1. PARANEOPLASTIC SYNDROMES
Steven K. Gerhardt, M.D.
Neurology Consultants of Dallas
9/20/2018

2. DEFINITION
“All neurologic abnormalities not caused by the cancer’s spread to the nervous system are paraneoplastic”
“Remote effects of cancer on the nervous system”

3. PARANEOPLASTIC SYNDROMES
Neurologic symptoms of paraneoplastic syndromes usually precede the identification of the cancer

4. PARANEOPLASTIC SYNDROMES
Usually when the paraneoplastic-related cancer is identified, it is small, nonmetastatic, and indolently growing

5. PARANEOPLASTIC SYNDROMES
Neurologic disability caused by paraneoplastic syndromes is often profound in the absence of any other cancer symptoms

6. PARANEOPLASTIC SYNDROMES
Paraneoplastic syndromes are generally, but not always, irreversible

7. Paraneoplastic Syndromes May Affect Any Portion of the Nervous System
Cerebral cortex
Brainstem
Spinal cord
Peripheral nerves
Neuromuscular junction
Muscle

8. Importance of Paraneoplastic Syndromes
Although rare, recognition by the physician is important:
Neurologic symptoms precede and prompt the diagnosis of systemic cancer in about 50% of patients
Some syndromes direct search to particular organs
In many cases the syndrome’s onset is while the cancer is small and curable

9. Pathogenesis Onconeuronal Immunity
“Tumor expression of proteins that normally are restricted to the nervous system triggers an immune response against the tumor that also affects the nervous system”
Only a small amount of tumor may trigger response

10. Pathogenesis continued
Tests for antibodies against the cancer-expressed neuronal proteins
Some disorders caused by antibodies
Myasthenia gravis
LEMS
Other disorders most likely caused by B and T cell mechanisms of neuronal injury

11. Diagnosis Paraneoplastic syndromes occur in patients:
not known to have cancer (most common)
with active cancer
in remission after treatment
exclude other cancer-associated process

12. Diagnosis with Known Cancer
Search for metastases
MRI of involved site
CSF cytology
Search for nonmetastatic disorders
Vascular, infectious, metabolic disorders, chemotherapy, radiation therapy
Serum/CSF for autoantibodies

13. Diagnosis without Known Cancer
Exclude other causes of nervous system dysfunction
Search for Cancer
CXR, pelvic examination,
mammograms, examine lymph nodes, serum cancer markers (CEA)
CSF for cells, IgG, OCB, cytology examination
Serum/CSF for autoantibodies
If CSF or autoantibodies positive then follow and search again

14. Diagnosis Suggestive clinical features:
Subacute onset, progress over weeks to months
Severe neurologic disability
One portion of nervous system more than widespread involvement
Some syndromes present stereotypically

15. Diagnosis Autoantibodies
Presence of autoantibodies:
helps to confirm the clinical diagnosis
focus the search for an underlying malignancy
Anti-Hu, Anti-Yo, Anti-Ri, Anti-Tr, Anti-CV2, etc.

16. Treatment Unrewarding in general
Most patient left with severe neurologic disability
Immunosuppression ineffective in most, except LEMS
? rapid onset without diagnosis or treatment before irreversible neuronal damage has occurred

17. Frequency of Paraneoplastic Syndromes
“Clinically significant paraneoplastic syndromes probably occur in fewer than 1% of patients with cancer”
If a patient without a known cancer presents with one of the “classic” paraneoplastic syndromes the likelihood he/she has cancer is considerable
i.e., LEMS 60% paraneoplastic
Subacute cerebellar degeneration 50%

18. “Classic Paraneoplastic Syndromes”
A group of disorders, when present, strongly suggests an underlying cancer
Lambert-Eaton myasthenic syndrome (LEMS)
Opsoclonus/myoclonus found in children
Subacute cerebellar degeneration
Encephalomyelitis
Subacute motor neuronopathy
Sensory neuronopathy

19. “Non-classic” Paraneoplastic Syndromes
Second group of clinical syndromes “sometimes” associated with cancer
More often appearing in the absence of a neoplasm
Polymyositis
Amyotrophic lateral sclerosis
Sensorimotor polyneuropathy
Extensive search for a neoplasm is generally unwarranted

20. “Classic Paraneoplastic Syndromes” Specific Syndromes
Paraneoplastic cerebellar degeneration
Most common
Best characterized
Rare disorder
300 cases report by 1995
A group of related disorders that differ in clinical features, prognosis, and types of malignancies

21. Paraneoplastic Cerebellar Degeneration
Disorders can be separated by characteristic antibodies to particular tumor-associated antibodies
PCD can be associated with any cancer, but most common:
lung cancer (small-cell)
ovarian
uterine
lymphomas

22. Paraneoplastic Cerebellar Degeneration
Neurologic symptoms prompt patient to see doctor before cancer is symptomatic
Cancer is usually found months to 2-4 years after onset of neurologic symptoms
Sometimes only at autopsy

23. Paraneoplastic Cerebellar Degeneration
Clinical features:
slight incoordination in walking
rapidly evolving over weeks to months with progressive gait ataxia
incoordination in arms, legs and trunk
dysarthria
nystagmus with oscillopsia

24. Paraneoplastic Cerebellar Degeneration
Within a few months it reaches its peak and then stabilizes
most cannot walk without support
cannot sit unsupported
handwriting is impossible
eating independently difficult
speech very difficult to understand
oscillopsia may prevent reading
diplopia & vertigo

25. Paraneoplastic Cerebellar Degeneration
Neurologic signs always bilateral, usually symmetric
Deficits frequently limited to cerebellar dysfunction
Other neurologic deficits (mild)
sensorineural hearing loss
dysphagia
hyperreflexia
extrapyramidal signs
peripheral neuropathy
dementia

26. Paraneoplastic Cerebellar Degeneration
Laboratory evaluation
diffuse cerebellar atrophy months to years after onset on head imaging
CSF (early)
increased lymphocytes
slightly elevated protein and IgG concentrations
Pleocytosis resolves with time

27. Paraneoplastic Cerebellar Degeneration
Autoantibodies in serum and CSF
found in a subset of patients
number is unknown
react with Purkinje cells of cerebellum & tumor
well characterized
anti-Yo, anti-Hu, anti-Ri, anti-Tr, anti-CV2, anti-Ma proteins,

28. Paraneoplastic Cerebellar Degeneration
Autoantibodies in serum and CSF/cancer
anti-Yo ovary, breast
anti-Hu SCLC
anti-Ri Breast, SCLC,
anti-Tr Hodgkin’s lymphoma
anti-CV2 SCLC
anti-Ma proteins Testicular

29. Paraneoplastic Cerebellar Degeneration
Pathology
CNS may be normal at autopsy
usually the cerebellum is atrophic with abnormally widened sulci and small gyri
microscopic
extensive/complete loss of Purkinje cells of the cerebellar cortex
pathologic changes sometimes involving other parts of nervous system

30. Paraneoplastic Cerebellar Degeneration
Diagnosis
recognize characteristic clinical syndrome
exclude other causes of late-onset cerebellopathy
Leptomeningeal metastasis
infections
toxicity of chemotherapies
viral brainstem encephalitis
demyelinating disease
Creutzfeld-Jakob disease
infarction, hypothyroidism
alcoholic and hereditary cerebellar degenerations

31. Paraneoplastic Cerebellar Degeneration
Once the disease peaks it doesn’t usually change
Treatment or cure of underlying cancer usually doesn’t help
Immune suppression (steroids) or plasmapheresis is not effective
? clonazepam for ataxia

32. More “Classic” Syndromes Sensory Neuronopathy (SN)
<20% paraneoplastic
Also occurs in patients with autoimmune disorders, Sjogren’s syndrome
2/3 of paraneoplastic SN have small-cell lung cancer
Neurologic syndrome usually precedes diagnosis of cancer
dysesthetic pain and numbness of distal extremities
severe sensory ataxia
all sensory modalities affected, loss of DTRs
motor nerve action potentials are normal

33. Subacute Motor Neuronopathy (Spinal Muscular Atrophy)
Rare complication of Hodgkin’s and other lymphomas
Subacute, progressive, painless, patchy lower motor neuron weakness
Affects legs more than arms
Profound weakness
Degeneration of neurons in the anterior horns of the spinal cord

34. Encephalomyelitis
Cancer patients with clinical signs of damage to more than one area of the nervous system
Limbic encephalitis
rare complication of small-cell lung cancer
personality/mood changes develop over days or weeks
severe impairment of recent memory
sometimes with agitation, confusion, hallucinations, & seizures
brain MRI: normal or signal changes in the medial temporal lobe(s)
may improve with treatment of underlying tumor

35. Opsoclonus/Myoclonus Found in Children
involuntary, arrhythmic, multidirectional, high-amplitude conjugate saccades
associated with myoclonus
may have cerebellar signs
50% of children harbor a neuroblastoma
Neurologic signs precede discovery of tumor in 50%
Anti-Ri antibody associated with opsoclonus

36. Photoreceptor Degeneration*
07/16/96
Photoreceptor Degeneration
Cancer-associated retinopathy (CAR)
Rare syndrome
Small-cell lung cancer, melanoma, gynecologic tumors
Episodic visual obscurations, night blindness, light-induced glare, photosensitivity, impaired color vision progressing to painless vision loss
Typically precedes diagnosis of cancer
? prednisone *

37. Lambert-Eaton Myasthenic Syndrome (LEMS)
Presynaptic disorder of neuromuscular transmission
Proximal weakness, areflexia or hyporeflexia, autonomic dysfunction
45% to 60% associated with SCLC, reported also with renal cell carcinoma, lymphoma and breast
Syndrome precedes tumor diagnosis by several months to years

38. Lambert-Eaton Myasthenic Syndrome (LEMS)
Onset with proximal lower extremity weakness
Later proximal upper extremity weakness
Respiratory and craniobulbar involvement uncommon
Autonomic dysfunction prominent
dry mouth, dry eyes, impotence, orthostatic hypotension, hyperhidrosis
Facilitation with sustained contraction
>100% CMAP increase with repetitive stimulation

39. Lambert-Eaton Myasthenic Syndrome (LEMS)
>92% with antibodies against P/Q-type voltage-gated calcium channels (presynaptic)
Impaired influx of calcium into nerve terminal with reduced neuromuscular junction transmission
A LEMS diagnosis warrants a thorough investigation for underlying carcinoma, SCLC
Careful observation and serial evaluations until tumor found

40. Lambert-Eaton Myasthenic Syndrome (LEMS)
Unlike most paraneoplastic syndromes LEMS usually responds to:
plasmapheresis
corticosteroids
azathioprine
intravenous immunoglobin
Long-term treatment often needed

41. Summary Paraneoplastic syndromes are rare
Often precede the diagnosis of cancer
Thought to result from cross-reactivity of antibodies to a common antigen within tumor and nervous tumor
Disability persists despite treatment of underlying tumor