1. Paraneoplastic Syndromes
VANESA ADAME, ROSANGELA GARAY, SHEBA JOHN, JAY MARTINEZ, AND CYNTHIA SCHLECK
PHYSIOLOGY IN MEDICAL PRACTICE

2. 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.

3. 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.

4. 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

5. 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:

6. 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:

7. 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)

8. 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 Lambert- Eaton patients.

9. 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:

10. 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)

11. 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)

12. Lambert-Eaton Treatment
Treatment for both paraneoplastic and non-tumor Lambert-Eaton begins with 3,4-diaminopyridine (3,4-DAP).
3,4-DAP treats muscle weakness in Lambert-Eaton patients by inhibiting presynaptic voltage- gated 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.

13. 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.

14. 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.

15. 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

16. 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.

17. 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.

18. 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.

19. Paraneoplastic Opsoclonus- Myoclonus 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)

20. Presentation of Opsoclonus-Myoclonus Syndrome
Children
Usually associated with neuroblastomas
50% of cases present opsoclonus-myoclonus syndrome
Seen in patients between 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)

21. 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 Opsoclonus- Myoclonus Syndrome
(Sahu and Prasad, 2011)

22. Pathophysiology of Opsoclonus-Myoclonus 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

23. Treatment and Management of Opsoclonus-Myoclonus 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).

24. 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)

25. 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.

26. 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

27. 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

28. 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

29. 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 mmol/L per hour

30. 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.

31. Carcinoid Syndrome Presentation
Location
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
Rectum 13
The median age at diagnosis is 63 years.
Disease incidence was reported to be 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.

32. 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.

33. 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.

34. 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.

35. Carcinoid Syndrome Mechanism of Action
Tryptophan is transported from blood into the cell via a transmembrane proteins.
Tryptophan is converted to 5- hydroxytryptophan (5-HTP).
5-HTP is converted to serotonin.
Serotonin is stored in secretory granules by vesicular monoamine transporters (VMATs).
Serotonin is released through the basal lateral membrane into the circulation.
Hypersecretion of serotonin by carcinoid tumors disrupts neuroendocrine homeostasis and leads to the symptoms associated with carcinoid syndrome.

36. 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.

37. 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.

38. 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
Thymoma
Acetylcholine Receptors
Opsoclonus-Myoclonus Syndrome
Neuroblastoma or
General Neurons
Syndrome of Inappropriate Antidiuretic Hormone Secretion
Endocrine
Antidiuretic Hormone
Carcinoid Syndrome
Carcinoid Tumor
Serotonin

39. 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
Autonomic dysfunction
Diminished reflexes
Voltage Gated Calcium Channel Antibodies
Small Cell Lung Carcinoma
Myasthenia Gravis
Oculobulbar weakness; moves craniocaudally
Acetylcholine receptor Antibodies
Thymoma

40. 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
Autonomic dysfunction
Diminished reflexes
Voltage Gated Calcium Channel Antibodies
Small Cell Lung Carcinoma
Myasthenia Gravis
Oculobulbar weakness; moves craniocaudally
Acetylcholine receptor Antibodies
Thymoma

41. 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.
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.
Disorder
Clinical Features
Serology
Tumor association
Lambert-Eaton Myasthenic Syndrome
Leg weakness; moves caudocranially
Autonomic dysfunction
Diminished reflexes
Voltage Gated Calcium Channel Antibodies
Small Cell Lung Carcinoma
Myasthenia Gravis
Oculobulbar weakness; moves craniocaudally
Acetylcholine receptor Antibodies
Thymoma

42. 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.
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.
Disorder
Clinical Features
Serology
Tumor association
Lambert-Eaton Myasthenic Syndrome
Leg weakness; moves caudocranially
Autonomic dysfunction
Diminished reflexes
Voltage Gated Calcium Channel Antibodies
Small Cell Lung Carcinoma
Myasthenia Gravis
Oculobulbar weakness; moves craniocaudally
Acetylcholine receptor Antibodies
Thymoma

43. 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 opsoclonus- myoclonus syndrome, uncoordinated and multidirectional eye movement is observed
Disorder
Clinical Features
Serology
Tumor association
Paraneoplastic Opsoclonus-Myoclonus Syndrome
involuntary eye movements
myoclonus
cerebellar ataxia
tremors
encephalopathy
irritability
sleep disturbances
General neurons
Neuroblastoma or
Small Cell Lung Carcinoma
Myasthenia Gravis
Oculobulbar weakness; moves craniocaudally
Acetylcholine receptor Antibodies
Thymoma

44. 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 opsoclonus-myoclonus targets neurons in general.
While the mechanism of opsoclonus-myoclonus 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
Clinical Features
Serology
Tumor association
Paraneoplastic Opsoclonus-Myoclonus Syndrome
involuntary eye movements
myoclonus
cerebellar ataxia
tremors
encephalopathy
irritability
sleep disturbances
General neuronal antibodies
Neuroblastoma or
Small Cell Lung Carcinoma
Myasthenia Gravis
Oculobulbar weakness; moves craniocaudally
Acetylcholine receptor Antibodies
Thymoma

45. 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
Clinical Features
Serology
Tumor association
Paraneoplastic Opsoclonus-Myoclonus Syndrome
involuntary eye movements
myoclonus
cerebellar ataxia
tremors
encephalopathy
irritability
sleep disturbances
General neuronal antibodies
Neuroblastoma or
Small Cell Lung Carcinoma
Myasthenia Gravis
Oculobulbar weakness; moves craniocaudally
Acetylcholine receptor Antibodies
Thymoma

46. 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
Clinical Features
Serology
Tumor association
Paraneoplastic Opsoclonus-Myoclonus Syndrome
involuntary eye movements
myoclonus
cerebellar ataxia
tremors
encephalopathy
irritability
sleep disturbances
General neuronal antibodies
Neuroblastoma or
Small Cell Lung Carcinoma
Myasthenia Gravis
Oculobulbar weakness; moves craniocaudally
Acetylcholine receptor Antibodies
Thymoma

47. 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
Anti-diuretic Hormone
Small Cell Lung Carcinoma
Lambert- Eaton
Blurry Vision
Difficulty Swallowing
Blood Pressure Changes
Decreased reflexes
Voltage-gated Calcium Channel Antibodies
Small Cell Lung
Carcinoma :

48. 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.

49. 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

50. 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.
Serology - Are there any abnormalities detected in the patient’s lab work?
Special attention should be paid to hormonal imbalances and unusual antibodies.
Presentation of original symptom – Location of the patient’s original symptom can help differentiate between syndromes that present with common symptoms.
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.

51. Sources
Blaes, F., Jauss, M., Kraus, J., Oschmann, P., Krasenbrink, I., Kaps, M., & Teegen, B. (November 01, 2003). Adult paraneoplastic opsoclonus-myoclonus syndrome associated with antimitochondrial autoantibodies. Journal of Neurology, Neurosurgery & Psychiatry, 74, 11.)
Fauci, A. S. (2008). Harrison's principles of internal medicine. New York: McGraw-Hill Medical.
Hulsbrink, R. and Hashemolhosseini, S Lambert-Eaton myasthenic syndrome – Diagnosis, pathogenesis and therapy. Clinical Neurophysiology. Vol. 125:
Pelosof, L., & Gerber, D. (n.d.). Paraneoplastic Syndromes: An Approach to Diagnosis and Treatment. Retrieved April 24, 2015, from
Sahu, J. K., & Prasad, K. (June 01, 2011). The opsoclonus--myoclonus syndrome.Practical Neurology, 11, 3.)
Stoelting, R. K., Hillier, S. C., & Stoelting, R. K. (2006). Handbook of pharmacology & physiology in anesthetic practice.
Syndrome of Inappropriate Antidiuretic Hormone Secretion . (n.d.). Retrieved April 24, 2015, from
Titulaer, M.J., Lang, B. and Verschuuren, J.J.G.M Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neural. Vol. 10:
Williams, R. H., & Melmed, S. (2011). Williams textbook of endocrinology. Philadelphia: Elsevier/Saundersur, R. H. (January 01, 2009). Carcinoid syndrome. Cmaj : Canadian Medical Association Journal = Journal De L'association Medicale Canadienne, 180, 13.)
Yoo, M., Bediako, E., & Akca, O. (n.d.). Syndrome of Inappropriate Antidiuretic Hormone (SIADH) Secretion Caused by Squamous Cell Carcinoma of the Nasopharynx: Case Report. Retrieved April 24, 2015, from