This document discusses neurological paraneoplastic syndrome, a heterogeneous group of neurological disorders caused by an immune response to cancer rather than directly from the cancer or its treatment. Key points: - The immune system mounts an abnormal response against antigens expressed by the cancer that are similar to neuronal antigens, leading to damage of nerve or muscle tissue. - Symptoms can include problems in the cerebral cortex, neuromuscular junction, or multiple areas of the nervous system. Neurological disability is often severe and irreversible. - Diagnosis involves identifying well-characterized antibodies, detecting cancer within 5 years, and ruling out other causes. Screening cancer patients without neurological symptoms still occasionally finds paraneoplastic antibodies.

1. Neurological Paraneoplastic
Syndrome

2. Introduction
• Heterogeneous group of disorders caused by mechanisms other than
metastases, metabolic, and nutritional deficits, infections
coagulopathy or side effects of cancer treatment
• May affect any part of nervous system
• Cerebral cortex  NMJ  Muscle
• Damaging one area (purkinje cell, presynaptic cholinergic synapses)
• Multiple areas ( encephalomyelitis)

3. Remote effect of cancer on nervous system
Differ from non metastatic complications:
Often precede identification of canceer
Time of development, cancer often
small and non metastatic
Neurological disability
Irreversible

4. Pathogenesis
• Not understood
• Believed immunologic because ab and T cell response
• Directed against antigens that are ectopically expressed by tumor
• Immune system identifies these antigen as foreign and mount immune
reaction against them
• T cell response to normal protein in cancer cell
• Suggest different expression of self antigen protein in cancer cells
• Ab can be detected in serum and CSF of many neoplastic syndromes
• Small cell lung cancer accounts for a disproportionate number of variety of
paraneoplastic

5. Features:
Subacute progression of
over weeks to months
Severe neurologic
disability
CSF often with cells IgG
and OCBs

6. • Direct pathogenic effect on target neuronal neuromuscular antigens
• P/Q type voltage gated calcium channel ab in LEMS
• ACH receptor ab in MG
• NMDA receptor NR1 ab in anti NMDAR encephalitis
• AMPA receptor (GluR1/2) ab in subgroup of limbic Encephalitis
• Ganglionic ACH receptor ab in autonomic neuropathy
• Recoverin ab in carcinoma associated retinopathy
Possible pathogensis:

8. Diagnostic criteria
• Definite
• Classical syndrome and cancer that develops within five years
• Nonclassical sx that resovles or significantly improves after cancer Rx
• Nonclassical sx with paraneoplastic ab and cancer that develops within five
years of diagnosis
• Neurological syndrome classical or not with well characterized ab
• Possible
• Classical, no paraneoplastic ab, no cancer but high risk for a tumor
• Neurological sx partially characterized by ab
• Nonclassical no paraneoplastic abs and cancer present within 2 yrs of dx

9. Antibody screening
• CSF may reveal antibody undetected in serum
• Well characterized and described in a table previously
• Important tenents:
• P/Q type voltage gated ca channel or ACH receptor ab with specific disorders
do not differentiate between paraneoplastic and non paraneoplastic cases
e.g., stiff person syndrome associated with GAD or amphiphysin
• Serum of cancer patients without paraneoplastic neurologic sx may contain
paraneoplastic ab although titers are usually lower
• Different ab can be associated with the same paraneoplastic and conversely
also that different paraneoplastic with same antibody
• Several paraneoplastic antibodies may co-occur in the same patients

10. Other diagnostics
• Can be difficult when antibodies not detected
• Absence of ab does not exclude paraneoplastic syndrome
• Several diagnostic tests are helpful:
• MRI: limbic encephalitis because medial temporal lobe show increased FLAIR
• Paraneoplastic cerebellar degeneration may develop atrophy significant on MRI
• PET: fluorodeoxyglucose will occasionally identify hypermetabolism of medial
temporal lobe with limbic encephalopathy
• LP: detection of AB confirms diagnosis, anti-Tr antibodies and patients with
antibodies to antigen expressed in the cell membrane of neurons of the
neuropil of hippocampus ANTI NMDA receptor titres in the CSF but not serum
• Electrophysiology: LEMS, myasthenia gravis, neuromyotonia, dermatomyositis
• Cancer search: Lung with LEMS, thymus with MG

12. Occult malignancy
• Not uncommon to develop before cancer is identified
• Antibody suggest specific underlying tumor
• Aided with best radiography to diagnose tumor
• PET scan for small occult neoplasms
• However negative PET/CT does not R/O cancer
• Workup done to R/O tumours is often carried
• LEMS screening for two years
• If found another cancer not related to specific paraneoplastic
syndrome then search again till you find it haha!

13. Treatment
• Two approaches:
• Removal of antigen source by treatment of underlying tumours
• Suppression of immune system
• LEMS and MG plasma exchange or IVIG
• Anti-B cell therapy rituximab for Ab mediated such as: stiff man sx,
dermatomyositis anti Yo positive paraneoplatic cerebellar degeneration,
and anti Hu antibody associated encephalomyelitis
• Oncologic treatment and immunotherapy (immunomodulation,
immunosuppression) can be beneficial
• Immunologic tx adjunct to oncologic should stratified accordingly
• Corticosteriods IV IG
• Immunosuppressive cyclophosphamide, tacrolimus or cycosporine