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Table 2 Characteristics of autoimmune encephalitis associated with neuronal surface antibodies

From: The autoantibody-mediated encephalitides: from clinical observations to molecular pathogenesis

Neuronal surface target Antigenic target characteristics Demographics (age/gender) Clinical presentation Investigations Coexistent antibodies Paraneoplastic association Relapse rate and outcomes
CASPR2 [60, 62, 64, 82, 109] Cell adhesion molecule which colocalises with Kv1.1 and Kv1.2 at the neural juxtaparanodes in both the CNS and PNS Median age 60 s-70 s; M:F 9:1 Neuromyotonia, neuropathic pain (up to 40%), muscle cramps/fasciculations; LE; Morvan’s syndrome with neuropsychiatric changes, dysautonomia, sleep disturbance (insomnia, agrypnia excitata) and neuromyotonia CSF normal in up to 70%
Imaging normal in up to 70%. May have T2 hippocampal hyperintensities as with LGI1 antibodies
Association with HLA- DRB1*11:01
Can be present concurrently with LGI1 and contactin-2 antibodies in Morvan’s syndrome 12-50%; mainly thymomas in Morvan’s syndrome; also, lung cancer, endometrial adenocarcinoma >80% have favourable responses to immunotherapy – especially in absence of a tumour; 10% mortality rate; up to 30% relapse rate
GlyR [6, 92, 110,111,112] Ionotropic receptor with five subunits (α1–4 and β); facilitates inhibitory neurotransmission in the brainstem and spinal cord; antibodies target the α subunit Median age 40 s, range (3-70 s); roughly equivalent gender distribution in adults Progressive encephalomyelitis with rigidity and myoclonus (PERM), over 10% of stiff person syndrome, epilepsy CSF usually normal, ~ 50% may have inflammatory changes
MRI largely normal, few patients may have signal change in temporal lobes, and patchy or longitudinal involvement of spinal cord
Coexistent GAD65 antibodies in some patients Up to 10%; thymoma, lymphoma, metastatic breast cancer Generally, respond well to immunotherapy, with GlyR antibody stiff person syndrome being more immunotherapy responsive than seronegative cases; may relapse in 15%; 10% mortality rate
GABAAR [93, 113, 114] Ionotropic receptor which mediates fast inhibitory synaptic transmission; relevant antibodies target the α1, b3, and γ2 subunits Median age in 40 s (range 2 months-88 years); M:F 1:1 Encephalitis with severe seizures (inclusive of status epilepticus, epilepsia partialis continua); confusion, disorientation, hallucinations and other psychiatric features, cognitive dysfunction, movement disorders; lower titres associated with stiff person syndrome, opsoclonus-myoclonus Many have CSF lymphocytic pleocytosis ± oligoclonal bands and elevated protein; few may be normal
Frequently have FLAIR and T2 abnormalities on MRI, usually multifocal or diffuse “fluffy” cortical and subcortical involvement
Coexistent antibodies to GAD65, GABABR > LGI1, NMDAR, and thyroid peroxidase < 20% with tumours including thymomas, non-Hodgkin lymphoma, SCLC, rectal cancer Over 80% may respond to immunotherapy ± tumour removal; but full recovery in only 30%; up to 20% mortality rate (especially in context of status epilepticus); relapses in 10%
GABABR [6, 24, 115,116,117] Neuronal synaptic G protein-coupled receptor involved in inhibitory synaptic transmission Median age 60 s, range 16-75; M:F 1.5:1 LE, with a prominent seizure phenotype (often temporal with secondary generalisation; status epilepticus), confusion, memory loss CSF lymphocytic pleocytosis common.
Frequently have unilateral or bilateral medial temporal lobe T2 hyperintensity on MRI, may be normal
Coexistent antibodies to GAD65, thyroid peroxidase, N-type voltage-gated calcium channels, Hu, CV2, and SOX1 in some patients Tumour association ~ 50%; SCLC in up to half the patients Some patients are immunotherapy responsive, poor outcomes largely attributed to underlying malignancy; up to 10% may relapse, mortality in up to 40%
AMPAR [6, 91, 117] Ionotropic glutamate receptor made up of four subunits (GluR1-4); critical in synaptic plasticity and excitatory neurotransmission; antibodies directed against GluR1/2 subunits median age mid 50-60 s; range young adults-90 s; M:F 1:2.5 LE, encephalopathy, confusion, seizures, cognitive impairment, amnesia, disordered sleep, movement disorders May show CSF lymphocytic pleocytosis ± oligoclonal bands, may be normal
Frequently have unilateral or bilateral medial temporal lobe hyperintensity on MRI, atrophy at follow up; may be normal
  In 50%, SCLC, breast, thymic, and ovarian cancers Most patients show a partial response to oncological management and immunotherapy responsiveness; relapses appear common
mGluR5 [6, 118, 119] Involved in hippocampal synaptic depression Median age late 20 s (range 6-75): M:F 1.5:1 LE, cognitive impairment, memory deficits, confusion, psychiatric symptoms; ‘Ophelia syndrome’ in context of Hodgkin lymphoma May show CSF lymphocytic pleocytosis
MRI may be normal in half
  Hodgkin lymphoma Generally responsive to treatment of Hodgkin lymphoma and immunotherapy
DPPX [120,121,122] Extracellular subunit of the Kv4.2 potassium channel, influences potassium channel gating in cerebellum, hippocampus, and myenteric plexus Median age 50 s-60 s (range 13-76); M:F 2.5:1 Prodrome of severe diarrhoea and weight loss. Subacute onset of cognitive impairment, agitation, confusion, hallucinations, seizures, sleep dysfunction; tremor, hyperekplexia, myoclonus; bulbar dysfunction and autonomic dysfunction CSF lymphocytic pleocytosis ± elevated protein and oligoclonal bands, but may be normal
Imaging mostly non-specific changes
  B cell neoplasms in < 10% (such as gastrointestinal follicular lymphoma, chronic lymphocytic leukaemia) May have multiple relapses in close to 25%; 60% can respond partially or significantly to (often intensive) immunotherapy, mortality 17%
D2R [123, 124] Postsynaptic receptor with striatal expression, important in dopaminergic neurotransmission and motor control; antibodies bind to amino acids 20-29 and 23-37 of N-terminus Median age 6 years (range 1-15); M:F 1:1; high proportion of patients of non-Caucasian ethnicity Parkinsonism, dystonia, chorea, hypersomnolence, neuropsychiatric features (obsessive compulsive disorder, psychosis, emotional lability), ‘basal ganglia encephalitis’ CSF may show lymphocytic pleocytosis and/or oligoclonal bands
50% have MRI changes including basal ganglia swelling, hyperintensity or enhancement acutely; and atrophy and gliosis on follow up
  No associated cancer Immunotherapy responsive, 25% may relapse
IgLON5 [104, 125,126,127] Member of the immunoglobulin superfamily of cell adhesion molecules in neurons Median age 60 s (range 13-80 s); M:F 1:1 Progressive dyssomnia, movement disorders and behaviour, gait abnormalities, bulbar and respiratory dysfunction, and cognitive impairment; disease onset often more insidious compared to other autoimmune encephalitis syndromes CSF may be non-contributory or may show lymphocytosis in third, elevated protein in half; oligoclonal bands rare
MRI changes may be non-specific
Histopathologically characterised by neuronal accumulation of hyperphosphorylated tau involving hypothalamus and brainstem, and associated neuronal loss, gliosis, and absence of inflammatory infiltrate
Strong HLA Class II association
  Unknown Severe and progressive, with early reports stating > 70% mortality and minimal response to immunotherapy; later series identify broader phenotype and show immunotherapy may result in improvement and stabilisation
Neurexin-3α [128] Presynaptic cell adhesion molecule which plays a role in synapse formation and maturation Median age 44, range 23-57; M:F 1:4 Prodromal fever, headache, gastrointestinal symptoms; subsequent encephalopathy with agitation, seizures, orofacial dykinesias, and central hypoventilation (marked overlap with NDMAR encephalitis); may have a rapid course CSF lymphocytic pleocytosis in most
Imaging may be normal or may show FLAIR/T2 temporal lobe abnormalities
  Unknown Severe syndrome but only one case series to date
GluRD2 [129] Cerebellar expressed ionotropic receptor with a role in synaptic organisation Paediatric onset 12-36 months; M:F 1:1.4 Opsoclonus, myoclonus, ataxia, cognitive and behavioural impairment associated with low-titre antibodies Acute imaging may be normal, with later cerebellar and cortical volume loss   Neuroblastoma in about half of the children Not known
  1. AMPAR α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, CASPR2 contactin-associated protein 2, CNS central nervous system, CSF cerebrospinal fluid, DPPX dipeptidyl-peptidase-like protein-6, D2R dopamine 2 receptor, F female, FLAIR fluid-attenuated inversion recovery, GABA γ-aminobutyric acid receptor, GAD glutamic acid decarboxylase, GluRD2 glutamate receptor delta 2, GlyR glycine receptor, HLA human leucocyte antigen, LE limbic encephalitis, LGI1 leucine-rich glioma-inactivated 1, M male, mGluR metabotropic glutamate receptor, MRI magnetic resonance imaging, NMDAR N-methyl-d-aspartate receptor, PERM progressive encephalomyelitis with rigidity and myoclonus, PNS peripheral nervous system, SCLC small cell lung cancer