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Table 1: Key demographic, clinical, and AI/oncologic associations of the GABA B R, GABA A R, and GlyR-α1 antibodies
GABA B R GABA A R GlyR-α1
Clinical features Limbic encephalitis (memory High serum antibodies concentration: Axial/limb spasms, rigidity, and myoclonus
impairment, hallucination, rapidly progressive encephalopathy, (SMS) + brainstem signs (PERM)
confusion, behavior changes) with refractory seizures, and status Optic neuropathy, seizures, cognitive
early and prominent seizuresLess epilepticusLow serum antibodies impairment, autonomic disturbance,
commonly: cerebellar ataxia, concentration: seizures, SMS, respiratory failure, and transverse
opsoclonus‑myoclonus, brainstem opsoclonus‑myoclonus, behavioral myelitis also reported in isolation or with
encephalitis, chorea, myelopathy, change, psychosis, confusion, chorea, SMS or PERM
peripheral neuropathy, and myopathy ataxia, hallucinations, and hemiparesis
Onset Mostly subacute/acute Acute/subacute Subacute > acute > chronic
Age group Wide range, children, and adults Wide range, children, and adults Wide range, children, and adults
Gender, male:female 1.3:1 2:1 1:1
Inflammatory CSF* 73% 40% 50%, but OCB frequently negative
MRI 65% abnormal (medial temporal > High serum antibodies concentration: < 30% T2/FLAIR abnormalities in
extratemporal changes) 100% multifocal temporal temporal lobes, SC abnormalities rarely
and extratemporal T2/FLAIR reported (short, multifocal, and LETM)
hyperintensities
EMG ‑ ‑ 60% abnormal (continuous motor activity,
stimulus induced motor activity)
Other coexisting 56% (VGCC, AGNA, GAD‑65, 70% (AChR, NMDAR, GABA , GAD‑65, Rare (GAD‑65, MOG, NMDAR,
B
neural antibodies VGKC‑complex, NMDAR, ANNA‑1, VGKC‑complex) aquaporin‑4, VGKC‑complex)
‑2 and ‑3,CRMP‑5 IgG, amphiphysin,
BRSK2)
Associated tumors 62% (SCLC most common, also 15% (invasive thymoma, Hodgkin Approximately 10% to date (breast
neuroendocrine lung, malignant lymphoma) cancer, lymphoma (both Hodgkin and
melanoma, esophageal, malignant NHL), leukemia, lung cancer, melanoma)
melanoma, thymus anaplastic carcinoid)
Fatalities (%) 36 20 < 10
*Inflammatory CSF includes pleocytosis, high protein, raised IgG index, and/or oligoclonal bands. AChR: acetylcholine receptor; AI: autoimmune; AGNA: anti‑glial
nuclear autoantibody; ANNA: antineuronal nuclear autoantibody; BRSK2: BR serine/threonine‑protein kinase‑2; CRMP‑5: collapsing response mediator protein 5; CSF:
cerebrospinal fluid; EEG: electroencephalogram; EMG: electromyography; FLAIR: fluid attenuated inversion recovery; GABA A R: γ‑aminobutyric acid receptor A subunit;
GABA B R: γ‑aminobutyric acid receptor B subunit; GAD‑65: glutamic acid decarboxylase‑65; GlyR‑α1: glycine receptor alpha‑1 subunit; LETM: longitudinally extensive
transverse myelitis; MOG: myelin oligodendrocyte glycoprotein; MRI: magnetic resonance imaging; NHL: nonHodgkin lymphoma; NMDAR: N‑methyl‑D‑aspartate receptor;
OCB: oligoclonal bands; PERM: progressive encephalomyelitis with rigidity and myoclonus; SC: spinal cord; SMS: stiff‑man syndrome; SCLC: small cell lung carcinoma;
VGCC: voltage‑gated calcium channel; VGKC‑complex: voltage‑gated potassium channel complex
inhibitory neurons in the CNS, has a complex functional the synaptic membrane. Antibodies to gephyrin, an
pathway that involves pre‑ and post‑synaptic GlyR anchoring protein in the postsynaptic GlyR, have been
interacting with other neurotransmitters (GABA and described only in a single case to date. [40]
glutamate), NMDAR, and postsynaptic anchoring
proteins like gephyrin. Antibodies directed at any Classic neurologic manifestations associated with GlyR
of these targets may affect the glycinergic system, antibodies are progressive encephalomyelitis with
resulting in neurological dysfunction. Whether due rigidity and myoclonus (PERM) and SMS. [39,41,42] PERM
[34]
to strychnine (a GlyR antagonist) poisoning, genetic and SMS were first described as separate clinical entities,
mutations of the GlyR gene (hereditary hyperekplexia), but today these 2 conditions are considered to belong
or immune‑mediated encephalitis, GlyR dysfunction to a continuum of CNS hyperexcitability disorders.
may be associated with severe muscle spasms, stiffness, Patients with PERM and SMS share common features
agitation, seizures, myoclonus, autonomic instability, of rigidity, painful spasms, autonomic disturbances,
and/or respiratory failure. [35,36] hyperekplexia, and myoclonus. The widespread
distribution of hyperexcitability and brainstem
GlyRs, pentamers of α1‑α4 and β‑subunit proteins, are involvement classically distinguishes PERM from SMS
ligand‑gated chloride ion channels, widely distributed and associated psychiatric symptoms such as anxiety
in the CNS. They are predominantly expressed in are more commonly observed in SMS patients. [43‑46]
the olfactory bulb, retina, hippocampus, brainstem The autoimmune nature of these conditions, and
(auditory, visual, vestibular, and sensory nuclei), specifically the involvement of GlyR antibodies in
cerebellum, and spinal cord. [37,38] Glycine binding some cases was not appreciated until recently. [41,42]
mediates opening of the GlyR chloride channel, resulting SMS was initially associated with antibodies to
[40]
in hyperpolarization of the membrane potential and GAD‑65 (60‑70% of cases), [47,48] gephyrin (1 case), and
reduced neuronal excitability. The GlyR antibody targets amphyiphysin (< 5% cases, in the setting of both small
the α1 subunit of the postsynaptic GlyR and is associated cell lung and breast cancers). [48,49] In 2008, Hutchinson
with hyperexcitable neurologic disorders [Table 1]. et al. [41] reported the first case of PERM with GlyR
[39]
Gephyrin allows multiple GlyR to cluster together on antibodies. It remains unresolved whether all of these

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