This document discusses paraneoplastic syndromes of the nervous system. It defines paraneoplastic syndromes as disorders that accompany benign or malignant tumors but are not directly caused by tumor invasion or mass effects. It then lists and describes various paraneoplastic syndromes that can affect the central nervous system, peripheral nervous system, neuromuscular junction, and muscles. The document discusses the pathogenesis of paraneoplastic syndromes and antibodies associated with different syndromes. It provides information on incidence, diagnostic criteria, treatment approaches, prognosis, and testing considerations for paraneoplastic syndromes.

1. Paraneoplastic syndromes of
the nervous system
Dr. Sunil Thomas George

2. Introduction
 Heterogenous group of disorders that accompany benign or malignant
tumors BUT are NOT directly related to mass effects or invasion

3. Paraneoplastic syndromes
Central nervous system
Peripheral nervous system

4. Paraneoplastic syndromes
of the central nervous
system
 Encephalomyelitis
 Myelitis
 Limbic encephalomyelitis
 Brainstem encephalitis
 Cerebellar degeneration
 Opsoclonus myclonus ataxia
• Visual syndromes:
 Cancer associated retinopathy
 Melanoma associated
retinopathy
 Stiff person syndrome
 Subacute sensory
neuronopathy
Note:
Listed here are syndromes in which specific
paraneoplastic markers have been identified in
more than three patients

5. Paraneoplastic syndromes
of the peripheral nervous
system
 Autonomic neuropathy
Paraneoplastic syndromes
of the neuromuscular
junction and muscle
 Myasthenia gravis
 Lambert-Eaton myasthenic
syndrome
 Neuromyotonia

6. Pathogenesis
 Immunological factors believed to be responsible.
 Immunologic response is directed against shared antigens that are ectopically expressed by the
tumor, but otherwise exclusively expressed by the nervous system, or rarely by the nervous
system and testes . For unknown reasons, the immune system identifies these antigens as foreign
and mounts an immune attack against them. One report suggests that the immune system can
mount a T-cell response to a normal protein when it is expressed in a cancer cell, suggesting that
normal self-antigens may be processed differently in cancer cells than in the normal cells

7. Pathogenesis
 Antibodies that occur in paraneoplastic disorders have been divided in two categories depending
on the location of the antigen.
 Antibodies directed against
intracellular neuronal proteins
(called classical paraneoplastic or
well-characterized antibodies)
 Antibodies directed against neuronal
cell surface or synaptic proteins

8. Antibody Syndrome Associated cancers
Anti-Ma proteins(Ma1,
Ma2)
Limbic, hypothalamic,
brainstem
encephalomyelitis
(infrequently cerebellar
degeneration)
Testicular germ cell
tumors, lung cancer, other
solid tumors
Anti-VGCC Cerebellar degeneration SCLC
Well-characterized paraneoplastic antibodies:Antibodies to Ma2: younger than 45 years, usually men with testicular germ cell tumors; older than
45, men or women with lung cancer and less frequently other tumors. Ma1 antibodies often
associated with tumors other than germ cell neoplasms and confer a worse prognosis, with more
prominent brainstem and cerebellar dysfunction.
The identification of these antibodies in a patient with cerebellar dysfunction indicates paraneoplasia,
almost always associated with an SCLC. These antibodies are also found in patients with Lambert-
Eaton myasthenic syndrome, in which only approximately 50% of patients have cancer.

9. Partially characterized paraneoplastic antibodies:
Antibody Syndrome Associated cancers
Anti-Zic 4
Cerebellar degeneration SCLC
Anti-ANNA-3 Sensory neuronopathy,
encephalomyelitis
No tumor or Hodgkin
lymphoma

10. Antibody screening
 Well-characterized paraneoplastic antibodies against intracellular antigens (Classical) are almost
always detectable in Serum
 Rare instances detectable in CSF and NOT in Serum

11. Antibody screening
In contrast,
 Antibodies to all surface or synaptic proteins (those that associate with encephalitis with or
without a cancer association) are only seen in CSF
OR
 Serum may give misleading results

12. Incidence
 LEMS -> seen in 3% of SCLC
 MG -> seen in 15% of Thymoma
 One or more paraneoplastic neurologic disorder is present in up to 9% of patients with SCLC.
Most commonly - LEMS
Sensory neuronopathy
Limbic encephalitis

13. Incidence
 Paraneoplastic peripheral neuropathy affect 5-15 % of patients with – Plasma cell dyscrasias
associated with malignant monoclonal gammopathies
 Motor paraneoplastic peripheral neuropathy is seen in more than 50 % of cases of osteosclerotic
form of myeloma.

14. Incidence
 Patients with myeloma, usually osteosclerotic type can develop- Severe, symmetric, sensorimotor
neuropathy with muscle atrophy in association with POEMS syndrome
Polyradiculopathy
Organomegaly
Endocrinopathy
M-Protien Skin

15. Diagnostic criteria – 2 categories
Definite
Possible

16. Definite
 A classical syndrome and cancer that develops within 5 years of diagnosis of the neurologic
disorder.
 A non classical syndrome that resolves or significantly improves after cancer treatment without
concomitant immunotherapy. (provided syndrome is not susceptible to spontaneous remission)

17. Definite
 A non classical syndrome with paraneoplastic antibodies and cancer that develops within 5 years
of diagnosis of the neurologic disorder.
 A neurologic syndrome (classical or not) with well characterized paraneoplastic antibodies and no
cancer

18. Possible
 A classical syndrome with no paraneoplastic antibodies, no cancer BUT at high risk to have
underlying tumor.
 A neurologic syndrome (classical or not) with partially characterized paraneoplastic antibodies
and no cancer

19. Possible
 A non classical syndrome with no paraneoplastic antibodies, cancer present within 2 years of
diagnosis.

20. MRI of the brain – is sometimes useful

21. Treatment and prognosis
 Since most are immune mediated
 There are two general approaches
Removal of antigen source by
treatment of underlying tumor
Suppression of the immune
response

22. Syndromes likely to respond to treatment
 Immunosuppression is beneficial for :
 Plasma exchange
or
 IVIG (0.4 g/kg daily x 5 days)
LEMS
MG

23. Encephalitis with antibodies against cell
surface antigens fairly respond to
immunosuppressive therapy
These disorders usually treated with 1st
line immunotherapy (Steroid,IVIG or
plasma exchange)
Failure?

24. Failure?
Second line therapy e.g. Rituximab or
cyclophosphamide

25. Further on antibody screening
 Antibodies such as P/Q type voltage-gated calcium channel antibodies in LEMS,
ACTH receptor antibodies in MG and most encephalitis syndromes related to neuronal cell surface
and synaptic antibodies associated with specific syndromes DO NOT DIFFRENTIATE BETWEEN
PARANEOPLASTIC AND NON PARANEOPLASTIC SYNDROMES.

26. In contrast,
 Other antibodies e.g. GAD – rarely have cancer
Amphiphysin – underlying tumor always present

27.  Serum of cancer patients without paraneoplastic syndrome may show low titers of antibodies
 Different antibodies can be associated with same paraneoplastic neurologic syndrome and vice
versa
 Testing for paraneoplastic antibodies can facilitate recognition of simultaneous occurrence of 2 or
more or ever 3 paraneoplastic syndromes in 1 patient.
 Examples: SCLC
Paraneoplastic Cerebellar degeneration LEMS
Anti-Hu antibody associated paraneoplastic encephalomyelitis can develop LEMS

28. In absence of characteristic antibodies in serum
 Specific diagnostic tests can be done
 MRI
 PET
 LP –CSF
 Electrophysiology
 CT abdomen/chest/pelvis
 Mammogram
 Breast MRI
 USG testes or pelvis

30.  Repeating imaging 3-6 months after evaluation can be fruitful.
 Negative evaluation to be followed up with up to 4 years.
 In LEMS up to 2 years is sufficient.

31.  If identified cancer is not consistent with paraneoplastic syndrome
Evaluate for another neoplasm

32. Thank you