1. PARANEOPLASTIC neurological SYNDROMES*
07/16/96
PARANEOPLASTIC neurological SYNDROMES
Dr. zana a. Mohammed
m.b.cH.b. , f.i.b.m.s. *

2. DEFINITION All neurological abnormalities Not Caused By :*
07/16/96
DEFINITION
All neurological abnormalities Not Caused By :
Invasion by the tumor or its metastases
Infections
Ischemia, metabolic or nutritional deficits
Surgery or other treatment modalities
“Remote effects of cancer on the nervous system” *

3. Paraneoplastic syndromes are generally, but not always, irreversible.*
07/16/96
Neurological symptoms of paraneoplastic syndromes usually precede the identification of the cancer.
Usually when the paraneoplastic-related cancer is identified, it is small, nonmetastatic, and indolently growing.
Neurological disability caused by paraneoplastic syndromes is often profound in the absence of any other cancer symptoms.
Paraneoplastic syndromes are generally, but not always, irreversible. *

4. Paraneoplastic Syndromes May Affect:*
07/16/96
Paraneoplastic Syndromes May Affect:
Cerebral cortex
Brainstem
Spinal cord
Peripheral nerves
Neuromuscular junction
Muscle *

5. Why we should diagnosis the pns:*
07/16/96
Why we should diagnosis the pns:
Neurological 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 *

6. *
07/16/96
Incidence
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
LEMS 60% paraneoplastic
Subacute cerebellar degeneration 50% *

7. Onconeuronal Immunity *
07/16/96
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 *

8. Autoimmunity
9/18/2018

9. Tests for antibodies against the cancer-expressed neuronal proteins *
07/16/96
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 *

10. pleocytosis – intrathecal synthesis of IgG – oligoclonal band*
07/16/96
Pathologically:
loss of neurons + inflammatory infiltrates
CSF:
pleocytosis – intrathecal synthesis of IgG – oligoclonal band *

11. Pan-neuronal nuclei SCLC PEM/PSN, PCD Purkinje cytoplasm Ovary, breast*
07/16/96
Antibody
Target
Tumor
Syndrome Hu
Pan-neuronal nuclei
SCLC
PEM/PSN, PCD Yo
Purkinje cytoplasm
Ovary, breast
PCD Ri
As Hu but not PNS
Breast
POM Tr
As with Yo but M layer
Hodgkin’s
GluR1
mGluR1 receptor
Hodgikin’s
CV2
Oligo cytoplasm
SCLC, uterine sarcoma
LEMS, PCD, LE
PEM; paraneoplastic encephalomyelitis – PSN; paraneoplastic sensory neuropathy – PCD; paraneoplastic cerebellar deg – POM; paraneoplastic opsoclonis myoclonis – LEMS; lambert eaton myasthenic syndrome – LE; limbic encephalitis *

12. *
07/16/96
Diagnosis
PNS is the differential diagnosis of unexplained neurological syndromes
NOT A WAIST BASKET FOR UNEXPLAINED CASES *

13. Relation of the PND to tumor*
07/16/96
Relation of the PND to tumor
70% of cases PND proceed the diagnosis of cancer
70% of cases identification of the tumor in the 1st screening
Screening:
CT chest, abdomen and pelvis
FDG-PET whole body *

14. Paraneoplastic syndromes
Classic
Non-classic
Brain, cranial n, retina
Cerebellar deg
Limbic encephalitis
Encephalomyelitis
Ospoclonus-myoclonus
Brainstem encephalitis
Optic neuritis
Cancer-related retinopathy
Melanoma-associated retinopathy
Spinal cord
Stiff-person syndrome
Myelitis
Necrotizing myelopathy
Motor-neuro syndromes
NMJ
Lambert-Eaton myasthenic synd
Myasthenia gravis
Peripheral nerves or muscle
Sensory neuronopathy
Dermatomyositis
Intestinal pseudo-obstruction
Sensorimotor neuropathy
Acquired neuromyotonia
Autonomic neuropathy
Polymyositis
Acute necrotising myopathy

15. Diagnosis Paraneoplastic syndromes occur in patients:*
07/16/96
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 *

16. Diagnostic criteria of PND*
07/16/96
Diagnostic criteria of PND *

17. Suspected PND
Know cancer
Abs -ve
Rule out other
Neuro complications
Of cancer
Abs +ve
No cancer diag
Ab +ve
Search of tumor

18. Diagnosis with Known Cancer*
07/16/96
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 *

19. Diagnosis without Known Cancer*
07/16/96
Diagnosis without Known Cancer
Exclude other causes of nervous system dysfunction
Search for Cancer
CXR, pelvic examination,
mammograms, examine lymph nodes, serum cancer markers.
CSF for cells, IgG, OCB, cytology examination
Serum/CSF for autoantibodies
If CSF or autoantibodies positive then follow and search again *

20. Diagnosis Suggestive clinical features:*
07/16/96
Diagnosis
Suggestive clinical features:
Subacute onset, progress over weeks to months
Severe neurological disability
One portion of nervous system more than widespread involvement
Some syndromes present stereotypically *

21. Presence of autoantibodies:*
07/16/96
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. *

22. Treatment Unrewarding in general*
07/16/96
Treatment
Unrewarding in general
Most patient left with severe neurological disability
Immunosuppression ineffective in most, except some PNS.
Treatment of underlying tumor; stabilization of the condition *

23. *
07/16/96
Classic PNS
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 *

24. Second group of clinical syndromes “sometimes” associated with cancer *
07/16/96
Non-classic pns
Second group of clinical syndromes “sometimes” associated with cancer
More often appearing in the absence of a neoplasm
Polymyositis
Amyotrophic lateral sclerosis
Sensorimotor polyneuropathy *

25. “Classic Paraneoplastic Syndromes” Specific Syndromes*
07/16/96
“Classic Paraneoplastic Syndromes” Specific Syndromes *

26. Paraneoplastic Cerebellar Degeneration*
07/16/96
Paraneoplastic Cerebellar Degeneration
Most common
Best characterized
Rare disorder
A group of related disorders that differ in clinical features, prognosis, and types of malignancies *

27. PCD can be associated with any cancer, but most common: *
07/16/96
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 *

28. Sometimes only at autopsy*
07/16/96
Neurological symptoms prompt patient to see doctor before cancer is symptomatic
Cancer is usually found months to 2-4 years after onset of neurological symptoms
Sometimes only at autopsy *

29. slight incoordination in walking *
07/16/96
Clinical features:
slight incoordination in walking
rapidly evolving over weeks to months with progressive gait ataxia
incoordination in arms, legs and trunk
dysarthria
nystagmus *

30. most cannot walk without support cannot sit unsupported *
07/16/96
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 *

31. Neurological signs always bilateral, usually symmetric *
07/16/96
Neurological 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 *

32. *
07/16/96
Investigations
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
Oligoclonal band *

33. Ovarian carcinoma

34. Autoantibodies in serum and CSF*
07/16/96
Autoantibodies in serum and CSF
found in a subset of patients
react with Purkinje cells of cerebellum & tumor
well characterized
anti-Yo, anti-Hu, anti-Ri, anti-Tr, anti-CV2, anti-Ma proteins *

35. Autoantibodies in serum and CSF/cancer*
07/16/96
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 *

36. Once the disease peaks it doesn’t usually change *
07/16/96
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 *

37. Sensory Neuronopathy (SN)*
07/16/96
Sensory Neuronopathy (SN)
<20% paraneoplastic
Also occurs in patients with autoimmune disorder
2/3 of paraneoplastic SN have small-cell lung cancer
dysesthetic pain and numbness of distal extremities
severe sensory ataxia
all sensory modalities affected, loss of DTRs
motor is normal *

38. Proprioceptive loss: Prominent Ataxia: Sensory Pseudoathetosis *
07/16/96
Onset
Painful paresthesias & dysesthesias
Asymmetric; Distal or Proximal
No tumor at initial workup: 50%
Sensory loss (95%)
All modalities involved
Proprioceptive loss: Prominent
Ataxia: Sensory
Pseudoathetosis
Distribution
Proximal & Distal
Asymmetric (35%) or Symmetric
Upper limb only (25%)
Lower limb only (45%)
Discomfort: Pain (80%); Paresthesias *

39. rare complication of small-cell lung cancer *
07/16/96
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 *

40. *
07/16/96 *

41. *
07/16/96 *

42. Opsoclonus/Myoclonus Found in Children*
07/16/96
Opsoclonus/Myoclonus Found in Children
Opsoclonus
involuntary, arrhythmic, multidirectional, high-amplitude conjugate saccades
associated with myoclonus
may have cerebellar signs
50% of children have a neuroblastoma
Neurologic signs precede discovery of tumor in 50%
Anti-Ri antibody associated with opsoclonus *

43. Lambert-Eaton Myasthenic Syndrome (LEMS)*
07/16/96
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 *

44. Onset with proximal lower extremity weakness *
07/16/96
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 *

45. *
07/16/96
>92% with antibodies against P/Q-type voltage-gated calcium channels (presynaptic)
A LEMS diagnosis warrants a thorough investigation for underlying carcinoma, SCLC *

46. Unlike most paraneoplastic syndromes LEMS usually responds to: *
07/16/96
Unlike most paraneoplastic syndromes LEMS usually responds to:
plasmapheresis
corticosteroids
azathioprine
intravenous immunoglobin
Long-term treatment often needed *

47. Summary Paraneoplastic syndromes are rare*
07/16/96
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 [Onconeural Ab]
Disability persists despite treatment of underlying tumor *

48. Thanks