Download Paraneoplastic Syndromes

Paraneoplastic
Syndromes
VANESA ADAME, ROSANGELA GARAY, SHEBA JOHN, JAY MARTINEZ, AND CYNTHIA
SCHLECK
PHYSIOLOGY IN MEDICAL PRACTICE
Introduction
● It is estimated that 8% of all cancer patients suffer from some sort of paraneoplastic syndrome.
● A paraneoplastic syndrome is a disease state caused by the presence of cancer cells within the body.
● Paraneoplastic syndromes can arise from:
○Antihumoral immune response
○Hormone excretion by a tumor
● Paraneoplastic syndromes are categorized by the organ systems they affect. We focus on two systems:
○Neurological
○Endocrine
● Within each category there are syndromes with extremely similar presentations, but vastly different
oncological implications.
Paraneoplastic Syndromes: Differential
Diagnosis
● It is often difficult to diagnose a patient with a paraneoplastic syndrome because the signs and
symptoms associated with the syndrome can present before cancer is detected.
● Paraneoplastic syndromes can affect any organ system in the body. Patients are often referred to a
specialist in the field related to the symptomatic location rather than an oncologist.
● Treatment of the patient’s symptoms is often ineffective because the underlying cause, the cancer
itself, is not targeted by the treatment administered.
● We suggest that in cases where conventional treatment does not improve the patient’s condition,
the symptomatic presentation should be considered paraneoplastic.
● We believe that comparing and contrasting known paraneoplastic syndromes can be used as a
diagnostic tool to aid in identification of the underlying tumor state.
Paraneoplastic Syndromes
•We are presenting five paraneoplastic syndromes:
◦Lambert-Eaton Myasthenic Syndrome
◦Myasthenia Gravis Syndrome
◦Opsoclonus-Myoclonus Syndrome
◦Syndrome of Inappropriate Antidiuretic Hormone Secretion
◦Carcinoid Syndrome
Lambert-Eaton Myasthenic Syndrome
●Lambert-Eaton Myasthenic Syndrome is an
autoimmune disease of the neuromuscular
junction. Estimated global incidence is 0.48
cases per million.
●Lambert-Eaton can occur in the absence of
cancer, but about 50-60% of cases are
associated with some type of malignancy and
it is therefore characterized as a
paraneoplastic neurological syndrome.
●Paraneoplastic Lambert-Eaton is most
commonly associated with small cell lung
carcinoma.
Retrieved from: www.aboutcancer.com
Paraneoplastic Lambert-Eaton
Presentation
●The mean age of onset for paraneoplastic
Lambert-Eaton is 60 years. Approximately 65%
of patients with the condition are male, this
likely reflects the gender’s increased tendency
to smoke.
●Paraneoplastic Lambert-Eaton is
characterized by fatigue, weakness in proximal
muscle groups, autonomic dysfunction, and
abnormal reflexes.
●Symptoms of paraneoplastic Lambert-Eaton
almost always precede detection of lung
cancer because patients rarely complain of
lung issues.
Retrieved from: www.aan.com
Paraneoplastic Lambert Eaton Signs
and Symptoms
●Muscle weakness
○ Muscle weakness in proximal leg muscles
presents first in a majority of patients.
○ Weakness commonly develops in proximal arm
muscles after initial onset of leg weakness.
○ Muscle weakness generally spreads proximally
to distally and caudally to cranially as the
disease progresses.
○ Muscle weakness commonly terminates with the
oculobulbar muscles.
○ The diagram shows muscle groups commonly
affected by Lambert-Eaton. Darker shades of
green represent more frequent involvement in
the disease state.
(Titulaer and Verschuuren, 2011)
Paraneoplastic Lambert-Eaton Signs
and Symptoms
●Autonomic dysfunction
○ 80-96% of Lambert-Eaton patients report some kind of autonomic dysfunction.
■ The most common dysfunctions include:
● Xerostomia – dry mouth syndrome resulting from insufficient saliva production
● Erectile dysfunction
● Constipation
● Hypohidrosis – diminished sweat production
●Areflexia
○ Abnormal or absent tendon reflexes are commonly observed.
○ Post-exercise facilitation, where reflex response temporarily increases, is observed in 40% of LambertEaton patients.
Paraneoplastic Lambert-Eaton
Pathophysiology
●Small cell lung carcinoma is a tumor which
commonly expresses voltage gated calcium
channels on its surface.
●Calcium channels on the tumor’s surface act
as antigens to the immune system.
●Autoantibodies are produced against calcium
channels antigens.
●Paraneoplastic Lambert-Eaton is caused by a
cross-reactive immune response at
presynaptic calcium channels of the
neuromuscular junction.
Retrieved from: www.lems.com
Paraneoplastic Lambert-Eaton
Mechanism of Action
●Antibodies disrupt normal function of calcium
channels on the presynaptic neuron by
blocking calcium ion influx during
depolarization.
●Calcium ions are important for promoting the
binding of vesicles containing acetylcholine
(Ach) to the SNARE complex and the
subsequent exocytosis of the
neurotransmitter into the synaptic gap.
●Reduced calcium ion influx reduces the
release of Ach from the presynaptic
membrane.
(Hulsbrink and Hashemolhosseini 2014)
Paraneoplastic Lambert-Eaton
Mechanism of Action
●Reduced quantities of acetylcholine (Ach)
released into the synaptic gap results in less
frequent binding of postsynaptic Ach
receptors.
●If the Ach receptors do not bind their ligand,
their associated chemically gated ion channels
do not open.
●Diminished ion influx at the motor end plate
causes the membrane of the sarcomere to
reach threshold potential less frequently.
●Fewer action potentials are generated at the
motor end plate which results in decreased
muscle contractility (weakness).
(Hulsbrink and Hashemolhosseini 2014)
Lambert-Eaton Treatment
●Treatment for both paraneoplastic and non-tumor Lambert-Eaton begins with 3,4diaminopyridine (3,4-DAP).
●3,4-DAP treats muscle weakness in Lambert-Eaton patients by inhibiting presynaptic voltagegated potassium channels. This serves to prolong presynaptic membrane depolarization and
allows the unblocked calcium channels to stay open longer.
●If muscle weakness is not improved with 3,4-DAP treatment, pyridostigmine, a cholinesterase
inhibitor can be added to increase acetylcholine concentration in the synaptic gap.
Paraneoplastic Lambert-Eaton
Treatment
For patients with paraneoplastic Lambert-Eaton, treatment of the tumor should begin
immediately upon detection.
Oncological treatment courses include:
○ Surgical resection of the tumor – usually results in symptomatic improvement due to
reduced immune response and autoantibody recession.
○ Radiotherapy
○ Chemotherapy
●If full remission is not achieved, long-term treatment with the immunosuppressant,
prednisone, may lead to symptomatic improvement.
Myasthenia Gravis Syndrome
● Myasthenia gravis is a rare autoimmune disorder that
affects the neuromuscular junctions of skeletal muscles.
The body’s immune system creates antibodies against its
own postsynaptic acetylcholine receptors.
● This rare syndrome occurs in 2 out of every million people
in the U.S.
● Paraneoplastic myasthenia gravis is typically associated
with thymomas.
● Thymomas don’t directly produce symptoms. Onconeural
antibodies produced against the cancer are the causative
agents of the disease state.
Myasthenia Gravis Presentation
● More than 50% of myasthenia gravis patients
present with eye-related issues as their initial
symptom. Symptoms include:
◦ Ptosis - drooping of the eyelids
◦ Diplopia - double vision
● About 15% of myasthenia gravis patients
present with symptoms involving face and throat
muscles which can result in:
◦ Altered speech
◦ Difficulty swallowing
◦ Problems chewing
◦ Loss of facial expression
Retrieved from www.clinicaladvisor.com
Myasthenia Gravis Signs and Symptoms
◦Myasthenia gravis is characterized by specific muscle weakness rather than generalized
muscle weakness.
◦Extraocular weakness (ptosis) is present in 50% of patients at disease onset and develops
in 90% of patients over the course of the illness.
◦In 16% of patients the syndrome exclusively affects ocular muscles.
◦Bulbar muscle weakness is also a common symptom resulting in cranial extensor and
flexor weakness.
◦Weakness of proximal muscles occurs before it spreads to distal muscles.
◦Symptoms of weakness tend to progress throughout the day.
Myasthenia Gravis Pathophysiology
○
○
○
○
Anti-acetylcholine receptor antibodies produced by the
immune system block the target receptors on the
postsynaptic membrane.
Reduction of acetylcholine receptors at the motor
endplate and flattening of the postsynaptic folds reduce
the number of excitatory postsynaptic potentials even
though there is a normal amount of acetylcholine getting
released.
Insufficient neuromuscular transmission causes reduced
action potential production on the motor end plate and
muscle weakness.
Patients tend to experience symptoms after postsynaptic
acetylcholine receptor density decrease to less than 30%
of normal levels.
Myasthenia Gravis Treatments
○
○
○
There is no standard treatment strategy for myasthenia gravis.
Commonly used treatments include: anticholinesterase medication and
immunosuppressive agents.
Surgical removal of the thymus gland, known as thymectomy, has become a
common treatment for patients suffering from myasthenia gravis.
◦ Up to 85% of patients experience symptomatic improvements following
thymectomies and up to 30% experience complete remission.
Paraneoplastic OpsoclonusMyoclonus Syndrome
● “Dancing Eye Syndrome”
● Rare disorder which arises
from paraneoplastic
neurological disorders
● Many associations
○ Paraneoplastic
○ Cancer is usually
diagnosed before
Opsoclonus-Myoclonus
Syndrome
(Sahu and Prasad, 2011)
Presentation of OpsoclonusMyoclonus Syndrome
Children
● Usually associated with
neuroblastomas
○ 50% of cases present
opsoclonus-myoclonus
syndrome
● Seen in patients between 6-36
months
Adults
● Paraneoplastic association in
60% of cases
○ especially associated with
small-cell lung cancers and
breast cancer
● Cases present in 60’s
(Sahu and Prasad, 2011)
Opsoclonus-Myoclonus Syndrome
Signs and Symptoms
● rapid, chaotic, involuntary
multidirectional eye movements
○ continues during sleep
● myoclonus
● cerebellar ataxia
○ acute or subacute
○ inability to sit or stand
● uncoordinated movements
● tremors
● encephalopathy
○ disorientation
○ inattentiveness
● irritability
● sleep disturbances
evaluation
algorithm for
suspected
OpsoclonusMyoclonus
Syndrome
(Sahu and Prasad, 2011)
Pathophysiology of OpsoclonusMyoclonus Syndrome
● Immune mediated
○ Anti-neuronal antibodies in serum and cerebrospinal fluid
detected in some patients
■ Anti-RI, Anti-Zic2, anti-polyposis coli antigen
● Mechanism still under investigation
○ Possible de-inhibition of cerebellar nuclei
○ Possible dysfunction in brainstem premotor neurons
premotor
neurons
(Esposito et al., 2014)
Netter et al., 2002
Treatment and Management of OpsoclonusMyoclonus Syndrome
Immunomodulation
● Adrenocorticotropic hormone and oral corticosteroids
○ modulate B cell proliferation and antibody production
○ inhibits antibody response to T cell dependent antigens
● Corticosteroids decrease lymphocyte differentiation and proliferation,
inhibit macrophage function, and suppress interleukin production
● Intravenous immunoglobulin
● Rituximab: monoclonal antibody binding to CD20 antigen on mature B
cell surface
Symptomatic management
● A number of drugs are administered to control involuntary muscle
movement, tremors, anxiety, sleep problems (Sahu and Prasad, 2011).
Prognosis of Opsoclonus-Myoclonus
Syndrome
● In children, opsoclonus-myoclonus syndrome can be
monophasic or chronic relapsing
○ results in long-term motor, behavioral, and cognitive
problems
● In adults, the prognosis is poor
○ The results are severe as mortality remains high despite
treatments
(Sahu and Prasad, 2011)
Syndrome of Inappropriate Antidiuretic
Hormone Secretion
•Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) is an endocrine disorder in which
the body is exposed to higher than normal levels of antidiuretic hormone (ADH).
•SIADH can develop in persons of any age group but is most common in the elderly.
•It is estimated that 67% of SIADH cases are caused by a hormone secreting tumor.
•70% of these cases are link to small cell carcinoma of the lung
•Small cell carcinomas have been shown to express the ADH synthesis gene.
•Cancers of the head and neck account for 1.5% of cases.
•In rare instances, SIADH can be caused by a thymoma.
•SIADH leads to increased body fluid volume which causes electrolyte imbalance.
Paraneoplastic SIADH Signs and
Symptoms
•Hyponatremia:
sodium concentration in the body fluid decreases due to excess water content.
• Symptoms of hyponatremia become more severe as the body fluids becomes more dilute.
• Between 5-10% dilution:
• Confusion
• Loss of equilibrium
• Unconsciousness
◦ Between 15-20% dilution:
◦ Altered mental status
◦ Seizures
◦ Coma
Antidiuretic Hormone (ADH)
Normal physiological role of ADH:
• When osmolarity rises above a certain threshold,
osmoreceptors stimulate neurons that cause
secretion of antidiuretic hormone (ADH) from
the anterior pituitary gland of the hypothalamus.
• Water conservation in the human body under
normal circumstances is controlled by ADH
secretion.
• ADH-mediated water conservation is essential
in cases of hemorrhaging and severe diarrhea to
maintaining adequate body fluid volume.
Retrieved from www.flipper.org
SIADH Pathophysiology
Normal amounts of ADH are produced by
the anterior pituitary gland. The ADH
secreting tumor causes systemic ADH level
to rise far above the normal value.
○ Aquaporins are localized on storage
vesicles in the cytoplasm of the epithelial
cells which make up the collection ducts
of the kidneys.
○ High ADH level stimulates mass fusion of
aquaporin-carrying storage vesicles with
the plasma membrane.
○ High aquaporin density facilitates high
diffusion of water across the plasma
membrane.
○ Excess water is resorbed from the
nephrons and is returned to the blood.
Retrieved from www.fmarion.edu
SIADH Treatment
• Optimal treatment of paraneoplastic SIADH is surgical removal of the underlying tumor, along with
fluid restrictions.
• Administration of IV hypertonic saline solution.
• In cases of severe hyponatremia involving symptoms such as, altered mental status, seizures, and
coma, treatment involves:
• Raising the patient’s serum sodium levels by 1-2 mmol/L per hour, not to exceed 8-10 mmol/L in
the first 24 hours of treatment
• In cases of moderate to minor hyponatremia involving symptoms such as confusion, loss of
equilibrium and unconsciousness, treatment involves:
•Raising the patient’s serum sodium levels by 0.5-1 mmol/L per hour
Carcinoid Syndrome
● Carcinoid syndrome refers to the various
symptoms typically exhibited by patients
with metastases from carcinoid tumors.
● A carcinoid tumor is a rare
neuroendocrinological malignancy that
originates from enterochromaffin cells in
the gastrointestinal tract.
●
Only 30-40% of neuroendocrine tumors
cause clinical syndromes which are
characterized as a paraneoplastic
syndrome.
Contrast-enhanced computed tomography scan of the liver showing
numerous masses compatible with metastases.
Carcinoid Syndrome Presentation
Location
● The median age at diagnosis is 63 years.
● Disease incidence was reported to be
5.25 cases per 100,000 persons in 2004.
● Carcinoid syndrome is characterized by
facial flushing, diarrhea, and abdominal
pain.
● Symptoms are similar to those in more
common conditions, such as irritable
bowel syndrome.
● It takes an average of 4 to 7 years to
diagnose carcinoid syndrome depending
upon the locations (table) of the tumors.
Location (% of total)
Esophagus
<0.1
Stomach
4.6
Duodenum
2.0
Pancreas
0.7
Gallbladder
0.3
Bronchus, lung, trachea
27.9
Jejunum
1.8
Ileum
14.9
Meckel's diverticulum
0.5
Appendix
4.8
Colon
8.6
Liver
0.4
Ovary
1.0
Testis
<0.1
Rectum
13
Carcinoid Syndrome Signs and
Symptoms
Facial Flushing
◦ Flushing in the face and upper trunk are
usually the first signs to present in
patients suffering from a midgut carcinoid
tumor.
◦Flushing is seen initially in 69–70% of
patients and in up to 78% as the disease
progresses..
◦Flushing may be worsened by hot foods
and beverages, chocolate, spicy foods,
tomatoes, alcohol, cheeses or emotional
stress.
Carcinoid Syndrome Signs and Symptoms
Diarrhea
◦Initial onset occurs in 32–73% of patients and
in 68–84% throughout the course of the
disease.
◦Steatorrhea, excess lipids in feces, is present in
67% of patients.
◦Diarrhea and flushing present together in 85%
of cases.
Abdominal Pain
◦ Abdominal pain commonly presents with
diarrhea, but occurs independently in 10–34%
of cases.
Carcinoid Syndrome Pathophysiology
● One of the main secretory products of carcinoid tumors involved in
carcinoid syndrome is 5HT (serotonin) which is synthesized from
tryptophan.
● Many different polypeptides such as insulin, gastrin, and somatostatin are
excreted by carcinoid tumors.
● CgA, a glycoprotein associated with serotonin excretion, is an important
tissue and serum marker for different types of carcinoid tumors found in
the foregut, midgut, or hindgut.
Carcinoid Syndrome Mechanism of Action
1. Tryptophan is transported from blood into
the cell via a transmembrane proteins.
2. Tryptophan is converted to 5hydroxytryptophan (5-HTP).
3. 5-HTP is converted to serotonin.
4. Serotonin is stored in secretory granules by
vesicular monoamine transporters (VMATs).
5. Serotonin is released through the basal lateral
membrane into the circulation.
6. Hypersecretion of serotonin by carcinoid
tumors disrupts neuroendocrine homeostasis
and leads to the symptoms associated with
carcinoid syndrome.
Serotonin
● About 90% of the body’s stores of
serotonin are present in
enterochromaffin cells in the
gastrointestinal tract.
● Serotonin is thought to be responsible
for the diarrhea because of its effects on
gut motility and intestinal secretion
through 5HT3 receptors.
● Serotonin binding to the 5HT3 receptor
results in increased acetylcholine release.
● Acetylcholine increases intestinal
motility, as it is an excitatory
neurotransmitter in the gastrointestinal
system.
Carcinoid Syndrome Treatment
● Treatments include:
◦Avoiding activities that precipitate flushing
◦Dietary supplementation with nicotinamide
◦Controlling the diarrhea with antidiarrheal agents such as loperamide or diphenoxylate.
● If symptoms persist, serotonin receptor antagonists or somatostatin analogues can provide
relief by reducing binding of serotonin to the receptor.
● Oncological treatments are also available but have limited success because the cancer has
usually metastasized.
Comparison of Paraneoplastic
Syndromes
•There are striking similarities between several of
the paraneoplastic syndromes surveyed, but also
many diagnostically relevant differences.
•We believe that identifying the key physiological
differences between the resulting signs,
symptoms, and presentations will lead to a better
understanding of and ability to detect instances
of paraneoplasticity.
•The table outlines the basic syndrome classes,
causes, and pathophysiological action.
Paraneoplastic
Syndrome
Class
Associated Tumor
Hormone Excreted/
Antibody Target
Lambert-Eaton
Myasthenic Syndrome
Neurological
Small Cell Lung
Carcinoma
Voltage Gated Calcium
Channels
Myasthenia Gravis
Syndrome
Neurological
Thymoma
Acetylcholine
Receptors
Neurological
Neuroblastoma
or
Small Cell Lung
Carcinoma
Opsoclonus-Myoclonus
Syndrome
Syndrome of
Inappropriate
Antidiuretic Hormone
Secretion
Carcinoid Syndrome
General Neurons
Antidiuretic Hormone
Endocrine
Small Cell Lung
Carcinoma
Endocrine
Carcinoid Tumor
Serotonin
Lambert-Eaton Myasthenic Syndrome
and Myasthenia Gravis
●Lambert-Eaton myasthenic syndrome and
myasthenia gravis are both autoimmune disorders
affecting acetylcholine-mediated neuromuscular
junctions.
●The main difference between the two syndromes is
the target of the antibodies produced by the body’s
immune system.
●The ultimate effect of the two antibodies is
remarkably similar: reduction of excitatory
postsynaptic potentials on the motor end plate.
●Lambert-Eaton and myasthenia gravis are difficult
to clinically differentiate due to similar presentation
of muscle weakness.
Disorder
Clinical Features
Serology
Tumor association
Lambert-Eaton
Myasthenic Syndrome
Leg weakness; moves
caudocranially
Voltage Gated Calcium
Channel Antibodies
Small Cell Lung
Carcinoma
Acetylcholine receptor
Antibodies
Thymoma
Autonomic dysfunction
Diminished reflexes
Myasthenia Gravis
Oculobulbar weakness;
moves craniocaudally
Key Symptomatic Differences Between
Lambert-Eaton and Myasthenia Gravis
•
•
•
Clinical presentation of muscle weakness can be distinguished
between the two syndromes based on the initial muscle groups
affected, progression of weakness, and fluctuation of
weakness.
Initial muscle group affected:
◦ 90% of Myasthenia Gravis patients experience weakness of
the oculobulbar muscles as their first symptom.
◦ 80% of Lambert-Eaton patients experience weakness of the
thigh muscles as their first symptom.
We hypothesize that the difference is due variation in the
density of the two antibodies’ targets in the neuromuscular
junctions found in the eye muscles versus the leg muscles.
•
Neuromuscular junctions in oculobulbar muscles would
have fewer acetylcholine receptors than those in the leg
muscles which would cause them to be more susceptible
to receptor-targeting antibodies.
•
Neuromuscular junctions in the leg muscles would have
fewer calcium channels than those in the oculobulbar
muscles which would cause them to be more susceptible
to calcium channel-targeting antibodies.
Disorder
Clinical Features
Serology
Tumor association
Lambert-Eaton
Myasthenic Syndrome
Leg weakness; moves
caudocranially
Voltage Gated Calcium
Channel Antibodies
Small Cell Lung
Carcinoma
Acetylcholine receptor
Antibodies
Thymoma
Autonomic dysfunction
Diminished reflexes
Myasthenia Gravis
Oculobulbar weakness;
moves craniocaudally
Key Symptomatic Differences Between
Lambert-Eaton and Myasthenia Gravis
•
Progression of muscle weakness:
◦ Muscle weakness spreads caudocranially (tail to head) in
Lambert-Eaton.
◦ Muscle weakness spreads craniocaudally (head to tail) in
myasthenia gravis.
•
Disorder
Clinical Features
Serology
Tumor association
Lambert-Eaton
Myasthenic Syndrome
Leg weakness; moves
caudocranially
Voltage Gated Calcium
Channel Antibodies
Small Cell Lung
Carcinoma
Acetylcholine receptor
Antibodies
Thymoma
Autonomic dysfunction
We hypothesize that the difference in the spread of
muscle weakness is due to the location of the causative
tumor and association with either the circulatory or
lymphatic system.
•
•
Small cell carcinomas of the lungs are linked with the
circulatory system and this may play a role in
distribution of the antibodies that cause Lambert-Eaton.
Tymomas are integrated into the lymphatic system and
therefore intertwined with the immune system. This
association may allow antibodies that cause myasthenia
gravis to cross the blood brain barrier more readily than
others and target the cranial nerves involved in eye
movement.
Diminished reflexes
Myasthenia Gravis
Oculobulbar weakness;
moves craniocaudally
Key Symptomatic Differences Between
Lambert-Eaton and Myasthenia Gravis
•Fluctuation of muscle weakness:
• Strength of muscle contraction increases with continued
contraction in Lambert-Eaton.
• Strength of muscle contraction decreases with continued
contraction in myasthenia gravis.
Disorder
Clinical Features
Serology
Tumor association
Lambert-Eaton
Myasthenic Syndrome
Leg weakness; moves
caudocranially
Voltage Gated Calcium
Channel Antibodies
Small Cell Lung
Carcinoma
Acetylcholine receptor
Antibodies
Thymoma
Autonomic dysfunction
•We hypothesize that this difference is due to the disparity
in the density of acetylcholine receptors on the
postsynaptic membrane.
• In Lambert-Eaton, continued contraction releases small
amount of acetylcholine, but sustained release of
neurotransmitter leads to increased binding of the
postsynaptic receptors and increased strength of muscle
contraction.
• In myasthenia gravis, continued contraction releases
normal amounts of acetylcholine, but receptors for the
neurotransmitter quickly become saturated and muscle
contraction diminishes.
Diminished reflexes
Myasthenia Gravis
Oculobulbar weakness;
moves craniocaudally
Myasthenia Gravis Syndrome and Paraneoplastic
Opsoclonus-Myoclonus Syndrome
● Myasthenia gravis and paraneoplastic
opsoclonus-myoclonus syndrome are
both autoimmune mediated
neurological disorders.
● Both present with ocular problems,
however, initial symptoms are unique:
○ In myasthenia gravis, eye drooping is
observed and double vision is
reported
○ In paraneoplastic opsoclonusmyoclonus syndrome,
uncoordinated and multidirectional
eye movement is observed
Disorder
Paraneoplastic
Opsoclonus-Myoclonus
Syndrome
Clinical Features
involuntary eye
movements
Serology
Tumor association
General neurons
Neuroblastoma
or
Small Cell Lung
Carcinoma
Acetylcholine receptor
Antibodies
Thymoma
myoclonus
cerebellar ataxia
tremors
encephalopathy
irritability
Myasthenia Gravis
sleep disturbances
Oculobulbar weakness;
moves craniocaudally
Myasthenia Gravis Syndrome and Paraneoplastic
Opsoclonus-Myoclonus Syndrome Mechanisms
The main difference between the two syndromes is
that myasthenia gravis specifically affects the
acetylcholine receptors while opsoclonusmyoclonus targets neurons in general.
◦While the mechanism of opsoclonusmyoclonus syndrome is still under
investigation, it seems that anti-neuronal
antibodies generally react with and target
neurons of the central and peripheral nervous
system
◦In myasthenia gravis, onconeural antibodies
are found. Anti-acetylcholine receptor
antibodies block the target receptors on the
postsynaptic membrane
Disorder
Paraneoplastic
Opsoclonus-Myoclonus
Syndrome
Clinical Features
involuntary eye
movements
Serology
Tumor association
General neuronal
antibodies
Neuroblastoma
or
Small Cell Lung
Carcinoma
Acetylcholine receptor
Antibodies
Thymoma
myoclonus
cerebellar ataxia
tremors
encephalopathy
irritability
Myasthenia Gravis
sleep disturbances
Oculobulbar weakness;
moves craniocaudally
Key Symptomatic Differences Between Myasthenia
Gravis and Opsoclonus-Myoclonus
• Clinical presentation of the two
syndromes can be distinguished based on
the timing and presentation of ocular
movement, progression of ocular
weakness, and neurological symptoms.
• Initial signs or symptoms:
◦ 90% of Myasthenia Gravis patients
experience weakness of the oculobulbar
muscles as their first symptom.
◦ Opsoclonus-myoclonus patients usually
are diagnosed with cancer first,
followed by the onset of further signs
and symptoms.
Disorder
Paraneoplastic
Opsoclonus-Myoclonus
Syndrome
Clinical Features
involuntary eye
movements
Serology
Tumor association
General neuronal
antibodies
Neuroblastoma
or
Small Cell Lung
Carcinoma
Acetylcholine receptor
Antibodies
Thymoma
myoclonus
cerebellar ataxia
tremors
encephalopathy
irritability
Myasthenia Gravis
sleep disturbances
Oculobulbar weakness;
moves craniocaudally
Key Symptomatic Differences Between
MG and Opsoclonus-Myoclonus
•
We hypothesize that the difference in signs and
symptoms is due specificity of the two antibodies’
targets in the central nervous system (CNS).
• In myasthenia gravis, acetylcholine receptors are
targeted by receptor antibodies causing ocular
weakness.
• In opsoclonus-myoclonus, generalized neuronal
antibody activity leads to random, involuntary
eye movements due to the lack of
communication between neurons.
Disorder
Paraneoplastic
Opsoclonus-Myoclonus
Syndrome
Clinical Features
involuntary eye
movements
Serology
Tumor association
General neuronal
antibodies
Neuroblastoma
or
Small Cell Lung
Carcinoma
Acetylcholine receptor
Antibodies
Thymoma
myoclonus
cerebellar ataxia
tremors
encephalopathy
irritability
Myasthenia Gravis
sleep disturbances
Oculobulbar weakness;
moves craniocaudally
Key Symptomatic Differences between
SIADH and Lambert-Eaton
We hypothesize that though small cell lung carcinoma is
the common underlying case in both of these
syndromes, the differences in the symptoms are striking
because SIADH acts through hormonal imbalance while
Lambert-Eaton involves antibody production.
•In syndrome of inappropriate antidiuretic hormone
section, the small cell lung carcinoma will produce and
secrete tiny amounts of ADH, which will lead to
increased water retention in the body and
hyponatremia, causing seizures and tremors.
• In Lambert-Eaton, the voltage-gated calcium channel
antibodies makes it hard for the neurotransmitter to be
released into the neuromuscular junction, which causes
less binding to the post-synaptic neurotransmitter
receptor. This leads to a decrease in muscle strength
and reflex.
Disorder
:
Clinical Features
Serology
Tumor
Association
SIADH
Nausea/vomiting
Cramps/tremors
Irritability
Seizures
Antidiuretic
Hormone
Small Cell
Lung
Carcinoma
LambertEaton
Blurry Vision
Voltagegated
Calcium
Channel
Antibodies
Small Cell
Lung
Carcinoma
Difficulty
Swallowing
Blood Pressure
Changes
Decreased
reflexes
Carcinoid Syndrome and Syndrome of
Inappropriate Antidiuretic Hormone
Secretion
• Carcinoid syndrome and syndrome of
inappropriate antidiuretic hormone
secretion (SIADH) are both endocrine
disorders caused by excessive secretion of
hormones.
• The main difference between the two
syndromes is the over-secretion of
different hormones:
• The signs and symptoms can be easily
differentiated due to different
manifestations.
Carcinoid Syndrome and Syndrome of
Inappropriate Antidiuretic Hormone Secretion
• The syndromes can both result from tumors in the lungs.
•27.9% of all carcinoid tumors occur in the lungs, bronchus and trachea.
•Small cell lung carcinomas are associated with SIADH.
• Carcinoid tumors are neuroendocrine carcinomas, a family that also includes
small cell carcinoma.
• Principle cytologic features of carcinoid tumors include:
•Round or spindle-shaped cells with a salt-and-pepper chromatin pattern
•Variably sized nucleoli
•Granular cytoplasm
• The distinction is clinically essential because prognosis and treatment are
substantially different between the two syndromes.
• Misdiagnosis of a carcinoid tumor as a small cell carcinoma is common, while
the reverse is not often confused.
We hypothesize that the best clinical method of differentiation between
carcinoid syndrome and syndrome of inappropriate antidiuretic hormone
secretion is assessing hormone levels for imbalances through urine, saliva and
blood testing.
Small Cell Lung Carcinoma:
cytologystuff.com
Carcinoid Tumor of the Lung:
Surgicalpathologyatlas.com
Conclusion
•Though our survey of paraneoplastic syndromes was limited to just five examples of these strange
cancer-linked phenomena, we believe that through the comparisons drawn, we have identified several
potentially relevant parameters to consider when diagnosing a patient.
1. Serology - Are there any abnormalities detected in the patient’s lab work?
◦ Special attention should be paid to hormonal imbalances and unusual antibodies.
2. Presentation of original symptom – Location of the patient’s original symptom can help differentiate
between syndromes that present with common symptoms.
3. Progression of symptoms – Is there a directionality to the spread of the patient’s symptoms?
◦ Caudocranial versus crainocaudal may indicate the tumor’s location or blood supply.
Identification of the causative tumor may still prove difficult owing to the fact that some tumors are
able to secrete hormones and express antigenic proteins the immune system will react against.
However, a larger scale study would undoubtedly uncover more patterns and could lead to improved
diagnosis and treatment for the thousands of individuals suffering from paraneoplastic syndromes.
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