Paraneoplastic Neurological Syndromes and Associated Disorders - PNS

Diagnosis

Indications for Testing

• Neurologic disease of unknown etiology without evidence of malignancy
• Neurologic disease with high suspicion of malignancy or known risk factors for malignancy

Criteria for Diagnosis

• PNS can be classified based on consensus criteria (Graus et al, 2004)
  • Presence or absence of tumors
  • Presence of classic symptoms
  • Characterization of onconeuronal antibodies

Laboratory Testing

• PNS are rare
  • Initial antibody testing should be targeted toward well-characterized antibodies
• Rule out central nervous system (CNS) infection or metabolic abnormality before testing for PNS
  • Cerebrospinal fluid (CSF) analysis
    • Protein, glucose, cell count
    • Viral polymerase chain reaction (PCR) testing (eg, herpes simplex virus [HSV], human herpesvirus 6 [HHV6], varicella-zoster virus [VZV])
    • Oligoclonal band profile
    • Bacterial culture and Gram stain
    • Fungal culture
  • CBC
  • Electrolyte panel/metabolic profile
• If initial evaluations for infection and metabolic abnormalities are negative
  • Follow-up testing should be based on clinical presentation, age, and history – consider workup based on presence or absence of malignancy
    • No known malignancy – consider antibody tests based on their characterization, patient’s specific clinical manifestations (central versus peripheral nervous system; neuromuscular system), age, and sex
      • Characterization of antibodies – dependent on the number of studies describing their clinical relevance as well as the nature of antibodies and their effect on the disease process
      • PNS and some defined autoimmune neurologic diseases – may be confirmed by the presence of specific antibodies in the presence of clinically defined symptoms
      • No antibodies present – evaluate for other disorders associated with neurological symptoms
        • If infectious and metabolic evaluations are negative, proceed with further neurologic evaluation, including electromyography (EMG), muscle biopsy, CT, MRI
          • Negative neurologic testing – reevaluate in 6 months or sooner depending on symptoms
          • Positive neurologic testing – further evaluation based on test results
      • In children with encephalitis of unknown origin, PNS is very rare
        • Consider testing for voltage-gated potassium channel (VGKC) complex antibodies, N-methyl-D-aspartate receptor (NMDAR), and glutamic acid decarboxylase (GAD) autoantibodies
    • Known malignancy – antibody testing based on clinical symptoms and tumor type
      • Antibodies present – PNS confirmed
        • Titers may correlate with severity of neurological symptoms
        • Correlation between response to treatment and decline in antibody titer is antibody dependent
          • Antibodies to Hu (ANNA-1), Yo (PCCA-1), Ri (ANNA-2), CV2/CRMP5 (collapsin response mediator protein 5), Ma2/Ta (intracellular targets) may not decline with treatment
          • Neuronal surface antibodies (NSAbs) (eg, NMDAR) may decline
          • Decline associated with positive treatment response
      • Antibodies not present – evaluate for other cancer-related complications
        • CSF studies – spinal tap with cell count, protein level, culture with gram stain; also consider immunoglobulin G (CSF) and oligoclonal bands testing
          • Expected results in PNS – lymphocytic pleocytosis, increased protein concentration, change in oligoclonal bands (may be positive)
        • Electrolyte testing – comprehensive metabolic screening (electrolytes, blood urea nitrogen [BUN]/creatinine, hepatic enzymes, calcium)
        • EMG, muscle biopsy, MRI, positron emission tomography (PET) (may be the most sensitive imaging for detecting occult malignancy)

Antibody Tests to Consider

• Most antibodies have low positivity rates – initial testing should take these rates into account
  • Comprehensive panels – generally not cost effective due to low rate of positivity of less commonly observed antibodies
• Well-characterized antineuronal (also referred to as onconeuronal) antibodies
  Well-characterized antibodies by clinical syndromes and associated tumors

  Well-Characterized Antibodies (Target Intracellular Antigens)

  Antibody	Clinical syndromes	Associated tumors
  Hu	Sensory neuronopathy, encephalomyelitis, limbic/brainstem encephalitis, opsoclonus-myoclonus, subacute cerebellar degeneration, autonomic neuropathy, enteric neuropathy (gastrointestinal [GI] dysmotility)	Small cell lung carcinoma (SCLC), neuroblastoma
  Yo	Subacute cerebellar degeneration, GI dysmotility (occasionally), chorea	Ovary, breast
  CV2/CRMP5	Encephalomyelitis, chorea, limbic encephalitis, sensory neuronopathy, sensorimotor neuropathy, optic neuropathy (retinitis, optic neuritis, uveitis), subacute cerebellar degeneration, autonomic neuropathy, GI dysmotility	SCLC, thymoma
  Ri	Opsoclonus-myoclonus, brainstem encephalitis, subacute cerebellar degeneration, myelitis, jaw dystonia	SCLC, breast, ovary
  Ma2/Taa	Limbic/diencephalic/brainstem encephalitis, encephalomyelitis, subacute cerebellar degeneration, atypical Parkinsonism	Germ cell tumor (usually testicular), non-SCLC (male predominance)
  Amphiphysinb	Stiff-person syndrome, encephalomyelitis, subacute sensory neuronopathy, sensorimotor neuropathy, limbic encephalitis	SCLC, breast, ovary
  Recoverin	Retinopathy	SCLC, melanoma, others
  aBrainstem encephalitis and subacute cerebellar degeneration are usually associated with tumors other than testicular cancer. Sera from these patients also react with the Ma1 protein. bSynaptic antigenic target; associated with response to treatment

  • Target intracellular nuclear and cytoplasmic antigens
  • Neurologic symptoms and survival vary with both types of antibodies and tumors
    • Hu, Yo, Ri, CV2/CRMP5, Ma2/Ta, amphiphysin – all considered classic and diagnostic for PNS
      • Hu, Ri, Yo – most commonly observed antibodies
      • Hu and CV2/CRMP5  – may coexist
      • Yo and Ma2/Ta – associated with specific clinical manifestations and gender specific tumors
        • Warrant customized testing based on suspected tumor
      • Amphiphysin – synaptic target with a strong association for breast cancer and treatment response
• Cell surface and synaptic autoantibody targets
  Cell surface and synaptic antibodies by clinical syndromes and associated tumors

  Antibodies Against Cell Surface and Synaptic Antigens

  Antibody	Clinical syndromes	Associated tumors
  Extracellular Antibody Targets
  VGCC P/Q type	Lambert-Eaton myasthenic syndrome, subacute cerebellar degeneration	Small cell lung carcinoma (SCLC)
  VGCC N type	Lambert-Eaton, sensorimotor and autonomic neuropathy	SCLC, breast
  AChR	Myasthenia gravis	Thymoma
  nAChR (α3)	Subacute autonomic neuropathy	SCLC
  VGKC complex antibodies	Limbic encephalitis, neuromyotonia (Isaac syndrome), Morvan syndrome (limbic encephalitis and neuromyotonia), gastrointestinal (GI) dysmotility, undulating myeloma, cramp-fasciculation syndrome	Thymoma, SCLC
  LGI1a	Limbic encephalitis	SCLC, neuroendocrine
  Caspr2a	Limbic encephalitis, Morvan syndrome (limbic encephalitis and peripheral nerve hyperexcitability), neuromyotonia	Thymoma
  NMDAR (NR1)	Limbic/brainstem encephalitis, psychiatric syndromes	Ovarian teratoma
  AMPAR	Limbic encephalitis, agitation/psychiatric disturbances (not reported in children)	SCLC, breast, thymoma
  GABAB R	Limbic encephalitis (with early prominent seizures)	SCLC
  Intracellular Antibody Targets
  Amphiphysinb	Stiff-person syndrome, encephalomyelitis, subacute sensory neuronopathy, sensorimotor neuropathy, limbic encephalitis	SCLC, breast, ovary
  GAD	Stiff person syndrome, cerebellar degeneration, limbic encephalitis	Thymoma
  aVGKC-complex antibodies; may also occur independently of VGKC-complex antibodies bSynaptic antigenic target; associated with response to treatment AChR, acetylcholine receptor; AMPAR, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor; GABAB R, γ-aminobutyric acid-B receptor; GAD, glutamic acid decarboxylase; LGI1, leucine-rich glioma inactivated 1; nAChR, nicotinic acetylcholine receptor; NMDAR, N-methyl-D-aspartate receptor; SCLC, small cell lung carcinoma; VGCC, voltage-gated calcium channel; VGKC, voltage-gated potassium channel

  • Antibodies target cell surface (extracellular) or synaptic antigens
  • Not age dependent
  • May or may not be associated with malignancy
  • Generally thought to be pathogenic
  • Usually treatment responsive
  • NSAb syndromes – may be indistinguishable at presentation from classical PNS (eg, limbic encephalitis [LE])
    • ≥1 autoantibodies can be considered in the differential based on age and sex
    • NMDAR encephalitis – frequent in individuals of both genders and age groups and may mimic LE
      • Frequently nonparaneoplastic patients do respond to immunotherapy with a good chance for substantial recovery
    • LGI1 (leucine-rich glioma-inactivated 1) and CASPR2 (contactin-associated protein-like 2) – previously thought to be VGKC
    • Less common – AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor), GABA_BR (γ aminobutyric acid-B receptor), and mGluR1 (metabotropic glutamate receptor) antibodies
• Partially characterized antibodies
  Partially characterized antibodies by clinical syndromes and associated tumors

  Partially Characterized Antibodies (Target Intracellular Antigens)

  Antibody	Clinical syndromes	Associated tumors
  PCCA-Tr	Subacute cerebellar degeneration	Hodgkin lymphoma
  ANNA-3	Encephalomyelitis, subacute sensory neuronopathy, limbic encephalitis	SCLC
  PCCA-2	Encephalomyelitis, subacute cerebellar degeneration	SCLC
  Zic4	Subacute cerebellar degeneration	SCLC
  Anti-rod/bipolar cell	Optic neuropathy	Melanoma
  AGNA-1	Lambert-Eaton myasthenic syndrome	SCLC
  AGNA-1, anti-glial nuclear antibody; ANNA, antineuronal nuclear antibody; PCCA, Purkinje cell cytoplasmic antibody; SCLC, small cell lung carcinoma

  • ANNA-3, PCCA-2, PCCA-Tr, anti-glial nuclear antibody (AGNA-1, also referred to as SOX-1)
    • Autoantibodies are very rare and poorly characterized
    • Not recommended as first-line tests for PNS evaluation
    • Unlike Hu, Ri, amphiphysin, CV2/CRMP5, and Ma2/Ta antibodies, the presence of these antibodies is not sufficient to make a diagnosis of PNS
• Most antibodies have low positivity rates – initial testing should take these rates of positivity into account
  • Comprehensive panels – generally not cost effective due to low rate of positivity of less commonly observed antibodies

Antibodies, PNS, and Associated Tumors

Differential Diagnosis

• Subacute cerebellar degradation
  • Alcohol abuse
  • Vitamin deficiency (eg, B₁ (thiamine), B₁₂, vitamin E)
  • Medications (eg, lithium, anticonvulsants, 5-fluorouracil, and arabinofuranosyl cytidine [araC])
  • Infectious encephalitis – HIV, HSV, Creutzfeldt-Jakob disease, VZV, Epstein-Barr virus (EBV), Whipple disease
  • Immune-mediated nonparaneoplastic
    • GAD-associated cerebellar ataxia
    • Miller Fisher syndrome (anti-GQ1b antibodies)
    • Gluten sensitivity enteropathy (anti-gliadin antibodies)
  • Cerebrovascular accident
  • Malignancy – cerebellar metastases
  • Hypothyroidism, hypoparathyroidism
• Limbic encephalitis and variants
  • Alcohol abuse (Wernicke-Korsakoff syndrome)
  • Immune-mediated nonparaneoplastic
    • CNS vasculitis – primary angiitis of CNS
    • Connective tissue disease
      • Systemic lupus erythematosus
      • Sjögren syndrome
    • Multiple sclerosis
    • Hashimoto encephalopathy
  • Psychiatric disorders
  • Metabolic encephalopathy
  • Infectious encephalitis (eg, Treponema pallidum, HSV, HIV, West Nile virus (WNV), HHV6, Creutzfeldt-Jakob disease)
  • Malignancy
    • Metastases
    •  CNS gliomas
• Retinopathy
  • Vascular
  • Optic neuritis
  • Leber hereditary optic neuropathy (LHON)
  • Tobacco-alcohol amblyopia
• Lambert-Eaton myasthenic syndrome
  • Myasthenia gravis
  • Infectious encephalitis (eg, T. botulinum)
  • Episodic ataxia type 2
• Subacute sensory neuropathy
  • Immune-mediated nonparaneoplastic
    • Sjögren syndrome
    • Celiac disease
    • Cryoglobulinemia
    • Autoimmune ganglio neuropathies
  • Medications (eg, cisplatinum)
  • Vitamin disturbances
    • B₁₂ deficiency
    • B₆ excess
  • Infectious encephalitis (eg, HIV)
• Opsoclonus-myoclonus
  • Infectious encephalitis (eg, HIV, HSV, hepatitis C virus (HCV), Borrelia spp, Creutzfeldt-Jakob disease)
  • Postinfectious encephalitis (eg, M. pneumoniae, Streptococcus spp)
  • Metabolic encephalopathy (eg, hyperosmolar coma, hypoxia)
  • Medications (eg, lithium, tricyclic antidepressants)
  • Intracranial hemorrhage
  • Systemic disease
    • CNS vasculitis
    • Diabetes mellitus
    • Sarcoidosis
• Neurodegenerative disorders
• Malignancy
  • Cerebral metastases
  • Hydrocephalus
  • Neuroblastoma (children)

Background

Epidemiology

• Incidence – rare (Didelot, 2014)
• Exceptions
  • 3% of patients with SCLC are affected by Lambert-Eaton myasthenic syndrome (LEMS)
  • ~10% of patients who have plasma cell disorders with malignant monoclonal gammopathy may be affected by paraneoplastic peripheral neuropathy
  • 15% of patients with myasthenia gravis (MG) have thymoma

Pathophysiology

• Etiology
  • Some forms are autoimmune mediated
  • Immune response against tumors ectopically expressing neuronal antigens is provided by onconeuronal antibodies
  • Except in a very few cases (eg, LEMS and recoverin), the direct role of antibodies in the pathogenesis of a PNS has not been proven
• Classification of antibodies based on immunohistochemical staining pattern – refer to tables in Diagnosis

Clinical Presentation

• Central nervous system syndromes
  • Encephalomyelitis – brainstem, motor dysfunction
  • Limbic encephalitis – short-term memory loss, seizures, confusion, dementia
  • Subacute cerebellar degeneration – ataxia, slurred speech
  • Opsoclonus-myoclonus – involuntary saccadic eye movements may have truncal myoclonus
• Peripheral nervous system syndromes
  • Subacute sensory neuropathy
  • Chronic gastrointestinal pseudo-obstruction
• Neuromuscular junction, muscle, joint, bone syndromes
  • LEMS – less ocular involvement and more lower limb involvement than classic MG
  • Peripheral nerve hyperexcitability (neuromyotonia, Morvan syndrome)
  • Dermatomyositis
• Visual afferent system (neuro-ophthalmologic PNS) syndromes
  • Cancer-associated retinopathy
  • Melanoma-associated retinopathy