Paraneoplastic Neurological Syndromes, Mechanisms, Molecular Mimicry, Autoantibodies, Treatment, Clinical Assessment

1. Immunostaining with Anti-Tr antibody
10:41 PM

2. Paraneoplastic Neurological
Syndromes
A Review.
10:41 PM

3. Objectives
• To understand when in the course of
malignancy the syndromes occur
• To know the antineural antibodies associated
with the syndromes
• To differentiate efficacy of symptomatic
treatment vs. treatment of underlying disease
in the different syndromes
10:41 PM

4. Outline for the Session
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Introduction
History and Evolution of knowledge
Pathogenesis – Concept of ―Onconeural‖ Antigen
Definition – Terminology
Criteria for Diagnosis
Individual Syndromes
Summary

5. Outline for the Session
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•
•
•
•
Introduction
History and Evolution of knowledge
Pathogenesis – Concept of ―Onconeural‖ Antigen
Definition – Terminology
Criteria for Diagnosis
Individual Syndromes
Summary

6. Background
• Heterogeneous group of disorders
– Associated with systemic cancers
– Mechanisms other than…
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10:41 PM
Metastases
Metabolic and nutritional deficits
Infections
Coagulopathy
Side effects of treatment

7. DEFINITION
• ―All neurologic abnormalities not caused by the
cancer’s spread to the nervous system are
paraneoplastic‖
• Seminars Neurol 2004
• ―Remote effects of cancer on the nervous system‖
• NEJM 2004
• ―Distal, non metastatic menifestations of a tumor‖
• OTO 2005
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8. • Most symptomatic paraneoplastic syndromes
are rare, affecting perhaps 0.01 percent of
patients with cancer
• Rudnicki SA, Dalmau J. Paraneoplastic syndromes of
the spinal cord, nerve, and muscle. Muscle Nerve
2000;23:1800-18
• Exceptions…..
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9. • Lambert–Eaton myasthenic syndrome, which affects
about 3 percent of patients with small-cell lung cancer
• Sculier J-P, Feld R, Evans WK, et al. Neurologic disorders in
patients with small cell lung cancer. Cancer 1987;60:2275-83
• Myasthenia gravis, which affects about 15 percent of
patients with thymoma
• Levy Y, Afek A, Sherer Y, et al. Malignant thymoma associated
with autoimmune diseases: a retrospective study and review of the
literature. Semin Arthritis Rheum 1998;28:73-9.
• Demyelinating peripheral neuropathy, which affects
about 50 percent of patients with the rare osteosclerotic
form of plasmacytoma
• Latov N. Pathogenesis and therapy of neuropathies associated with
monoclonal gammopathies. Ann Neurol 1995;37:Suppl 1:S32-S42
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10. PARANEOPLASTIC SYNDROMES
• Neurologic symptoms of paraneoplastic
syndromes usually precede the identification
of the cancer
– Antoine JC, Cinotti L, Tilikete C, et al.
[18F]fluorodeoxyglucose positron emission tomography in the
diagnosis of cancer in patients with paraneoplastic neurological
syndrome and anti-Hu antibodies. Ann Neurol 2000;48:105-8
10:41 PM

11. PARANEOPLASTIC SYNDROMES
• Usually when the paraneoplastic-related cancer
is identified, it is small, nonmetastatic, and
indolently growing
– Graus F, Dalmou J, Reñé R, et al. Anti- Hu antibodies in
patients with small-cell lung cancer: association with complete
response to therapy and improved survival. J Clin Oncol
1997;15:2866-72
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12. PARANEOPLASTIC SYNDROMES
• Paraneoplastic syndromes are generally, but
not always, irreversible
• Neurologic disability caused by paraneoplastic
syndromes is often profound in the absence of
any other cancer symptoms
– Graus F, Keime-Guibert F, Reñe R, et al. Anti-Hu-associated
paraneoplastic encephalomyelitis: analysis of 200 patients.
Brain 2001;124:1138-48
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13. •
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Paraneoplastic Syndromes May
Affect Any Portion of the Nervous
System
Cerebral cortex
Brainstem
Spinal cord
Peripheral nerves
Neuromuscular junction
Muscle
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14. Background
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Occur in < 1% of pts with systemic cancer
Heralds diagnosis of cancer in up to 60%
Highly specific antineuronal antibodies
Most common (presence overlaps)
– Paraneoplastic cerebellar degeneration (PCD)
– Paraneoplastic encephalomyelitis /
sensory neuronopathy (PEM/PSN)
– Paraneoplastic opsoclonus myoclonus (POM)
– Lambert-Eaton myasthenic syndrome (LEMS)
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15. 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
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16. 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
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17. 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
10:41 PM

18. Outline for the Session
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Introduction
History and Evolution of knowledge
Pathogenesis – Concept of ―Onconeural‖ Antigen
Definition – Terminology
Criteria for Diagnosis
Individual Syndromes
Summary

19. • The concept of immune surveillance of cancer was first
formally put forward by Thomas and Burnet in the mid1950s
– Burnet, F. M. Cancer: a biological approach. Brit. Med. J. 1, 841-847 (1957).
• they proposed that immune mechanisms could act as a
natural defence against tumour cells
– Thomas, L. Cellular and humoral aspects of the hypersensitivity states.
in Discussion to P. B. Medawar's paper. (ed. Lawrence, H. S.) 529-534
(Harper, New York, 1959).
• link between the neurological degeneration and cancer in
PND is an immunological one
– Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer
immunoediting: from immunosurveillance to tumor escape. Nature
Immunol. 3, 991-998 (2002)
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20. • Symptoms usually develop rapidly in days or a
few weeks and then stabilize, leaving the patient
severely disabled.
• Exceptions do occur, and some patients develop
insidious forms of PND that can be misdiagnosed
as chronic degenerative disorders
– Graus F, Bonaventura I, Uchuya M, et al. Indolent anti-Huassociated paraneoplastic sensory neuropathy. Neurology
1994;44:2258-2261
– Bataller L, Graus F, Saiz A, Vilchez JJ. Clinical outcome in adult
onset idiopathic or paraneoplastic opsoclonus-myoclonus. Brain
2001;124:437-443
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21. • Spontaneous neurological improvement,
although reported in some syndromes, is rare
and should lead to the consideration of a
nonparaneoplastic etiology.
– Voltz, R. D., Posner, J. B., Dalmau, J. & Graus, F.
Paraneoplastic encephalomyelitis: an update of the effects of
the anti-Hu immune response on the nervous system and
tumour. J. Neurol. Neurosurg. Psychiatr. 63, 133-136 (1997)
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22. Immune Mediated
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ANTIGEN !!!!!

23. Outline for the Session
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Introduction
History and Evolution of knowledge
Pathogenesis – Concept of ―Onconeural‖ Antigen
Definition – Terminology
Criteria for Diagnosis
Individual Syndromes
Summary

24. 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
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25. Pathogenesis continued
• Tests for antibodies against the cancerexpressed neuronal proteins
• Some disorders caused by antibodies
– Myasthenia gravis
– LEMS
• Other disorders most likely caused by B
and T cell mechanisms of neuronal injury
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26. • Darnell, R. B. & Posner, J. B. Observing the
invisible: successful tumor immunity in humans. Nat
Immunol. 4, 201 (2003).
• Darnell, R. B. & Posner, J. B. Paraneoplastic
syndromes of the nervous system. N. Engl. J.
Med. 349, 1543-1554 (2003)
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27. 10:41 PM

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31. Discovery of MHC
Role of MHC as APC…
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32. 10:41 PM

33. Target Cell - DC
The Problem, However…
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36. Are PNS only based on Humoral
Immunity ?
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38. 10:41 PM

39. Outline for the Session
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•
•
Introduction
History and Evolution of knowledge
Pathogenesis – Concept of ―Onconeural‖ Antigen
Definition – Terminology
Criteria for Diagnosis
Individual Syndromes
Summary

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

41. “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
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42. Outline for the Session
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•
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•
•
Introduction
History and Evolution of knowledge
Pathogenesis – Concept of ―Onconeural‖ Antigen
Definition – Terminology
Criteria for Diagnosis
Individual Syndromes
Summary

43. 10:41 PM

44. Outline for the Session
•
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•
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•
•
Introduction
History and Evolution of knowledge
Pathogenesis – Concept of ―Onconeural‖ Antigen
Definition – Terminology
Criteria for Diagnosis
Individual Syndromes
Summary

45. 10:41 PM

46. Some generalizations …
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47. Frequency of Paraneoplastic
Syndromes
• ―Clinically significant paraneoplastic syndromes
probably occur in fewer than 0.1% of patients with
cancer‖
– Robert B. Darnell, M.D., Ph.D., and Jerome B. Posner, M.D, N Engl J
Med 2003;349:1543-54.
• 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%
– Robert B. Darnell, M.D., Ph.D., and Jerome B. Posner, M.D, N Engl J
Med 2003;349:1543-54.
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48. Diagnosis
• Suggestive clinical features:
– Acute or Subacute onset, may progress over
commonly days, sometimes weeks to months
– Severe neurologic disability
– One portion of nervous system more than
widespread involvement
– Some syndromes present stereotypically
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49. 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.
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50. Treatment
• Unrewarding in general
• Most patient left with severe neurologic disability
• Immunosuppression ineffective in most, except
LEMS and MG
• Exceptions …
• LEMS, MG, Neuropathy with Myeloma
• Adult OMS – may respond
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51. “Classic Paraneoplastic
Syndromes”
Specific Syndromes
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Paraneoplastic cerebellar degeneration
Most common
Best characterized
Rare disorder
– 780 cases report by 2005
• A group of related disorders that differ in clinical
features, prognosis, and types of malignancies
– Peterson K, Rosenblum MK, Kotanides H, Posner JB. Paraneoplastic
cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody
positive patients. Neurology 2002; 42:1931-7
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52. 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:
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lung cancer (small-cell)
ovarian
uterine
lymphomas

53. 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
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54. 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
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55. Paraneoplastic Cerebellar
Degeneration
• Within a few months it reaches its peak
and then stabilizes
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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

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

57. 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
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58. 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,
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59. Paraneoplastic Cerebellar
Degeneration
• Autoantibodies in serum and
CSF/cancer
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anti-Yo
ovary, breast
anti-Hu
SCLC
anti-Ri
Breast, SCLC,
anti-Tr
Hodgkin’s lymphoma
anti-CV2
SCLC
anti-Ma proteins
Testicular

60. 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
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61. Paraneoplastic Cerebellar
Degeneration
• Diagnosis
– recognize characteristic clinical syndrome
– exclude other causes of late-onset cerebellopathy
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Leptomeningeal metastasis
infections
toxicity of chemotherapies
viral brainstem encephalitis
demyelinating disease
Creutzfeld-Jakob disease
infarction, hypothyroidism
alcoholic and hereditary cerebellar degenerations

62. 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
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63. 10:41 PM

64. 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
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dysesthetic pain and numbness of face, trunk, extremities
severe sensory ataxia
all sensory modalities affected, loss of DTRs
motor nerve action potentials are normal

65. Subacute Motor Neuronopathy
(Spinal Muscular Atrophy, ALS like diseases)
• Rare complication of Hodgkin’s and other lymphomas
• <3% of cases are paraneoplastic
• 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
• Sometimes can have associated UMN signs
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66. Encephalomyelitis
• Cancer patients with clinical signs of damage to
more than one area of the nervous system
• Limbic encephalitis
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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
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67. 10:41 PM

68. Opsoclonus/Myoclonus Found in
Children
• Opsoclonus
– involuntary, arrhythmic, multidirectional, highamplitude 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
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69. POM
• In adults, most commonly associated with…
– Small cell lung cancer
– Breast cancer
• Develops prior to diagnosis of cancer
• Manifestations
– Rapidly progressive cerebellar ataxia
– Opsoclonus
– Myoclonus
• Treatment of cancer > immunosuppressive tx
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70. 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
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71. 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
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72. Lambert-Eaton Myasthenic
Syndrome (LEMS)
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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
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73. 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
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74. Lambert-Eaton Myasthenic
Syndrome (LEMS)
• Unlike most paraneoplastic
syndromes LEMS usually
responds to:
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plasmapheresis
corticosteroids
azathioprine
intravenous immunoglobin
• Long-term treatment often needed
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75. 10:41 PM

76. Are PNS’s because of abberencies
within the immune system ??
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77. • “Specifically, an immune response to neuronal
proteins that are expressed by the tumour cells
(termed onconeural antigens) recognize and
suppress the growth of the malignancy”
» Darnell, R. B. & Posner, J. B. Observing the invisible:
successful tumor immunity in humans. Nat Immunol. 4,
201 (2003).
» Darnell, R. B. & Posner, J. B. Paraneoplastic syndromes of
the nervous system. N. Engl. J. Med. 349, 1543-1554
(2003)
10:41 PM

78. 10:41 PM

79. • The tumor is often occult, and the neurologic disorder
typically precedes the diagnosis of the tumor.8,22
• patients with the Hu paraneoplastic syndrome typically
harbor small-cell lung cancers that are limited to single
nodules (53 of 55 patients in one study)
– Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu–associated
paraneoplastic encephalomyelitis/sensory neuropathy: a clinical study of
71 patients. Medicine (Baltimore) 1992;71:59-72.
• This was despite the fact that most small-cell lung
cancers (over 60 percent) are widely metastatic at
diagnosis.
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80. • The histologic features of tumors in
paraneoplastic neurologic disorders do not differ
from those of other tumors, except that the tumors
may be heavily infiltrated with inflammatory
cells.
» Cooper R, Khakoo Y, Matthay KK, et al. Opsoclonusmyoclonus-ataxia syndrome in neuroblastoma:
histopathologic features — a report from the Children’s
Cancer Group. Med Pediatr Oncol 2001;36:623-9.
» Rosenblum MK. Paraneoplasia and autoimmunologic
» injury of the nervous system: the anti-Hu syndrome. Brain
Pathol 1993;3:199-212.
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81. • Many reports suggest that patients with
paraneoplastic neurologic disorders have a better
prognosis than patients with histologically
identical tumors that are not associated with
paraneoplastic neurologic disorders.
» Altman AJ, Baehner RL. Favorable prognosis for survival in
children with coincident opso-myoclonus and neuroblastoma.
Cancer 1976;37:846-52.
» Maddison P, Newsom-Davis J, Mills KR, Souhami RL.
Favourable prognosis in Lambert- Eaton myasthenic
syndrome and smallcell lung carcinoma. Lancet
1999;353:117- 8.
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82. Treatment
• two treatment approaches
• removal of the source of the antigen by treatment of the
underlying tumor, and,
• suppression of the immune response
• Overall results disappointing in majority.
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83. Immunotherapy
• Predominantly Ab mediated – Plasma
exchange, IvIg, Corticosteroids
• Example – MG, LEMS
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84. Immunotherapy
• Predominantly T cell mediated
• drugs such as tacrolimus or mycophenolate Mofetil
» Albert ML, Austin LM, Darnell RB. Detection and treatment of
activated T cells in the cerebrospinal fluid of patients with
paraneoplastic cerebellar degeneration. Ann Neurol 2000;47:9-17
» Schneider C, Gold R, Reiners K, Toyka KV. Mycophenolate mofetil
in the therapy of severe myasthenia gravis. Eur Neurol 2001; 46:7982.
• Examples - paraneoplastic cerebellar degeneration with
anti-Yo antibodies or encephalomyelitis with anti-Hu
antibodies
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85. Recommended Regime
• IVIG @ 0.5 gm/kg/day x 5 days
• IV methylprednisolone @ 1 gm/day x 3days,
• IV cyclophosphamide @ 600 mg/m-2 BSA X 1 day
• Keime-Guibert F, Graus F, Fleury A, et al. Treatment of
paraneoplastic neurological syndromes with antineuronal
antibodies (Anti-Hu, Anti-Yo) with a combination of
immunoglobulins, cyclophosphamide, and
methylprednisolone. J Neurol Neurosurg Psychiatry
2000;68:479-82.
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86. • If there is evidence of improvement or stability, the
treatment can be repeated three times at three-week
intervals.
• If the patient improves after the third treatment,
maintenance treatment with
– IVIG @ 0.5 gm/kg/day x 5 days
– IV methylprednisolone @ 1 gm/day x 3days,
– IV cyclophosphamide @ 600 mg/m-2 BSA X 1 day
• Keime-Guibert F, Graus F, Fleury A, et al. Treatment of
paraneoplastic neurological syndromes with antineuronal
antibodies (Anti-Hu, Anti-Yo) with a combination of
immunoglobulins, cyclophosphamide, and methylprednisolone.
J Neurol Neurosurg Psychiatry 2000;68:479-82.
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87. • Tacrolimus @ 0.15 mg/kg/per day for 14 days,
followed by 0.3 mg/kg/day for 7 days.
• This regimen decreased the number of
activated T cells in the spinal fluid but had no
substantial effect on the clinical course.
» Albert ML, Austin LM, Darnell RB. Detection and
treatment of activated T cells in the cerebrospinal fluid of
patients with paraneoplastic cerebellar degeneration. Ann
Neurol 2000;47:9-17.
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88. • Most of the syndromes may have both arms,
therefore preferable to block both.
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89. Outline for the Session
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•
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•
Introduction
History and Evolution of knowledge
Pathogenesis – Concept of ―Onconeural‖ Antigen
Definition – Terminology
Criteria for Diagnosis
Individual Syndromes
Summary

91. 10:41 PM

92. Summary, take home points
• 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
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93. 10:41 PM