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antibodies are truly pathogenic. [50,51] McKeon et al. [42] to date, 6 out of 52 (12%) patients continued to have
reported that 10 of 81 (12%) patients with SMS sporadic relapses whilst on treatment. [39]
spectrum disorders were positive for GlyR antibodies.
Interestingly, GlyR seropositivity was associated with CONCLUSION

better responsiveness to immunotherapy regardless of
GAD‑65 status, suggesting a pathogenic role. There are An increased awareness of the autoimmune mechanisms
no passive transfer animal models of GlyR antibodies to underlying cases of noninfective encephalitis and/or
date. [39,42] refractory seizures has led to increased recognition,
earlier treatment, and improved outcomes in a subgroup
The spectrum of GlyR antibody encephalitis of patients previously considered untreatable. Antibodies
manifestations is now widening beyond classic targeting the inhibitory receptors GABA , GABA ,
B
A
PERM and SMS. Various combinations of psychiatric and glycine are three more recently appreciated, but
disturbances, cognitive dysfunction, seizures (focal/ important antibodies to consider in refractory seizure
generalized epilepsy and new‑onset status epilepticus), disorders and encephalitis of unclear etiology. A high
and movement disorders, autonomic instability index of suspicion and an awareness of the expanding
with central hypoventilation, pseudobulbar and/or clinical spectrum of these antibody‑mediated disorders
oculomotor dysfunction, steroid responsive optic should prompt early neural antibody testing in patients
neuropathy, and transverse myelopathy have now been with typical constellations of neurological symptoms, in
described with GlyR antibodies. [39,52‑54] particular refractory seizure disorders and encephalitis
of unclear etiology. Once identified early, these
The onset of symptoms in GlyR antibody neurologic conditions may be responsive to immunotherapy. There
syndromes is typically acute to subacute. In the largest case are sparse data to recommend one immunotherapeutic
series of 52 GlyR antibody positive patients with a variety regime over another. Large cohort studies of patients
of presentations, there appears to be no sex predominance with anti‑NMDAR encephalitis suggest that first line
and all age groups are vulnerable. Patients frequently therapy should comprise corticosteroids, IVIg, and/
[39]
have a history of other autoimmune disorders. As with or PLEX, followed by second line immunotherapy
[39]
other autoimmune encephalopathies, GlyR antibodies (cyclophosphamide, rituximab, or both) in patients
[61]
may co‑exist with other antibodies, such as NMDAR, who fail to respond to initial treatment. A practical
GAD‑65, VGKC‑complex, myelin oligodendrocyte approach, guided by the literature on autoimmune
glycoprotein, and aquaporin‑4 antibodies although this encephalitis with antibodies against neuronal surface
is rare. [39,42,53,55,56] Tumors are identified in less than 20% antigens, is suggested in Figure 1. Immunotherapy
of cases (thymoma, lymphoma, breast cancer, small cell needs to be complemented by supportive, symptomatic
lung carcinoma and leukemia). [39,42,57,58] medical therapy. There is a consensus that early
treatment confers better outcomes. Age and antibody
GlyR antibodies may be detected in both serum and/or appropriate tumor screening should be performed in all
the CSF. [39,59] CSF evaluation is possibly more sensitive cases and may be aided by testing for other co‑existing
than serum, therefore testing both is recommended. neural antibodies. [62]
[42]
CSF lymphocytic pleocytosis or raised protein may be
seen, and oligoclonal bands were negative in 50‑70% of The neurologic hyperexcitability effects of antibody
2 case series recently published. [39,56] Imaging is typically binding to GABA , GABA , and GlyRs (and potentially
B
A
normal. Rarely, MRI temporal lobe T2‑weighted other receptors in the future) reflect the important
abnormality with subsequent hippocampal volume functions mediated by these inhibitory neuronal synaptic
loss is detected, particularly in cases associated with receptors. More research is needed in order to better
significant seizure activity. EEG may be normal, or show understand this novel category of immune‑mediated
features of focal or generalized ictal activity. [59] encephalitis. Further studies could focus on
immunopathogenic mechanisms of these antibodies
A combination of immunotherapies (corticosteroids, in causing disease, as these may be potential targets
IVIg, PLEX, cyclophosphamide), pharmacological for directed treatment. To date, the numbers of patients
therapies targeting symptoms of motor hyperexcitability reported with these antibodies remain small, with most
and pain (clonazepam, diazepam, baclofen, gabapentin), cases retrospectively identified. With increasing access
and anticonvulsants (levetiracetam) are required to to testing for neural antibodies, the clinical spectrum
control clinical symptoms. [39,42] Eighty percent of patients of these autoimmune encephalitides may continue to
with GlyR antibodies showed a substantial response expand. Systematic studies of prospectively identified,
to immunotherapy. [39,42] Two cases were reported that newly diagnosed cases should help to provide data on
responded dramatically to thymectomy in addition the long‑term course of the disease, prognostic factors,
to other immunotherapy. [39,60] In the largest case series and optimal immunotherapeutic regimes.

90 Neuroimmunol Neuroinfammation | Volume 3 | March 28, 2016