anatomy). In very close proximity to the target organ. Length of the axon between postganglionic cell body and target organ Long Short B. CNS Control of Micturition 1. There are several areas in the CNS that control micturition. a) The brain (1) Cerebral cortex – this controls the conscious component of urination. For example, this is why, if you are not in a bathroom when you have to urinate you hold it until you are in an appropriate location. (2) Brainstem- this is where the pontine micturition center is located. This center is involved with storage and evacuation of urine, it also received information from the SC and sends that information from the brain via the reticulospinal tract to the bladder. (3) Cerebellum – In general the cerebellum, no matter, what we are talking about sends out inhibitory signals. This is why, with cerebellar disease, movements, for example are exaggerated and of increased rate and range. Similarly, the cerebellum does have some control over frequency of urination with disease patients may have an increased frequency of urination. b) Spinal cord (1) The reticulospinal tract descends from the reticular formation in the brain (located throughout the brainstem) down the SC. It terminates in the ventral gray matter within the SC and signals LMN that innervate the bladder. c) In general, an easy way to remember how the ANS controls urination is to remember that “S” is for Storage and Sympathetic control. While, “P” is for Peeing and Parasympathetic. C. PNS Control of Micturition 1. There are 3 main peripheral nerves that control micturition. These neuronal cell bodies for this nerves are located with all LMN in the ventral gray horn of the SC. D. a) Hypogastric nerve b) Pelvic nerve c) Pudendal nerve Anatomy of the Urinary Bladder 1. The bladder muscle wall is called the detrusor muscle. It is made of smooth muscle. The internal urethral sphincter (IUS) is composed of smooth muscle and it not a true sphincter in that is basically composed of redundant smooth muscle. The external urethral sphincter (EUS) is the big gun (i.e. the strongest sphincter in the bladder); it is composed of skeletal muscle and is, therefore, under conscious control. E. Neural Control of Micturition (look at figure below) 1. As stated above, the type of receptors in the sympathetic nervous system are adrenergic receptors and the neurotransmitters (NT) that binds to these receptors are either norepinephrine or epinephrine. The hypogastric nerve is under sympathetic control. The hypogastric nerve innervates the detrusor muscle and the IUS. Thus, the receptor on the detrusor muscle which is the target organ for the hypogastric nerve is the B1 receptor. The hypogastric nerve innervates the IUS via the alpha-1 receptor. The neurotransmitter released at both the detrusor B1 receptor and the IUS alpha-1 receptor is norepinephrine. 2. The receptors for the parasympathetic NS are cholinergic and the NT that binds to these receptors is acetylcholine (Ach). The pelvic nerve is under parasympathetic control. The pelvic nerve innervates the detrusor muscle. Thus, the receptor on the detrusor muscle which is the target organ for the pelvic nerve is a muscarinic receptor and the NT is Ach. Sensory information related to bladder fullness also travels up this nerve to the SC and then onto the brain. When you get the sensation that your bladder is full it is because sensory signals have been sent via the pelvic nerve to your brain to tell you to think about urinating soon. 3. The receptors for the somatic nervous system are nicotinic and the NT that binds these receptors is Ach. The pudendal nerve is under somatic control. This nerve innervates the EUS. Thus the receptor on the EUS which is the target organ for the pudendal nerve is the nicotinic receptor and the NT is Ach. When you are in an appropriate location but get the urge to urinate and you hold your urine you are consciously controlling this EUS via the pudendal nerve. F. Normal Bladder Filling The bladder fills with urine pelvic nerve sends sensory information to the SC via reticulospinal tract, the information is relayed to the cerebral cortex if the patient is inside and it is not an appropriate time to urinate via the reticulospinal tract excitatory signals are sent to the hypogastric nerve relax the detrusor muscle and contract the IUS. Excitatory signals are also sent to the pudendal nerve contract the EUS. Inhibitory signals are sent to the pelvic nerve inhibit contraction of the detrusor muscle store urine. G. Normal Bladder Evacuation The bladder is full tight junctions of the detrusor muscle stretch pelvic nerve sends sensory information to the SC via reticulospinal tract, the information is relayed to the cerebral cortex if the patient is outside and it is an appropriate time to urinate via the reticulospinal tract inhibitory signals are sent to the hypogastric nerve relaxing the IUS. Inhibitory signals are sent to the pudendal nerve relaxing the EUS. Excitatory signals are sent to the pelvic nerve contract the detrusor muscle urine flows. H. Micturition and Spinal Cord Disease 1. There are two kinds of urinary bladders associated with neurologic dysfunction: UMN and LMN bladder. One key point to remember is that the bladder follows what is going on in the pelvic limbs. Meaning, if a patient is unable to move their pelvic limbs you can assume they are unable to consciously urinate. Conscious urination refers to what we discussed earlier, the idea that the cerebral cortex is in control of where and when you urinate. If there is disease of the SC, the reticulospinal tract will be unable to carry sensory information to the brain from the bladder and similarly the brain will be unable to send motor information via the reticulospinal tract to the SC. 2. Along the same line, if you feel as though reflexes and tone in the pelvic limbs are consistent with LMN disease then the bladder probably is a LMN bladder. Meanwhile, if you feel as though the tone and reflexes in the pelvic limbs are consistent with UMN disease, then the bladder is probably an UMN bladder. Neurologic Urinary Bladder Type UMN Bladder LMN Bladder Tone Great tone Poor tone Feel on palpation Firm Like a floppy water balloon Ease of Expression Difficult Easy Type of SC lesion T3-L3 SC (you can also see UMN L4-S2 SC bladder dysfunction with C1-C5 SC or C6-T2 SC disease) 3. UMN SC Lesion a) These patients are neurolocalized to L3 and cranial (most cases are T3L3 SC). Clinically these patients are paretic to plegic. They have increased pelvic limb tone and increased to normal pelvic limb reflexes. They may have disuse atrophy to the pelvic limbs. The bladder is firm and difficult to express. Side note, as discussed earlier, most patients who have lost the ability to consciously urine are plegic. 4. Bladder Function in Cases of UMN SC Disease a) The UMN system, as a general rule, is a system that inhibits all of the LMN that it communicates with. So, when there is disease of the spinal cord at T3-L3 (and less commonly C1-C5 or C6-T2 SC) there is disease of the UMN this leads to lack of inhibition to the nerves that these UMN tracts communicate with. (1) Parasympathetic Control: Lack of UMN inhibition of the pelvic nerve increased tone to detrusor muscle (2) Sympathetic Control: Lack of UMN inhibition of the hypogastric nerve tone to IUS. Remember, however, that the hypogastric nerve cell bodies are housed within the spinal cord gray matter from L1-L4/5 SC so it is possible with a lesion in the T3-L3 spinal cord segments that the cell bodies for the nerve itself could be affected leading to a hypogastric nerve that is not totally functional. That being said most diseases do not affect 4-5 spinal cord segments so some of the nerve cell bodies should be unaffected directly by the disease process. (3) Somatic Control: Lack of UMN inhibition of the pudendal nerve increased tone to EUS sphincter 5. LMN SC Lesion a) These patients are neurolocalized to L2-S2 SC. Clinically these patients are paretic to plegic. They have decreased pelvic limb tone and decreased to absent pelvic limb reflexes. They may have decreased to absent perineal reflex and anal tone. They may have neurogenic atrophy to the pelvic limbs. The bladder is floppy, and easy to express at the start. These bladders are difficult to completely get all urine out of, however, because the bladder wall has such poor tone. Side note, as discussed earlier, most patients who have lost the ability to consciously urine are plegic. 6. Bladder Function in Cases of LMN SC Disease (1) Parasympathetic Control: The nerve cell bodies for the pelvic nerve are located from S1-S3 SC decreased tone to detrusor muscle the bladder has poor tone on palpation. (2) Sympathetic Control: they hypogastric nerve cell bodies are located from L1-L4/5 so this nerve is unaffected by a lesion from L4-S2 SC. They have normal IUS tone. The IUS is the only functional sphincter in these cases. Because this sphincter is not as strong as the EUS it provides little resistance to expression. (3) Somatic Control: The nerve cell bodies for the pudendal nerve are located from S1-S3 SC decreased tone to EUS the bladder is easy to express and has the propensity to leak. 7. Reflex Micturition a) This condition develops only in cases of UMN disease and is not seen in cases with LMN disease. IT develops days to weeks after an UMN SC lesion. Basically a local reflex arc is set up between the bladder and the SC the brain is not involved. These are patients who have not improved neurologically from initial injury, but who start “urinating on their own” weeks after UMN injury. It is not a conscious urination and often they still to be expressed following urination as these reflex urination patients rarely urinate the entire contents of their bladder when they void. b) Pathophysiology of Reflex Micturition (1) The bladder fills with urine the bladder tight junctions are stretched Sensory (afferent) signals are sent via the pelvic nerve to the SC sacral motor neurons are stimulated (efferent neurons) pelvic nerve stimulates the detrusor muscle to contract. There is inhibition of the pudendal nerve relaxation of the EUS the patient urinates. NO signal is every relayed up the reticulospinal tract to the brain thus, urination is unconscious! I. Neural Control of Defecation 1. Defecation is controlled in a similar way to urination. 2. Parasympathetic control to the descending colon and rectum is by way of the Pelvic nerve (allowing expulsion of feces). 3. Sympathetic control to the descending colon and rectum is inhibitory but it is facilitory to the internal anal sphincter (allowing storage of feces). These sympathetic nerves are the hypogastric, caudal mesenteric ganglion, caudal mesenteric plexus and pelvic plexus. 4. Somatic control to the external anal sphincter which is skeletal muscle is via a branch of the Pudendal Nerve, the caudal rectal branch and also the sacral plexus. 5. Just like with urination the reticulospinal tracts carry information from the rectum and colon to and from the brain. J. Defecation and SC Disease 1. To be honest, with small animal SC disease we do not worry too much about defecation. It is very rare that anything has to manually be done to express the colon. I can think of one patient I have had where the patient (and it was a cat) required intermittent enemas. And also one (the same cat) who needs to have her colon expressed every few days. The reason this is not an issue as it is with the urinary bladder is because even in severe SC conditions that result in paraplegia involuntary reflex fecal evacuation usually takes place the colon it full it stretches and a local reflex arch results in relaxation of the anal sphincter and peristalsis of the colon. 2. There are two main types of fecal incontinence: UMN and LMN fecal incontinence. a) UMN fecal incontinence - clinically this is seen in two main instances, one is just like we chatted about earlier with the bladder, where an animal has a significant SC lesion cranial to L3 resulting in paraplegia and they are unaware they are defecating – unconscious defecation. The colon is stretched but that signal is blocked from getting to the brain via the SC the patient is unaware they are defecating and will common produce, formed feces but at inappropriate times. The second time this can be seen is in patients who only have mild pelvic limb neurologic deficits but they chief complaint is fecal incontinence. Usually these patients have disease of the dorsal portion of the SC (such as syringomyelia or a subarachnoid diverticula, for example). They realize they have to defecate but too late or sometimes are completely unaware that they are defecating. b) LMN fecal incontinence – this is just like we talked about with urination, seen in SC disease where the patient is localized to L4-S2. If they are localized to the all of the SC segments at L4-S2 then they have decreased pelvic limb tone, reflexes and are severely paraparetic or plegic and have poor anal tone and perineal reflex but they can also be localized to just S1-S3 (have poor anal tone, perineal reflex and poor tail function and have normally functioning pelvic limbs). These patients leak, often unformed stool often times constantly – fecal scald is a large problem in these patients. The leaking is secondary to poor external anal sphincter tone. K. Micturition Medications 1. In our neurologic patients it is usually our goal to get our patients to urinate. Thus, we use a combination of the first 5 drugs. We do not use phenylpropanolamine or estrogen very often for this reason. L. Urinary Bladder Management 1. Supportive care is key a) Keep patients clean and dry b) Bladder evacuation (1) Urinary catheterization (either intermittent or placement of an indwelling urinary catheter system) (2) Urinary expression (3) There have been some good publications in the veterinary literature addressing bladder management in our patients. A few are listed below: (a) This article showed that there was no preferred method of bladder management: (i) Bubenik L, Hosgood G. Urinary tract infection in dogs with thoracolumbar intervertebral disc herniation and urinary bladder dysfunction managed by manual expression, indwelling catheterization or intermittent catheterization. Vet Surg 2008; 37(8): 791-800. (b) This article showed low risk catheter-associated UTI if indwelling catheters were not left in more than 3 days at a time: (i) Smarick SD, Haskins SC, Aldrich J, Foley JE, Kass PH, Fudge M, Ling GV. Incidence of catheterassociated urinary tract infection among dogs in a small animal intensive care unit. JAVMA 2004; 224(12): 1936-40. (4) Frequency of intermittent bladder evacuation (a) Every 6-8 hours (b) Something to be aware of is that in a normal dog (value unknown for cats) after an animal properly urinates the dog will have anywhere from 0.2-0.4 ml/kg of urine left remaining in the bladder. This number becomes important in cases where you think a dog has regained conscious urinary function after having had SC disease. 2. Bladder management is VERY important. The major seqelae to poor management are: a) UTI – frequent urine cultures are important in patients who neurologically are unable to void. b) Urine scald – to avoid this keep patients clean and dry. Also rotating patients every 4 hours will prevent this as it allows wet, clean areas of the skin/fur to dry. You can also get fecal scalding in our incontinent patients as well – just another reason to keep them clean and dry. The below picture is from a paraplegic patient we had last semester who secondary to urine scald and licking her abdomen developed this wound in her inguinal area. c) d) Detrusor atony (this is a serious and often irreversible complication to poor bladder management. The detrusor muscle contains tight junctions, if those tight junctions are stretched there is the possibility that they will not be able to heal and even though the patient regains neurologic function, in his limbs, for example, the detrusor muscle will remain damaged and these patients commonly will still be incontinent and unable to completely void their bladders). 3. Important Thing to Remember a) **Just because an animal is laying in a large puddle of pee does NOT mean they are consciously able to urinate make sure they have not overflowed palpate the bladder and express them as needed** References A Practical Guide to Canine and Feline Neurology. Curtis Dewey, 2 nd ed., 2008 rd Veterinary Neuroanatomy and Clinical Neurology. Alexander de Lahunta and Eric Glass, 3 ed., 2009. IVMA 2017 More Obscure Myelopathies Stephanie Thomovsky, DVM, MS, DACVIM (Neurology), CCRP Clinical Assistant Professor of Neurology and Neurosurgery at Purdue University Director of Physical Rehabilitation at Purdue 1. Myelopathies Besides Intervertebral Disc Disease and Wobbler Syndrome 1. Degenerative Spinal Cord Conditions a) Lumbosacral disease (LS Disease) (1) This is a major cause of cauda equina syndrome. Cauda equina syndrome refers to compression of the cauda equina and the associated neurologic deficits that result when there is compression of these nerve roots. The main nerve roots affected are those that supply the sciatic nerve, pudendal and pelvic nerves. (2) LS disease is relatively common, it is definitely one you will diagnose regularly in private practice. (3) LS disease refers to degenerative joint disease at the L7-S1 space. For all intents and purposes you can think of it as “wobblers of the lumbosacral spine.” Meaning there is a combination of several disease processes going on all at the LS space that contribute to cauda equina compression in this area. (4) Compression is secondary to a combination of: (a) Type II IVDD at L7-S1 (b) DJD of the articular facet joint at L7-S1 (c) Bony proliferation stenosis at L7-S1 (d) Proliferation of two ligaments: the dorsal longitudinal ligament and ligamentum flavum (yellow ligament). The former is present dorsal to the disc while the latter is dorsal to the spinal cord. (5) Signalment of dogs with LS disease (a) This is a disease of dogs and if seen in cats, is very rare. It occurs in older, large breed dogs. It often occurs in working dogs. So if you work with military dogs or service (police) dogs you will definitely see LS disease on a fairly common basis. (6) Clinical Signs are secondary to compression of the cauda equina. As we mentioned earlier, this means signs you would associated with sciatic, pudendal and pelvic nerve disease. (a) * Fecal and urinary incontinence (i) This can become permanent if left untreated. This is something very different about LS disease as opposed to most other spinal cord diseases you will study. Because this disease affects the cauda equina rather than the spinal cord, per se, it is much less common to have actual paresis and certainly paralysis with disease back in this region. That being said because the pudendal nerve innervates both the external anal and external urethral sphincter incontinence is a huge sequela to disease at the LS space. (ii) If patients come in with LS disease and are incontinent there is a poor to guarded prognosis for return to function, and this is proportional to duration of the incontinence. Key point, if you see a dog who you suspect has LS disease that has fecal and urinary incontinence, this is an emergency and should be referred for further work up surgery. Time is important in these cases. (b) Pain on L-S palpation (c) Paresis (i) Pelvic limbs (ii) Tail (d) +/- CP deficits in the pelvic limbs (e) +/- pelvic limb ataxia (f) Decreased reflexes (i) Decreased pelvic limb withdrawal reflexes (ii) Decreased perineal reflex (iii) Decreased anal tone (g) Difficulty lifting back feet when ambulating (i) (h) Scuffs feet Possible decreased step distance (7) Diagnosis of LS disease can be done with several diagnostic modalities. (a) Survey spinal radiographs are quite effective in the diagnosis of LS disease or at least, lend suspicion that there is disease at this disc space. (i) Key things to look for are sclerosis of the caudal vertebral endplate at L7 and cranial endplate at S1, DJD of the facet joints at L7-S1, opacity within the intervertebral foramina at L7-S1. (b) MRI – in this disease multiple studies show that MR and CT both are adequate in the diagnosis of LS disease. (c) CT- in this disease multiple studies show that MR and CT both are adequate in the diagnosis of LS disease. (d) Myelography- this is a disease condition where myelogram is not as good as either MR or CT in the diagnosis of disease at the LS space. It is mainly because myelography is dependent on an intrathecal injection of contrast. Because nerve root as opposed to spinal cord are present at the LS space, compression is not as obviously seen after dye injection. Thus, when myelography was our only option (before the days of MR and CT) an epidurogram was done in these cases. (i) Epidural injection (epidurogram)- this is an epidural injection (similar to what you would give as analgesia before an orthopedic procedure involving the pelvic limbs or to women at the time of labor) of contrast agent. These are not pretty images and can be difficult to interpret. (8) Treatment (a) Like all spinal disease two treatment options exist, conservative vs. surgical management. (i) Conservative management is cage rest with controlled physical therapy. PT is very important in these cases as you want to maintain muscle mass and joint mobility. (ii) Surgical management is a dorsal laminectomy at L7-S1 with or without stabilization using a combination of screw and PMMA, or a plating system of surgeon’s choice. Surgical management should be strongly encouraged in cases where pain is refractory to medical management and certainly if there are signs of incontinence (ideally before these signs are observed). (9) Prognosis is slightly different here than in other areas of the spinal column. Deep pain is important, as always, except clinically with LS disease we are usually talking about DP to the tail and perineum. If this is absent the prognosis for recovery of this DP is poor. What makes LS disease different is that prognosis is also, as stated earlier, affected by incontinence. If the patient is incontinence (a LMN incontinence secondary to pudendal nerve involvement) then return to function is often poor. 2. Degenerative Spinal Cord Diseases (continued) a) Degenerative myelopathy (DM) (1) This is a common neurologic condition. You will see this in private practice. (2) Signalment (a) Older [>5 years of age (mean age = 9)] (b) Large breed dogs (except for the corgi!) (i) Most commonly, German Shepherd, Boxers, Chesapeake Bay Retriever, Rhodesian Ridgeback, Pembroke Welsh Corgis (3) Onset and progression of disease is key in this disease (a) Onset is slow, these patients have a chronic progressive history of non-painful pelvic limb paraparesis and ataxia (proprioceptive) (4) Clinical Signs (a) Early Signs (6-12 mths after onset) (i) Pelvic limb proprioceptive ataxia (ii) Can be asymmetric at start (iii) T3-L3 SC localization (a) (iv) (b) (UMN paresis) Non-painful Late Form (after 12 mths) (i) With time, signs become more symmetric (ii) Progression to LMN paraplegia (iii) Thoracic limbs start to become weak (iv) It can progress to flaccid tetraplegia and brainstem signs (v) Patients are often euthanized prior many of these late form signs developing. (5) Pathophysiology (a) Multisystem central and peripheral axonopathy (b) Degeneration of the white matter of SC (i) All funiculi affected (ii) Axon and associated myelin destroyed (this is why signs are UMN at the start) (iii) Defects in cells that support axon maintenance (i.e. astrocytes or oligodendrocytes) or defects in axoplasmic flow (6) Genetics behind this condition have been elucidated and there is genetic testing present for some breeds through the OFA. (a) Mutation in the superoxide dismutase 1 (SOD1) gene (b) This disease is similar to the human disease, Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig Disease) (c) Homozygosity SOD1 mutation is a major risk factor for canine DM. If genetic testing is pursued the results will indicate if you are homozygous, heterozygous for the disease (i.e. a carrier). Though the testing will tell you if the dog has the gene, it will however, not tell you if you will express the gene. (7) Cats have been described as also having a form of degenerative myelopathy, as well. But this condition is different from the canine form and is uncommon. (a) It is associated with FeLV infections. Cats chronically infected with this condition show signs of lethargy, behavior changes, vocalization, hyperesthesia and urinary incontinence. The most common sign, however, if pelvic limb paresis that can progress to paralysis within 1 year. (b) These cats are older with a chronic progressive history of paresis. (c) Histopathology shows white matter degeneration. (8) Diagnosis of canine DM – there is NO definitive ante-mortem way to diagnose DM. It remains a diagnosis of exclusion. That being said, the presumptive diagnosis of DM is made with a combination of tests (a) Genetic testing through OFA. (i) (b) Test for homozygosity of the SOD1 mutation Neuro diagnostic results (i) Normal thoracic and lumbar MRI (ii) Normal CSF tap (a) Hence the idea of it being a diagnosis of exclusion. (9) Treatment is supportive only (a) Intensive physiotherapy (i) Study showed improvement in survival time = mean 255 days (a) days Those that had moderate therapy = 130 (b) days Those that had no physiotherapy = 55 (ii) Some bias is present in this study, however, because those owners who are willing to do intensive PT are probably also those willing to keep an animal alive longer who is extremely weak in the pelvic limbs and who requires bladder maintenance, for example. (b) Other treatments have been discussed including Nacetylcysteine and possibly aminocaproic acid but controlled studies have yet to be performed. 3. Congenital Malformations a) Caudal Occipital Malformation (COMS) and Syringomyelia (SM) (a) This refers to malformation of caudal fossa and associated cerebellar overcrowding and herniation of the caudal portion of the cerebellum through foramen magnum. In human medicine COMS is synonymous with Chiari Type I. (b) Most commonly, the occipital bone is of abnormal shape and is displaced rostrally. Additionally, there is some thought that the caudal fossa is too small in size proportionally for the brain size. This leads to herniation of the cerebellum and an alteration in CSF flow at the level of the foramen magnum. (c) This alteration in CSF flow leads to SM. Syringomyelia refers to dilation of a section of the spinal cord with extracellular fluid. Hydromyelia refers to dilation of the central canal. It is difficult, other than on histopathology, to differentiate between syringomyelia and hydromyelia. So, most of the time we refer to them as syringo/hydromyelia or just refer to them both as SM (syringomyelia) or a syrinx. (i) The pathophysiology behind syrinx formation is not completely understood, although several theories exist for its formation. (picture of hydromyelia below – it is the cross section of the SC on the far left) (d) Signalment for COMS is (i) Young dogs who are 3 months – 5 yrs of age (ii) It is most common in toy or small breed dogs. The poster child for this disease is King Charles Cavalier Spaniels. It has also been described in the Maltese, Brussels Griffon, Chihuahua, Poodle. (e) Onset/progression (i) Acute, chronic and possibly progressive. (ii) Most clinical signs occur in adulthood (though this condition is present at birth, it is most common for dogs to present with signs attributed to it after 1 year of age. (f) Clinical Signs (i) Usually are a combination of brainstem and cerebellar signs such as vestibular signs and head tremors. (ii) They also display signs consistent with cervical spinal cord disease (such as spinal hyperesthesia, Scoliosis secondary to SM, CP deficits and paresis). (iii) Another common sign is scratching at the shoulder, neck and ears. These patients common are referred to dermatologists for this scratching. (g) Diagnosis (i) Made with MRI (+/- CSF tap). CSF tap is done to rule out other diseases of small breed dogs such as meningoencephalomyelitis. COMS cannot be diagnosed with CT or myelogram. It is an MRI diagnosis. (h) Treatment consists of medical therapy versus surgical treatment. (i) Medical (a) Pain medications, most commonly gabapentin as the scratching most believe to be secondary to neurogenic pain. (b) Medications to decreased CSF production (omeprazole, carbonic anhydrase inhibitors, furosemide). The goal of these medications is to reduce CSF flow and in that vein, reduce SM formation. (ii) Surgical (a) Foramen magnum decompression is the surgery of choice. The goal is to decompress the cerebellum and try to reduce/completely reverse syrinx formation. Interestingly enough, in human medicine the syrinx often goes away with surgery. The same cannot be said in our veterinary patients, more often than not, the syrinx is unchanged by surgery. As the syrinx is often the main cause of the patient’s clinical signs, in vet med, we typically try medical management first. We later pursue surgical treatment only if medical management is not helping the patient. 4. Infectious/inflammatory Spinal Cord Disease a) Diskospondylitis (disko) - infection of the intervertebral disc and adjacent vertebral endplate. This disease is completely different than spondylosis aka spondylosis deformans. Disko is a very common disease and one that can be confidently diagnosed with survey radiographs. (1) (2) Signalment (a) Mostly, large, middle-aged dogs (uncommon in cats) (b) Male > female (c) Rare in cats Clinical signs (a) #1 = spinal pain (> 80% of cases) (b) Neurologic signs are anything from ataxia to paralysis (c) Systemic signs of infection (30% of cases) (i) Fever, weight loss, inflammatory leukogram, sometimes these patients present for just being ADR (3) Etiology (a) The most common cause of disko is a bacterial infection. That being said the infection can also occur secondary to a fungal infection of the vertebral endplate. The most common type of bacterial infection is Staphylococcus. Infections can also be secondary to E. coli, Brucella canis and streptococcus organisms. (b) Fungal disko carries a worse prognosis than bacterial. Aspergillus is the most common organism described. (c) Foreign bodies (grass awn migration) have also been described as a cause. (4) Diagnosis (a) Survey spinal radiographs are the most common way disko is definitely diagnosed. That being said, there can be radiographic lag between onset of clinical signs and radiographic evidence of disease. (b) The most common radiographic abnormalities are: (i) Irregularity of vertebral end plates (ii) Lysis of vertebral endplates (iii) Later, with chronic disko infections you will see sclerosis of the endplates and osteophyte production (iv) Disko is most commonly diagnosed at the L7-S1 disc space (see picture below). However, it is fairly common to have more than one set of vertebral endplates that are infected. If you find disko in one site we usually do full spinal rads to make sure there are not multiple sites affected. (c) For cases wherein you cannot confidently use radiographs to diagnose disko (i.e. when you are suspicious a dog has disko, for example, there is definite back pain, but you are concerned the radiographic lag is not allowing you to see it on radiographs or when there is too much summation at the disc space in question – this can happen with summation for the ilial wing or the front limb) and you need a more sensitive modality to diagnose disko you can use a CT scan, MRI or nuclear scintingraphy. (5) Other diagnostics to pursue in cases of diskospondylitis (a) Urinalysis and urine culture this combination of diagnostics is done in every case of disko because this is the most common way to diagnose the infecting organism. Urine culture is positive 25-50% of the time in cases of disko. (b) CBC you will see changes consistent with an inflammatory leukogram. (c) Brucella serology (these are positive in 10% of disko cases) is done in all dogs because of the zoonotic potential of this infection. This is usually an infection most commonly seen in breeding animals. (d) Blood cultures (these are positive in 45-75% of disko cases) (e) +/- Echocardiogram – this diagnostic is pursued in cases where there is an audible heart murmur. Because disko lesions develop secondary to a period of bacteremia, for prognosis, it is good to determine if endocarditis is present (f) Disko can lead to osteomyelitis and/or meningomyelitis, for that reason, sometimes were pursue a CSF tap as a part of the diagnostic protocol. (g) Sometimes we also pursue FNA of intervertebral disc space. This is a bit of a risky procedure due to the potential for pneumothorax in the T spine and the proximity of the aorta to the IVD space in the lumbar spine. Sometimes we are able to, in cases of L7-S1 disko do ultrasound guided FNA of the surrounding soft tissues. This is especially successful if there is a considerable amount of proliferation at the disc space. After any FNA we culture the samples obtained. (h) Surgical biopsy is performed in rare cases for 1 of 2 reasons: the patient is unresponsive to empirical therapy, or there is associated compression of the spinal cord in the area of the disko lesion leading to significant neurologic deficits in the patient. (6) Treatment is based on culture and sensitivity but there are times when, despite our better efforts, we do not grow anything on urine, blood or FNA cultures. At these times we have to empirically treat the infection. (a) The choice of drug should be based on culture results, that being said, if you are empirically treating you want to pick an antibiotic that has good bone penetration and those that are good against gram positive organisms as Staph infections are most common. Such antibiotics include: cephalosporin’s such as cephalexin, clavamox, clindamycin or enrofloxacin can also be used. As for anti-fungals, if you are worried about CNS penetration fluconazole is the best anti-fungal to choose, if you think that the infection is solely in the intervertebral endplate then ketoconazole or itraconazole can also be used. (b) Treatment for bacterial disko is usually 6 months to 1 year of continuous antibiotic therapy. These are infections of bone and bone takes a long time to treat. Most patients if they are treated appropriately will heal completely and have a good prognosis. (c) Treatment for fungal disko can be much longer than 6-12 months. There has been a published paper of lifelong treatment with antifungals for fungal disko (every time the dog was taken off the drug signs came back). Prognosis with fungal disko is guarded, contributing to this is that fungal disko is harder to diagnose and so these patients probably are diagnosed and started on anti-fungals much later than dogs with bacterial disko. b) Meningomyelitis is inflammation of the meninges and spinal cord. This is an uncommon condition in either dogs or cats but often more quickly progressive than meningoencephalitis as the spinal cord is smaller in diameter than the brain, so it often takes less inflammation to cause more significant signs. (1) Onset is usually progressive although it can be acute. (2) Signalment in general (a) (3) Young to middle aged dogs Clinical Signs in general (a) Often causes multi-focal CNS signs involving the brain and SC, but you can see pure myelitis which presents with just a SC localization. (b) (4) Spinal hyperesthesia to ataxia to paralysis Diagnosis for all types of meningomyelitis (a) CSF tap – the main use of CSF is when it comes to CNS inflammation. This is the main tool used to definitively diagnose meningitis of any kind. (i) Increased WBC (nucleated cells) (elevated means more than 5 nucleated cells per microliter in the dog and cat) (ii) Increased protein (increased means more than 30-35 mg/dL via a cysternal tap or more than 40-45 mg/dL if CSF is done via a lumbar tap) (iii) CSF culture (this is often a low yield, even in cases where bacteria are seen on cytology of the CSF – mainly because CSF is so low in protein, traditionally it is difficult to isolate bacteria or fungal agents from it). (b) MRI (i) May show meningeal and SC enhancement with contrast (c) Infectious disease titers are pursued to determine if the meningomyelitis is infectious or non-infectious. More to come below on this… (5) Two main categories of meningomyelitis. The same holds true for meningoencephalitis. (a) Infectious (i) Viral such distemper or rabies, in cats FIP, FeLV or FIV (ii) Bacterial (iii) Rickettsia sp. (Ehlichia or Rocky Mountain Spotted Fever) (iv) Fungal such as aspergillus, cryptococcus, coccidiodes, blastomycoses (v) Protozoal such as Toxoplasma gondii or Neospora caninum (vi) Treatment and prognosis are variable depending on the infecting agent. (b) Non-infectious (i) Sterile supporative meningitis aka canine meningeal polyarteritis, steroid-responsive meningitisarteritis (SRMA) (a) Signalment –this disease is special in that it is only seen in young, medium to large breed dogs. (i) Young (< 2 yrs old) (ii) Medium-to-large breed dogs (b) Clinical Signs- also unique about this disease is that it traditionally causes a fever and only neck pain – no other neuro deficits (i) Fever (ii) Severe cervical pain (this is usually the only neuro deficit) (c) Blood Work shows a neutrophilic leukocytosis (d) Treatment is with immunosuppressive doses of steroids. This condition is unique for two other reasons, one is that these dogs can be slowly tapered, over a few months, off steroids and be cured (i.e. not require further immunosuppressive therapy). The second unique thing is that the prognosis for functional recovery is good. References A Practical Guide to Canine and Feline Neurology. Curtis Dewey, 2 nd ed., 2008 Small Animal Spinal Disorders Diagnosis and Surgery. Nicholas Sharp and Simon Wheeler, 2 nd ed. 2005. Veterinary Clinics of North America Small Animal Practice: Spinal Disease. Ronaldo da Costa, 20 (5); 2010. rd Veterinary Neuroanatomy and Clinical Neurology. Alexander de Lahunta and Eric Glass, 3 ed., 2009. IVMA 2017 Neurologic manifestations of systemic disease Stephanie Thomovsky, DVM, MS, DACVIM (Neurology), CCRP Clinical Assistant Professor of Neurology and Neurosurgery at Purdue University Director of Physical Rehabilitation at Purdue Neurologic signs can be a sequela to many of the common systemic diseases seen in veterinary patients. The purpose of today’s talk is to discuss the neurologic manifestations of common systemic diseases and the pathophysiology associated with these neurologic signs. We will discuss thyroid disease, diabetes mellitus, diseases of the adrenal gland and erythrocytosis. Hyperthyroidism is a common disease of older felines. One of the main neurologic signs observed in this disease is muscle weakness. This weakness is observed in 12-25% of cats with high thyroid hormone levels. This muscle weakness is secondary to decreased action potential formation and decreased muscle membrane excitability. A small number of cats, 1-3% cats, show ventral neck flexion as a sign of diffuse muscular weakness. Seizures can also be associated with hyperthyroidism. The mechanism behind seizure formation is not completely understood. It is thought that thyroid hormones may directly decrease the electrical threshold of cerebral tissue, making it easier to depolarize and create an action potential within cerebral neurons. Elevated thyroid hormones also alter neurotransmitter concentrations and activity which can potentiate neuronal depolarization. Neurologic signs may also be secondary to thyroid hormone’s effect on metabolism. Thyroid hormones increase the consumption of oxygen and glucose within the brain, this can lead to neuronal cell death. Another possible cause of neurologic signs in animals with hyperthyroidism is the fact that hypertension is often associated with hyperthyroidism. Hypertension can alter brain vasculature and lead to cerebrovascular disease in humans and animals. Unfortunately even one common treatment for hyperthyroidism, methimazole, can cause neurologic signs. Methimazole is a thioureylene anti-thyroid medication. This medication is actively concentrated within the thyroid gland; it inhibits thyroid peroxidase-catalyzed reactions, and binds to and alters the structure of thyroglobulin and is used to reduce the amount of thyroid hormone. The use of methimazole has been associated with neurologic signs, specifically myasthenia-like signs. Methimazole increases the number of acetylcholine receptor antibodies, thus causing exercise intolerance, fatigue and muscle weakness. This side effect of methimazole is normally observed 2-4 months following therapy initiation; signs are resolved with withdrawal of the medication. Hypothyroidism is also associated with neurologic signs. Hypothyroidism has been proven to cause both peripheral (PNS) and central nervous system (CNS) signs. CNS manifestations of hypothyroidism include central vestibular signs, myxedema coma and CVA. The mechanism of action as to how low thyroid levels can cause central vestibular signs is unknown, however, it is thought that these neurologic signs may be secondary to atherosclerosis and subsequent ischemic stroke formation, or central nervous system demyelination. In one report by Higgins et al (2006) up to 70% of dogs with central vestibular signs secondary to hypothyroidism had no other extra-neural clinical evidence of low thyroid levels (no alopecia, or weight gain). So even in cases where a dog may not “look hypothyroid” it should still be tested if the patient has central vestibular signs. Myxedema coma is also a sequela to a severe form of hypothyroidism. This disease results in mental obtundation and stupor secondary to reduced oxygen delivery and glucose utilization by brain tissues and altered cerebral blood flow. Hyponatremia can also be a result of this extreme form of hypothyroidism and can affect neurons, neuronal action potential formation and propagation. In addition to stupor these patients often have a non-pitting edema of the skin secondary to accumulation of hyaluronic acid within the dermis, hypothermia, lack of shivering reflex, bradycardia and weakness. This same hyaluronic acid deposition is also associated with PNS signs, as discussed in the next paragraph. Cerebrovascular disease is also a sequela to hypothyroidism as it can lead to atherosclerosis and/or hyperlipidemia. In addition to CNS signs, hypothyroidism can also cause PNS signs (a mononeuropathy or diffuse polyneuropathy). It is thought that low thyroid hormones levels can cause demyelination of peripheral nerves. In extreme forms, myxomatous disease secondary to deposition of hyaluronic acid within the dermis and surrounding soft tissues can also cause peripheral nerve compression. Most commonly, hypothyroidism has been reported to affect the peripheral portion of several cranial nerves including cranial nerve 5, 7, 8 and 10 (including its branch, the recurrent laryngeal nerve). Patients can therefore present with peripheral vestibular signs, laryngeal paralysis, and megaesophagus. Another manifestation of hypothyroidism is a diffuse polyneuropathy. These patients present with diffuse lower motor neuron weakness. Reflexes are diminished-to-absent in all four limbs. The mechanism of action behind the lower motor neuron signs is believed to be related to disruption of the sodium/potassium ATPase pump on the neuronal cell membrane. A build-up of intraneuronal sodium leads to cytoxic edema, slowed axonal transport and slowed neuronal firing and muscle contraction. Rossmeisl JH et al (2010) studied the neurologic manifestations of hypothyroidism in a group of dogs. He studied 18 female dogs; 9 control dogs and in 9 dogs in which hypothyroidism was induced via iodine 131 treatment. Neurologic and physical exams were performed in addition to electrophysiology testing. The result of the study, however, were very interesting. He found no clinical evidence of neuropathy on serial examinations in any of the dogs in his study. On electrophysiology testing he found some changes on electromyogram (EMG) but all other electrophysiology testing was normal in both groups. Rossmeisl’s findings seemed to indicate that hypothyroidism may NOT in fact cause peripheral nerve signs. The author conjectured that perhaps his findings were related to the fact that he ablated the thyroid gland in order to induce low thyroid in his study dogs. Naturally occurring hypothyroidism in the dog is secondary to immune mediated thyroiditis. He conjectured that, perhaps it is the immune system’s role in the naturally occurring hypothyroid animals that directly affects the peripheral nerve and its myelin rather than simply the low serum thyroid levels. Hypothyroidism also causes a myopathic disease, specifically muscle weakness and exercise intolerance. Thyroid hormone contributes to skeletal muscle stores of free carnitine. Carnitine is integral in transportation of fatty acids into the mitochondria of the myocyte. Once in the mitochondria, fatty acids go through beta-oxidation and energy is produced. Eighty percent of humans with hypothyroidism report problems associated with skeletal muscle dysfunction and 40% have clinical manifestations of skeletal muscle weakness at the time of diagnosis. Rossmeisl JH et al (2009) studied the effects of hypothyroidism on skeletal muscle. He studied 9 total dogs, 3 control dogs and 6 dogs in which he induced hypothyroidism via iodine 131 treatment. Similar to his nerve study, he performed monthly physical and neurologic examination, electrophysiology testing, but he also assessed CK, ALT, AST, lactate and LDH levels in addition to skeletal muscle biopsies and muscle carnitine concentrations in these dogs. Significant increases in CK, AST and LDH were recorded in affected dogs. There was also a significant depletion of skeletal muscle free carnitine in affected dogs. Muscle biopsy revealed nemaline rod inclusions, decreased mean type II fiber area and increase in the predominance of type 1 myofibers. There were accumulations of abnormal mitochondrial within the muscles biopsied and myofiber degeneration. In conclusion, the changes both in blood work and also muscle biopsy were consistent with altered muscle energy metabolism and skeletal muscle carnitine. That being said, all myopathic changes were subclinical, all physical and neurologic exams were normal between dogs studied. It could be that clinical evidence of muscle weakness was not observed due to abbreviated length of the study period. Diabetes mellitus is perhaps one of the more common endocrinopathies that veterinarians associate with neurologic manifestations. Patients can have PNS and CNS signs. The most common neurologic signs observed is a plantigrade stance secondary to a peripheral neuropathy. This stance is more commonly observed in diabetic cats as compared to dogs. In the grand scheme of animals who are diagnosed with diabetes mellitus, neurologic signs are not very common; 8% of cats have peripheral neuropathy signs at the time of diabetes mellitus diagnosis. Cats present with a history of progressive paresis and muscle atrophy, especially evident in the distal pelvic limbs. Pelvic limb reflexes are decreased, especially the ability of the patient to withdrawal his limb at the level of the hock. The neurologic signs are normally symmetric. This neuropathy is a mixed neuropathy with the disease affecting both the sensory and motor nerves. Human type II diabetic patients are affected by neuropathy roughly 50% of the time. There are several theories as to why these patients develop a plantigrade stance secondary to a peripheral neuropathy. These theories include: reduction of the sodium/potassium ATPase pump, deficiencies in growth factor, glycosylation of the structural protein in myelin and tubulin, abnormalities within the vasculature and alterations in the polyol pathway. The latter is the most researched and most accepted explanation for neuropathy signs in these patients. Normally glucose is converted to sorbitol and then to fructose in the polyol pathway. Aldose reductase converts glucose to sorbitol; for this to occur, NADPH is converted to NADP+. Sorbitol dehydrogenase converts sorbitol into fructose. In the presence of hyperglycemia there is excessive production of aldose reductase leading to an excessive production of NADP+. The production of NADP+ leads to decreased glutathione levels and increased free radical formation. It is thought that these excessive levels of free radicals affect the axon and its myelin. Electrophysiological testing in diabetic patients with peripheral nerve signs include electromyogram (EMG) and motor (MNCV) and sensory nerve conduction velocity (SNCV) testing, F wave and cord dorsum potentials (CDP). EMG shows spontaneous activity, positive sharp waves and fibrillation potentials in distal pelvic limb musculature. MNCV and SNCV show reduced velocities. The latency of CDP and F waves are prolonged. Polyphasia and temporal dispersion are also observed. The electrophysiological findings are supportive of demyelination. Demyelination leads to slowed action potential propagation and peripheral neuropathy signs. That being said, with these signs can often be reversed or significantly improved with appropriate blood glucose regulation. The CNS sign most commonly associated with diabetes mellitus is cerebrovascular disease. Cerebrovascular disease is most common in diabetic who are also hyperosmolar. Viscous blood is associated with a more turbulent flow within vasculature and can lead to ischemia. Adrenal diseases are also associated with neurologic signs. Canine patients with hyperadrenocorticism can present with either PNS or CNS signs. The most common PNS manifestation of Cushing’s disease is Cushing’s myopathy, however Cushing’s mytonia can also occur. Cushing’s myopathy is term used to describe generalized muscle atrophy observed in patients with Cushing’s disease. This muscle atrophy is seen in roughly 35% of canine patients with hyperadrenocorticism. Muscle weakness has been reported in between 14-57% of cases. Though observed, this muscle atrophy and weakness is often subclinical and creatinine kinase (CK) can sometimes be mildly elevated in these cases. Cats with Cushing’s disease do not typically have a distinct myopathy but they can have muscle atrophy. Cushing’s myotonia is a more rare and serious sequela to hyperadrenocorticism; it occurs in 0.6% of dogs with Cushing’s disease. This myotonia is often referred to as a pseudomyotonia. Cushing’s myotonia is more common observed in dogs suffering from untreated Cushing’s disease for a prolonged period of time. These patients present with severe limb stiffness and hypertrophy of the proximal appendicular musculature. Electrodiagnostic testing in these patients reveals spontaneous discharges on EMG. These discharges are referred to as pseudomyotonia and are considered a type of complex repetitive discharge. Unlike true myotonic discharges which wax and wane, pseudomyotonia discharges have an abrupt stop and start to them when they are heard. Muscle biopsy performed in patients with Cushing’s disease reveals atrophy of the fast twitch type 2 muscle fibers. Muscle atrophy occurs secondary to fibrosis of the perimysium and endomysium. In cases of Cushing’s myotonia muscle hypertrophy is the result of fat deposition within the perimysium and endomysium. Hyperadrenocorticism can also cause CNS signs. These signs are most commonly secondary to cerebrovascular disease. In one study, 6/33 dogs with CVA’s were diagnosed with Cushing’s disease at the time stroke. The exact pathophysiology behind stroke formation in these patients is not completely understood, however, hypercoagulability is thought to play a key role. Cushing’s patients are in a hypercoagulable state for one of two reasons: an increase in pro-coagulant factors or a decrease in antithrombin levels. The decrease in anti-thrombin is thought to be related to glomerular disease. The glomerulus becomes damaged secondary to hypertension and/or a delay in immune complex clearance and subsequent immune complex deposition at the glomerulus. Excessive glucocorticoid serum levels lead to diminished Immune complex clearance. Glomerular damage results in loss of anti-thrombin 3 in the urine, proteinuria and a resultant increased propensity for thrombus formation. The increase coagulation observed in Cushing’s disease is also related to an increase in the number of certain clotting factors within the blood stream. Humans with hyperadrenocorticism have increased numbers of clotting factors 2, 5 and 7-12, while dogs with Cushing’s disease have increased number of factors 2, 5, 7, 9, 10 and 12. Hypoadrenocorticism results in diffuse muscular weakness, shivering and muscle tremors. Some patients also have weakness of the pharyngeal and esophageal muscles; they can present with dysphagia. If weakness is severe patients can also show signs consistent with a lower motor neuron tetraparesis. Appendicular reflexes are reduced and dysphagia can be observed. It is thought that with mineralocorticoid deficiency alterations in sodium and potassium concentrations lead to alterations in muscle membrane potential and poor muscle membrane excitability and alterations in the Na/K+ ATPase activity. In extreme cases hyponatremia can cause cerebral edema secondary to dysfunction of the neuronal Na/K ATPase pump. Glucocorticoid deficiency Addisonians have decreased gluconeogenesis and glycogenolysis. Decreased glucose concentrations directly affect the brain and neuronal activity as neurons are dependent on whole body glucose stores. Decreased glucose leads to decreased ATP production, decreased neuronal energy and neuronal apoptosis. Polycythemia or erythrocytosis is can also be associated with central nervous system signs. 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