Neurological ParaneoplasticSyndrome

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)

Remote effect of cancer on nervous system

Differ from non metastatic complications:Often precede identification of canceerTime of development, cancer often small and non metastaticNeurological disabilityIrreversible

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

Features:Subacute progression of over weeks to monthsSevere neurologic disabilityCSF often with cells IgGand OCBs

• 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:

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

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

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

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 paraneoplasticsyndrome then search again till you find it haha!

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