GlyR Antibodies Research Articles

Progressive Encephalomyelitis With Rigidity and Myoclonus With Glycine Receptor and GAD65 Antibodies: Case Report and Potential Mechanisms.

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a severe form of stiff-person spectrum disorder that can be associated with antibodies against surface antigens (glycine receptor (GlyR), dipeptidyl-peptidase-like-protein-6) and intracellular antigens (glutamate decarboxylase (GAD65), amphiphysin). We report clinico-pathologic findings of a PERM patient with coexisting GlyR and GAD65 antibodies. A 75-year-old man presented with myoclonus and pain of the legs, subsequently developed severe motor symptoms, hyperekplexia, a pronounced startle reflex, hallucinations, dysautonomia, and died 10 months after onset despite extensive immunotherapy, symptomatic treatment, and continuous intensive care support. Immunotherapy comprised corticosteroids, IVIG, plasmapheresis, immunoadsorption, cyclophosphamide, and bortezomib. Intensive care treatment and permanent isoflurane sedation was required for more than 20 weeks. CNS tissue revealed neuronal loss, astrogliosis and microgliosis, representing a pallido-nigro-dentato-bulbar-spinal degeneration pattern, specifically along GlyR and GAD expression sites. Neurons showed pSTAT1, MHC class I, and GRP78 upregulation. Inflammation was moderate and characterized by CD8+ T cells and single CD20+/CD79a+ B/plasma cells. Focal tau-positive thread-like deposits were detected in gliotic brainstem areas. In the spinal cord, GlyR, glycine transporter-2, and GAD67 expression were strongly reduced. A possible potentiating effect of pathogenic GlyR antibodies together with T cells directed against neurons may have led to the severe and progressive clinical course.

Histopathological Investigation of Progressive Encephalomyelitis with Rigidity and Myoclonus: An Autopsy Case Characterized by Oculomotor Dysfunction and Autonomic Failure.

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare disease associated with the presence of anti-glycine receptor (GlyR) antibodies. We herein report an autopsy case of an 80-year-old man diagnosed with anti-GlyR antibody-positive PERM who presented with symptoms of oculomotor dysfunction and autonomic failure. Despite intensive immunotherapy, the neurological symptoms showed almost no improvement, and the patient succumbed to aspiration pneumonia and bacterial translocation. Postmortem pathology revealed mild inflammatory changes and neuronal loss that were disproportionate to a severe clinical presentation. These results suggest that the clinical symptoms of PERM may result from antibody-mediated GlyR internalization, leading to neuronal disinhibition, rather than a neuroinflammatory signature.

Prevalence, Clinical Profiles, and Prognosis of Stiff-Person Syndrome in a Japanese Nationwide Survey.

To elucidate current epidemiologic, clinical, and immunologic profiles and treatments of stiff-person syndrome (SPS) in Japan. A nationwide mail survey was conducted using an established method. Data processing sheets were sent to randomly selected departments of internal medicine, neurology, pediatrics, psychiatry, and neurosurgery in hospitals and clinics throughout Japan to identify patients with SPS who were seen between January 2015 and December 2017. Thirty cases were identified as glutamic acid decarboxylase 65 (GAD65)-positive SPS cases on the basis of detailed clinical data of 55 cases. Four patients had α1 subunit of glycine receptor (GlyR) antibodies, and 1 patient had both GAD65 and GlyR antibodies. The total estimated number of patients with GAD65-positive SPS was 140, and the estimated prevalence was 0.11 per 100,000 population. The median age at onset was 51 years (range, 26-83 years), and 23 (76%) were female. Of these, 70% had classic SPS, and 30% had stiff-limb syndrome. The median time from symptom onset to diagnosis was significantly longer in the high-titer GAD65 antibody group than in the low-titer group (13 months vs 2.5 months, p = 0.01). The median modified Rankin Scale (mRS) at baseline was 4, and the median mRS at the last follow-up was 2. Among the 29 GAD65-positive patients with ≥1 year follow-up, 7 received only symptomatic treatment, 9 underwent immunotherapy without long-term immunotherapy, and 13 received long-term immunotherapy such as oral prednisolone. The coexistence of type 1 diabetes mellitus and the lack of long-term immunotherapy were independent risk factors for poor outcome (mRS ≥3) in the GAD65-positive patients (odds ratio, 15.0; 95% CI 2.6-131.6; p = 0.001; odds ratio, 19.8; 95% CI 3.2-191.5; p = 0.001, respectively). This study provides the current epidemiologic and clinical status of SPS in Japan. The symptom onset to the diagnosis of SPS was longer in patients with high-titer GAD65 antibodies than in those with low-titer GAD65 antibodies. The outcome of patients with SPS was generally favorable, but more aggressive immunotherapies are necessary for GAD65-positive patients with SPS.

Searching for Neuronal Antibodies in Psychiatric Diseases: Uncertain Findings and Implications.

In recent years, neurology and psychiatry journals have been inundated with reports on individual symptoms of autoimmune encephalitis (AE) that are described as distinct entities such as autoimmune psychosis, obsessive-compulsive disorders, or depression. It is unquestionable that for AE the demonstration of antibodies against neuronal-surface proteins is intrinsically linked to distinct disorders (some defining new diseases) that are usually treatment-responsive and associate with comorbidities that vary according to the antigen. By contrast, for psychiatric diseases, the apparent detection of antibodies has not defined any disorder or affected the diagnosis and treatment of patients. Although these studies frequently use anti-N-methyl-D-aspartate receptor encephalitis to rationalize the findings, they rarely adopt the same rigorous investigations or address the clinical and pathogenic significance of the antibodies or discuss the limitations related to the biological sample or antibody-testing techniques. It is imperative to consider (1) some antibodies (GAD65, TPO) occur in serum of 8%-13% of healthy people; (2) VGKC antibodies are not useful unless LGI1 or CASPR2 are investigated; (3) commercial-clinical testing for Ma2, Zic4, and SOX1 antibodies causes a high number of false-positive results; (4) GlyR antibodies have unclear disease specificity when examined only in serum; and (5) the significance of antibodies against unknown antigens of endothelium, astrocytes, myelin fibers, or granule cells of hippocampus and cerebellum is questioned by the lack of disease specificity and appropriate controls. These limitations and problems are a frequent cause of neurologic consultations. Here we discuss some of these problems, emphasizing the importance of clinical judgment over antibody findings.

Modulation of Ligand-Gated Glycine Receptors Via Functional Monoclonal Antibodies.

Ion channels are targets of considerable therapeutic interest to address a wide variety of neurologic indications, including pain perception. Current pharmacological strategies have focused mostly on small molecule approaches that can be limited by selectivity requirements within members of a channel family or superfamily. Therapeutic antibodies have been proposed, designed, and characterized to alleviate this selectivity limitation; however, there are no Food and Drug Administration-approved therapeutic antibody-based drugs targeting ion channels on the market to date. Here, in an effort to identify novel classes of engineered ion channel modulators for potential neurologic therapeutic applications, we report the generation and characterization of six (EC50 < 25nM) Cys-loop receptor family monoclonal antibodies with modulatory function against rat and human glycine receptor alpha 1 (GlyRα1) and/or GlyRα3. These antibodies have activating (i.e., positive modulator) or inhibiting (i.e., negative modulator) profiles. Moreover, GlyRα3 selectivity was successfully achieved for two of the three positive modulators identified. When dosed intravenously, the antibodies achieved sufficient brain exposure to cover their calculated in vitro EC50 values. When compared head-to-head at identical exposures, the GlyRα3-selective antibody showed a more desirable safety profile over the nonselective antibody, thus demonstrating, for the first time, an advantage for GlyRα3-selectivity. Our data show that ligand-gated ion channels of the glycine receptor family within the central nervous system can be functionally modulated by engineered biologics in a dose-dependent manner and that, despite high protein homology between the alpha subunits, selectivity can be achieved within this receptor family, resulting in future therapeutic candidates with more desirable drug safety profiles. SIGNIFICANCE STATEMENT: This study presents immunization and multiplatform screening approaches to generate a diverse library of functional antibodies (agonist, potentiator, or inhibitory) raised against human glycine receptors (GlyRs). This study also demonstrates the feasibility of acquiring alpha subunit selectivity, a desirable therapeutic profile. When tested in vivo, these tool molecules demonstrated an increased safety profile in favor of GlyRα3-selectivity. These are the first reported functional GlyR antibodies that may open new avenues to treating central nervous system diseases with subunit selective biologics.

Case Report: Dexmedetomidine for Intractable Clusters of Myoclonic Jerks and Paroxysmal Sympathetic Hyperactivity in Progressive Encephalomyelitis With Rigidity and Myoclonus

Introduction: Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a severe form of stiff-person spectrum disorder characterized by painful spasms, myoclonic jerks, hyperekplexia, brainstem dysfunction, and dysautonomia, which is sometimes resistant to γ-amino-butyric acid (GABA)-ergic agents. The response to immunotherapy varies depending on identified autoantibodies. We report a dramatic response to dexmedetomidine in a patient with glycine receptor (GlyR) antibody-positive PERM who developed intractable clusters of myoclonic jerks and paroxysmal sympathetic hyperactivity (PSH) that was highly refractory to conventional symptomatic treatment with GABAergic drugs and immunotherapy.Case Presentation: A 62-year-old Japanese man was transferred to our center for intermittent painful spasms that progressed in severity over the preceding 7 weeks. On admission, he had gaze-evoked nystagmus, and paroxysmal painful spasms/myoclonic jerks triggered by sound or touch. The myoclonic jerks rapidly worsened, along with the development of hyperekplexia, opisthotonus, and PSH, leading to prolonged apnea requiring mechanical ventilation. Brain and spinal cord magnetic resonance imaging was unremarkable. Cerebrospinal fluid (CSF) examination revealed mild pleocytosis and oligoclonal bands. Surface electromyography confirmed simultaneous agonist-antagonist continuous motor unit activity. Based on the clinico-electrophysiological features, PERM was suspected. He was initially treated with intravenous steroids, immunoglobulin, benzodiazepines, and propofol, but the symptoms persisted. On day 9, he received a continuous infusion of dexmedetomidine, which resulted in dramatic reduction in the frequency of clusters of myoclonic jerks and PSH. The effect of dexmedetomidine was confirmed by surface electromyography. The addition of plasma exchange resulted in further clinical improvement. GlyR antibodies were identified in the CSF but not the serum, leading to the diagnosis of GlyR antibody-positive PERM.Conclusions: PERM is an immune-mediated disorder, but dexmedetomidine, a highly selective α2-adrenergic agonist, may alleviate paroxysmal symptoms by decreasing noradrenergic neuronal activity, resulting in attenuation of antibody-mediated disinhibited increased motor and sympathetic activity. Dexmedetomidine may be useful as an adjunctive symptomatic therapy in PERM and related disorders.

Novel clinical features of glycine receptor antibody syndrome: A series of 17 cases.

ObjectiveTo describe novel clinical features of GlyRα1-IgG–positive patients.MethodsPatients with a positive serum GlyRα1-IgG were identified during a 2-year period from July 2016 to December 2018 at 2 academic centers and followed prospectively. All patients in this series were evaluated in the Neuroimmunology and Autoimmune Neurology clinics at the University of Utah or the University of Colorado.ResultsThirteen of 17 patients had phenotypes more typically associated with glutamic acid decarboxylase (GAD65) antibody syndromes, consisting of stiff-person syndrome (SPS) with parkinsonism or cerebellar signs. One patient with parkinsonism had a presentation similar to rapidly progressive multiple system atrophy with severe dysautonomia. Ten of 17 patients had various visual symptoms including visual snow, spider web–like images forming shapes and 3-dimensional images, palinopsia, photophobia, visual hallucinations, synesthesia, and intermittent diplopia. Three of 17 patients presented with primarily autoimmune epilepsy accompanied by psychiatric symptoms.ConclusionsClinicians should consider testing for GlyR antibodies in GAD65 antibody–negative or low-positive GAD65 antibody patients with SPS-like presentations, especially in the setting of atypical features such as visual disturbances, parkinsonism, or epilepsy.

Clinical and Immunologic Investigations in Patients With Stiff-Person Spectrum Disorder.

Symptoms of stiff-person syndrome (SPS), stiff-limb syndrome (SLS), or progressive encephalomyelitis with rigidity, myoclonus, or other symptoms (SPS-plus) can occur with several autoantibodies, but the relative frequency of each antibody, syndrome specificity, and prognostic implications are unclear. To report the clinical and immunologic findings of a large cohort of patients with stiff-person spectrum disorder (SPSD), including SPS, SLS, and SPS-plus. This study retrospectively examined a case series (January 1, 1998, through December 31, 2014) of immunologic investigations performed in a neuroimmunology referral center. The study included 121 patients with clinical features of SPSD. Data analysis was performed from July 1, 2015, through November 1, 2015. Analysis of clinical-immunologic associations, including autoantibodies to 8 proteins expressed in inhibitory synapses. The median age of the patients was 51 years (interquartile range, 40-61 years), and 75 (62.0%) were female. Fifty (41.3%) had SPS, 37 (30.6%) had SPS-plus, 24 (19.8%) had SLS, and 10 (8.3%) had SPS or SLS overlapping with ataxia, epilepsy, or encephalitis. Fifty-two patients (43.0%) had glutamic acid decarboxylase (GAD65) antibodies (2 with γ-aminobutyric acid-A [GABA-A] receptor antibodies), 24 (19.8%) had α1-subunit of the glycine receptor (GlyR) antibodies (2 with GAD65 antibodies), 5 (4.1%) had other antibodies, and 40 (33.1%) tested negative for antibodies. None had gephyrin or glycine transporter antibodies. Among the main immunologic groups (GAD65 antibodies, GlyR antibodies, and antibody negative), those with GAD65 antibodies were more likely to be female (45 [86.5%] of 52, 8 [36.4%] of 22, and 18 [45.0%] of 40, respectively; P < .001), have systemic autoimmunity (34 [65.4%] of 52, 7 [31.8%] of 22, and 13 [32.5%] of 40, respectively; P = .004), and have longer delays in being tested for antibodies (median, 3 vs 0.5 and 1 year; P < .001). Patients with GAD65 antibodies were more likely to develop SPS (27 [51.9%] of 52) or overlapping syndromes (8 [15.4%] of 52) than patients with GlyR antibodies (5 [22.7%] and 0 [0%] of 22, respectively), who more often developed SPS-plus (12 [54.5%] of 22 vs 7 [13.5%] in those with GAD65 antibodies); antibody-negative patients had an intermediate syndrome distribution. In multivariable analysis, symptom severity (P = .001) and immunologic group (P = .01) were independently associated with outcome. Compared with patients with GlyR antibodies, those with GAD65 antibodies (odds ratio, 11.1, 95% CI, 2.3-53.7; P = .003) had worse outcome. Patients without antibodies had similar outcome than patients with GlyR antibodies (odds ratio, 4.2, 95% CI, 0.9-20.0; P = .07). In SPSD, symptom severity and presence and type of antibodies are predictors of outcome.

Central nervous system antibody-mediated diseases with autonomic involvement – Focus on VGKC-complex (LGI1, CASPR2), NMDAR and GlyR antibodies

Central nervous system antibody-mediated diseases with autonomic involvement – Focus on VGKC-complex (LGI1, CASPR2), NMDAR and GlyR antibodies

OP67 – 2451: Antibodies against neuronal surface antigens in children with inflammatory demyelinating diseases of the CNS

Objective To study if neuronal surface autoantibodies are present in children with a first demyelinating event. Methods Serum samples from 79 children with and without MOG antibodies were selected from an ongoing prospective study. All serum samples were evaluated for the presence of NMDAR-, GABA-A, B, Glycin-R, DR2 antibodies using cell-based assays and screened for the presence of cell surface and intracellular antibodies using different screening methods. Results Serum samples from 79 children with a complete data set, MRI, MOG, AQP4 antibody status were selected including 16 children with ADEM/MOGpos; 16 children with ADEM/MOGneg, 12 children with ON/MOGpos; 9 children with ON/MOGneg, 8 children with MS/MOGneg in addition to 8 children with acute cerebellits and 10 children with other inflammatory neurological disease (OIND). 4/79 children showed GlyR antibodies, 3/79 children had serum antibodies against DR2. No antibodies against GABA-A,B or NMDA-R were detected. Serum of 1/79 children revealed a neuropil staining pattern using rat hippocampal PFA-fixed section, but staining of rat hippocampal neuronal cell cultures did not reveal a single case with a moderate or intense positive staining pattern. Conclusion In children with a first demyelinating event with or without MOG antibodies only rarely autoantibodies against neuronal surface antigens are detected.

OP87 – 3001: Paediatric neurological syndromes associated with glycine receptor antibodies

Background In patients with glycine receptor antibodies (GlyRAb), a range of neurological syndromes that includes Stiff Person Syndrome (SPS) and its more severe variant Progressive Encephalitis with Rigidity and Myoclonus (PERM) have recently been reported in a predominantly adult cohort (Carvajal-Gonzalez et al., Brain 2014;137(Pt 8):2178–92). Objectives To report the clinical features and outcome of children with GlyR-Ab. Methods Cases were identified from samples sent to the Nuffield Department of Clinical Neurology, Oxford for a range of neuronal surface antibody testing. Results Six girls with a mean age of 8 years (median 7.5; range 1–15) were identified (2 London, 1 Oxford, and 3 Australia). The children presented with refractory focal seizures (n=2), or cognitive/behavioural changes (n=4) of whom two had tremor and gait abnormalities and one features of PERM. During the course of the illness, seizures featured in 5 patients and cognitive/behavioural changes in all. Electroencephalogram (EEG) during the illness revealed features of encephalopathy (n=3) and focal/multifocal epileptiform discharges (n=2). Two children had early imaging features of brain inflammation, and in another 2, global atrophy were identified on serial imaging despite normal acute scans. GlyR-Abs were detected in the serum (n=6) and/or CSF (n=2). Co-occurrence of low levels ( Conclusions The paediatric phenotype is predominated by female sex, seizures, and, where PERM occurs, it is associated with additional features. The clinical relevance of GlyR antibodies needs to be determined, to help guide therapies.

Antibodies to aquaporin 4, myelin-oligodendrocyte glycoprotein, and the glycine receptor α1 subunit in patients with isolated optic neuritis.

In patients with isolated optic neuritis (ON), the presence of antibodies to aquaporin 4 (AQP4) has diagnostic and prognostic value. In the same clinical setting, the significance of antibodies to myelin-oligodendrocyte glycoprotein (MOG) or the glycine receptor α1 subunit (GlyR) is unclear. To investigate the frequency of antibodies to AQP4, MOG, and GlyR in patients with unilateral or bilateral, severe, or recurrent isolated ON and to determine their clinical and prognostic correlates. Retrospective case-control study from November 1, 2005, through May 30, 2014 with the detection of autoantibodies in a neuroimmunology referral center. We included 51 patients with ON but without clinical and magnetic resonance imaging findings outside the optic nerves and 142 controls (30 healthy individuals, 48 patients with neuromyelitis optica, and 64 patients with multiple sclerosis). Clinicoimmunologic analysis. We determined the presence of antibodies to AQP4, MOG, and GlyR using cell-based assays. The median age of the patients at the onset of ON symptoms was 28 (range, 5-65) years; 36 patients (71%) were female. Antibodies were identified in 23 patients (45%), including MOG in 10 patients, AQP4 in 6 patients, and GlyR in 7 patients (concurrent with MOG in 3 and concurrent with AQP4 in 1). Patients with AQP4 antibodies (median visual score, 3.5 [range, 1-9]) had a worse visual outcome than patients with MOG antibodies alone (median visual score, 0 [range, 0-5]; P = .007), patients with seronegative findings (n = 28) (median visual score, 1.0 [range, 0-14]; P = .08), and patients with GlyR antibodies alone (n = 3) (median visual score, 0 [range, 0-2]; P = .10).The median age of the 7 patients with GlyR antibodies was 27 (range, 11-38) years; 5 (71%) of these were female. Among the 3 patients with GlyR antibodies alone, 1 patient had monophasic ON, 1 had recurrent isolated ON, and 1 had conversion to multiple sclerosis. The 3 patients with GlyR antibodies concurrent with MOG antibodies had recurrent isolated ON, and the patient with concurrent AQP4 antibodies had conversion to neuromyelitis optica. Of the 48 controls with neuromyelitis optica, 37 (77%) had AQP4 antibodies, 4 (8%) had MOG antibodies, 2 (4%) had AQP4 antibodies concurrent with MOG antibodies, and 5 (10%) were seronegative. Of the 64 controls with multiple sclerosis, 5 (8%) had GlyR antibodies. Forty-five percent of patients with unilateral or bilateral, severe, or recurrent isolated ON had antibodies to MOG, AQP4, or GlyR. Patients with AQP4 antibodies had the poorest visual outcomes, whereas patients with MOG antibodies had a better outcome that was similar to that of patients with seronegative findings. The significance of GlyR antibodies in the setting of ON is unclear and deserves further study.

Neuronal antibodies in patients with suspected or confirmed sporadic Creutzfeldt-Jakob disease

ObjectivesThere have been reports of patients with antibodies to neuronal antigens misdiagnosed as sporadic Creutzfeldt-Jakob disease (sCJD). Conversely, low levels of antibodies to neuronal proteins have been reported in patients...

Glycine receptor antibodies in a boy with focal epilepsy and episodic behavioral disorder

A wide range of clinical presentations including neuromuscular disorders and autoimmune encephalopathies is being recognized to be associated with various autoantibodies. Glycine receptor (GlyR) antibodies have so far been found mainly in adult patients with phenotypes comprising progressive encephalomyelitis with rigidity and myoclonus or stiff-person syndrome. We report a four-year-old boy who presented with a two-year-history of drug-resistant focal epilepsy with unusual seizure semiology, temper tantrums, headache, clumsiness, and intermittently impaired speech. While MRI and CSF were normal, screening for autoimmune antibodies revealed GlyR antibodies in serum. Immunomodulatory treatment with steroids resulted in rapid and complete resolution of symptoms. Our observation widens the spectrum of clinical presentations associated with GlyR antibodies and emphasizes the potential relevance of neuronal autoantibodies in epilepsies of unknown cause in children as well as in adults.

Progressive Encephalomyelitis with Rigidity and Myoclonus

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare autoimmune neurological condition. Antibodies targeting glycine receptors (GlyR) have been implicated in PERM. Because GlyR activity is enhanced by inhaled anesthetic drugs at clinically relevant concentrations, there is a theoretical possibility that these drugs may be less effective in the presence of GlyR antibodies. We describe a case of general anesthesia in a patient with PERM and GlyR antibodies. This patient did not demonstrate a clinically significant alteration in the behavioral effects of anesthesia using induction of anesthesia with sevoflurane and maintenance of anesthesia using sevoflurane and nitrous oxide.

Glycine receptor antibodies in stiff-person syndrome and other GAD-positive CNS disorders

Stiff-person syndrome (SPS) is characterized by stiffness in trunk and limb muscles, phobic anxiety, and sudden spasms. A disturbance in inhibitory GABAergic pathways, presumably by autoantibodies against GAD (the main GABA-synthesizing enzyme), is considered fundamental for SPS pathogenesis.1 As the precise role of anti-GAD antibodies in SPS remains unclear,2,3 several other candidate disease-specific autoantibodies associated with inhibitory pathways have been explored3,4 or are actively pursued. Recently, McKeon et al.5 described anti-glycine-α1 receptor (GlyR) antibodies in a subset of patients with SPS. Glycine is a neurotransmitter in spinal inhibitory interneurons and GlyR are primarily expressed in the spinal cord, brainstem, and cerebellum. Anti-GlyR antibodies have been associated with progressive encephalomyelitis with rigidity and myoclonus (PERM), a syndrome resembling SPS.6 Our aims were to search for GlyR antibodies in a large number of patients with well-characterized SPS and other CNS autoimmune controls and other GAD-positive disorders; and to correlate anti-GlyR titers with clinical symptomatology using quantitative scales of stiffness and spasms.7 The authors thank Dr. Goran Rakocevic and Beverly McElroy, RN, for helping with the care of patients studied at the NIH under Dr. Dalakas's protocols.

Hypoventilation in glycine-receptor antibody related progressive encephalomyelitis, rigidity and myoclonus

Glycine receptor (GlyR) antibodies have been identified in patients with rigidity and hyperekplexia, but the clinical phenotype associated with these antibodies has not been fully elucidated. The clinical features in two additional patients with GlyR antibodies are described. A 55-year-old man presented with stimulus-induced hyperekplexia and rigidity in the lower limbs and trunk. He initially responded to benzodiazepines, but presented after 18months with severe, painful, prolonged spasms associated with supraventricular and ventricular arrhythmias, hypoventilation and oxygen desaturation requiring intubation. He improved following treatment with clonazepam, baclofen and immunomodulatory therapies. A 58-year-old woman presented with stiffness in the legs and hyperekplexia associated with hypoventilation, at times leading to loss of consciousness. She responded to benzodiazepines and has remained in remission. The clinical picture associated with GlyR antibodies includes autonomic dysfunction, cardiac arrhythmias and hypoventilation. It is important to recognise these serious complications early to limit mortality from this treatable condition.

Glycine receptor antibodies are detected in progressive encephalomyelitis with rigidity and myoclonus (PERM) but not in saccadic oscillations

Glycine receptor (GlyR) antibodies were recently identified in a few patients with progressive encephalomyelitis with rigidity and myoclonus (PERM); none of these patients had antibodies against glutamic acid decarboxylase (GAD). An inhibitory glycinergic transmission defect has also been implicated in the mechanism underlying saccadic oscillations, including ocular flutter or opsoclonus; GlyR antibodies have not been reported in these patients. The purpose was to determine whether GlyR antibodies are found in patients with PERM, ocular flutter syndrome (OFS), and opsoclonus-myoclonus syndrome (OMS). GlyR antibodies were first measured in archived sera and CSF from five patients, including one patient with GAD antibody-positive PERM, two patients with OFS, and two patients with OMS. GlyR antibodies were also measured in archived sera from nine other adult patients with OMS. GlyR antibodies and GAD antibodies were both found at high titers in the serum and CSF of the patient with PERM, and their levels paralleled disease activity over time. GlyR antibodies were not found at significant levels in 13 patients with saccadic oscillations. GlyR and GAD antibodies can co-exist in PERM and follow the clinical course. Although saccadic oscillations are a feature of this condition, GlyR antibodies are not commonly found in patients with isolated saccadic oscillations.

Progressive encephalomyelitis with rigidity and myoclonus

The syndrome of progressive encephalopathy with limb rigidity has been historically termed progressive encephalomyelitis with rigidity and myoclonus (PERM) or stiff-person syndrome plus. The case is presented of a previously healthy 28-year-old man with a rapidly fatal form of PERM developing over 2 months. Serum antibodies to both NMDA receptors (NMDAR) and glycine receptors (GlyR) were detected postmortem, and examination of the brain confirmed an autoimmune encephalomyelitis, with particular involvement of hippocampal pyramidal and cerebellar Purkinje cells and relative sparing of the neocortex. No evidence for an underlying systemic neoplasm was found. This case displayed not only the clinical features of PERM, previously associated with GlyR antibodies, but also some of the features associated with NMDAR antibodies. This unusual combination of antibodies may be responsible for the particularly progressive course and sudden death.

A case of glycine-receptor antibody-associated encephalomyelitis with rigidity and myoclonus (PERM): clinical course, treatment and CSF findings

Over several months a 58-year-old man developed muscle stiffness, myoclonus and experienced several sudden falls caused by sensory and acoustic stimuli. On neurological examination, a severe startle reaction could be triggered by unexpected noises and there was stiffness, especially of the back and lower limb muscles, with myoclonus, lower limb paraparesis, muscle rigidity and increased tendon reflexes without further pyramidal signs. He was not able to walk without help. He also exhibited a mild pontine syndrome with disturbed smooth pursuit eye movements and diplopia. Electrophysiological studies revealed ubiquitous early recruitment and continuous motor unit activity as described for stiff person syndrome by Meinck and Thompson [1]. Cerebral MRI scans were normal. Antibodies against glutamic acid decarboxylase (GAD), amphiphysin, CYFRA 21-1, CEA, Ri, Hu, Yo, MA1, MA2, CV2 and CRMP5 could not be detected in serum. Neuron-specific enolase (NSE) enzyme concentrations were not raised. An extensive cancer search including 18-F-FDG-PET, abdominal ultrasound, X-ray of the chest and bronchoscopy was negative. However, serum glycine receptor (GlyR) antibodies were detected by a cell-based assay (Fig. 1) [2]. Initial lumbar puncture revealed oligoclonal IgG bands and 45 lymphocytes/ll (normal: \4 cells/ll) in the cerebrospinal fluid (CSF). GlyR antibodies could also be found in the patient’s CSF. Gamma-aminobutyric acid (GABA) and glutamate levels in CSF were measured by HPLC, with electrochemical detection after precolumn o-phthaldialdehyde sulphite derivatization, in the patient’s CSF and control samples from 10 subjects (4 males, 6 females); age range 35–83 years (mean 54 years) undergoing diagnostic lumbar puncture as part of their investigations. Their CSF analyses were normal and neurological disorders were excluded. All lumbar punctures were done between 11.00 am and 2.00 pm. Their GABA levels were 42.7 ± 14.2 nmol/l. As shown in Fig. 2, before any treatment the patient’s GABA level was higher (89.0 nmol/l) than upper limit of the control range (mean ? 3SDs, 85.3 nmol/l). Glutamate levels were also lower (initial: 0.33 lmol/l; after 18 months: 0.35 lmol/l) than controls (0.49 ± 0.2 lmol/l) although not significantly different. The neurological symptoms ameliorated after an initial therapy of six plasmaphereses followed by oral corticosteroids (1 mg/kg body weight). The GABAA receptor agonist clonazepam led to a further improvement of muscle stiffness and rigidity. Only a mild pontine symptom with diplopia persisted. CSF GABA levels fell over the treatment period to 28.5 nmol/l (18 months after initial lumbar puncture). GlyR antibody titers also declined but were still just detectable in the serum at 12 months (Fig. 1). Once the improvement had stabilised for 18 months, we tried to wean the steroids. After 2 weeks without steroids the patient developed again neurological symptoms with a left internuclear ophthalmoplegia, and without signs on the MRI. Steroids were therefore increased to 0.5 mg/kg and a steroidsparing drug, azathioprine (2 mg/kg), was introduced. Under this regime the patient is now without symptoms. Up to now, medical examinations are being done every 6 months. A. Piotrowicz (&) A. Thumen A. Moser Neurochemical Research Group, Department of Neurology, University of Lubeck, Ratzeburger Allee 160, 23538 Lubeck, Germany e-mail: agnieszka.piotrowicz@neuro.uni-luebeck.de