Progressive Encephalomyelitis With Rigidity And Myoclonus Research Articles

Glycine Receptor β-Targeting Autoantibodies Contribute to the Pathology of Autoimmune Diseases.

Stiff-person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM) are rare neurologic disorders of the CNS. Until now, exclusive GlyRα subunit-binding autoantibodies with subsequent changes in function and surface numbers were reported. GlyR autoantibodies have also been described in patients with focal epilepsy. Autoimmune reactivity against the GlyRβ subunits has not yet been shown. Autoantibodies against GlyRα1 target the large extracellular N-terminal domain. This domain shares a high degree of sequence homology with GlyRβ making it not unlikely that GlyRβ-specific autoantibody (aAb) exist and contribute to the disease pathology. In this study, we investigated serum samples from 58 patients for aAb specifically detecting GlyRβ. Studies in microarray format, cell-based assays, and primary spinal cord neurons and spinal cord tissue immunohistochemistry were performed to determine specific GlyRβ binding and define aAb binding to distinct protein regions. Preadsorption approaches of aAbs using living cells and the purified extracellular receptor domain were further used. Finally, functional consequences for inhibitory neurotransmission upon GlyRβ aAb binding were resolved by whole-cell patch-clamp recordings. Among 58 samples investigated, cell-based assays, tissue analysis, and preadsorption approaches revealed 2 patients with high specificity for GlyRβ aAb. Quantitative protein cluster analysis demonstrated aAb binding to synaptic GlyRβ colocalized with the scaffold protein gephyrin independent of the presence of GlyRα1. At the functional level, binding of GlyRβ aAb from both patients to its target impair glycine efficacy. Our study establishes GlyRβ as novel target of aAb in patients with SPS/PERM. In contrast to exclusively GlyRα1-positive sera, which alter glycine potency, aAbs against GlyRβ impair receptor efficacy for the neurotransmitter glycine. Imaging and functional analyses showed that GlyRβ aAbs antagonize inhibitory neurotransmission by affecting receptor function rather than localization.

Expanding clinical profiles and prognostic markers in stiff person syndrome spectrum disorders

ObjectiveTo describe the clinical features of a cohort of individuals with stiff person syndrome spectrum disorders (SPSD) and identify potential early predictors of future disability.BackgroundThere is a need to better understand the full spectrum of clinical and paraclinical features and long-term impact of SPSD.Design/MethodsObservational study from 1997 to 2022 at Johns Hopkins. Clinical phenotypes included classic SPS, partial SPS (limb or trunk limited), SPS-plus (classic features plus cerebellar/brainstem involvement), and progressive encephalomyelitis with rigidity and myoclonus (PERM). Outcome measures were modified Rankin scale (mRS) and use of assistive device for ambulation. Multivariate logistic regression was used to assess significant predictors of outcomes.ResultsCohort included 227 individuals with SPSD with mean follow-up of 10 years; 154 classic, 48 SPS-plus, 16 PERM, and 9 partial. Mean age at symptom onset was 42.9 ± 14.1 years, majority were white (69.2%) and female (75.8%). Median time to diagnosis was 36.2 months (longest for SPS-plus and PERM) and 61.2% were initially misdiagnosed. Most had systemic co-morbidities and required assistive devices for ambulation. Female sex (OR 2.08; CI 1.06–4.11) and initial brainstem/cerebellar involvement (OR 4.41; CI 1.63–14.33) predicted worse outcome by mRS. Older age at symptom onset (OR 1.04; CI 1.01–1.06), female sex (OR 1.99; CI 1.01–4.01), Black race (OR 4.14; CI 1.79–10.63), and initial brainstem/cerebellar involvement (OR 2.44; CI 1.04–7.19) predicted worse outcome by use of assistive device. Early implementation of immunotherapy was associated with better outcomes by either mRS (OR 0.45; CI 0.22–0.92) or use of assistive device (OR 0.79; CI 0.66–0.94).ConclusionsWe present the expanding phenotypic variability of this rare spectrum of disorders and highlight potential predictors of future disability.

Progressive encephalomyelitis with rigidity and myoclonus (PERM) associated with anti-glycine receptor antibodies and urothelial carcinoma: a case report

BackgroundProgressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare neurological condition with paraneoplastic etiology in about 20% of cases, usually presenting before or shortly after the oncological diagnosis is established. PERM associated with anti-glycine receptor antibodies is not previously reported in a patient with bladder cancer.Case presentationA 72-years-old Caucasian male was admitted with acute onset of dysarthria, dysphagia and trismus three years after initial surgical treatment for bladder cancer. The condition was initially diagnosed as tetanus and treated accordingly, but the diagnosis was reconsidered because of progression despite adequate treatment. Diagnostic workup on readmission revealed lung and paraaortal metastases from bladder cancer and anti-glycine receptor (anti-GlyR) antibodies both in the cerebrospinal fluid and in serum, which supplemented with the clinical presentation led to the diagnosis of PERM, presumably related to bladder cancer. The patient showed improvement and stabilization after treatment with intravenous immunoglobulin and chemotherapy against metastatic bladder cancer.ConclusionTo the best of our knowledge, this is the first reported case of anti-GlyR antibody positive PERM related to urothelial carcinoma. The symptoms mimicked tetanus, and responded to chemotherapy and immunotherapy.

Stiff-Person Syndrome

Stiff-person syndrome (SPS) is a rare autoimmune neurological disorder characterized by progressive axial muscle stiffness, central nervous system hyper-excitability, and painful stimulus-sensitive muscle spasms. SPS is classified into classic SPS and SPS variants, including stiff-limb syndrome (SLS) and progressive encephalomyelitis with rigidity and myoclonus (PERM), based on clinical presentation. SPS responds to immunotherapy, and several autoantigens have been identified. Most patients with SPS have high-titers of antibodies against glutamic acid decarboxylase (GAD), the rate-limiting enzyme for the synthesis of γ-aminobutyric acid (GABA), and up to 15% of the patients have antibodies against the glycine receptor α-subunit.

Early Predictors of Future Disability in Stiff Person Syndrome Spectrum Disorders (S40.001)

<h3>Objective:</h3> Assess for early predictors of future disability in a large cohort of individuals with stiff person syndrome spectrum disorders (SPSD). <h3>Background:</h3> SPSD are rare disorders with an increasing spectrum of phenotypes. There is a paucity of data identifying whether early predictors for future disability exist. <h3>Design/Methods:</h3> Retrospective review of medical records from 1997–2022 at Johns Hopkins yielded 235 individuals with SPSD. Clinical phenotypes were assigned: classic SPS (torso/back and limb), partial-SPS (limb, trunk), SPS-plus (classic features with cerebellar/brainstem findings), pure cerebellar ataxia (CA, without classic features), and progressive encephalomyelitis with rigidity and myoclonus (PERM). Outcomes were modified Rankin scale (mRS) and use of assistive device for ambulation at last follow-up. Multivariate logistic regression was used to assess for significant predictors of outcomes. <h3>Results:</h3> Mean age at symptom onset was 44 years (SD 14 years), and the majority were white (69%) and female (75%). Mean follow up was 9.8 years and mean disease duration was 9.7 years. Phenotype breakdown: 154 classic SPS, 45 SPS-plus, 16 PERM, 11 pure CA, and 9 partial-SPS. The mean mRS was 2.5. Over 70% required assistive devices for ambulation. Female sex (OR 2.08, CI 1.06–4.11, p=0.03), initial symptom of brainstem/cerebellar (OR 4.41, CI 1.63–14.33, p=0.006), and no immunotherapy in the first three years from symptom onset (OR 2.22, CI 1.09–4.55, p=0.03) predicted poorer outcome by mRS. Female sex (OR 1.99, CI 1.01–3.01, p=0.05), Black race (OR 4.14, CI 1.79–10.63, p=0.002), initial symptom of brainstem/cerebellar (OR 2.44, CI 1.04–7.19, p=0.04), and no immunotherapy in the first three years from symptom onset (OR 1.27, CI 1.06–1.52, p=0.007) predicted poorer outcome by use of assistive device for ambulation. <h3>Conclusions:</h3> Our study identified specific clinical and demographic features associated with future disability in SPSD. Further studies are needed to assess if treating subgroups of SPSD more aggressively will help long-term outcomes. <b>Disclosure:</b> The institution of Dr. Wang has received research support from Genentech. Miss Hu has nothing to disclose. Dr. Mukharesh has nothing to disclose. Dr. Aljarallah has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Aljarallah has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Aljarallah has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Sanofi Genzyme. Dr. Reyes-Mantilla has nothing to disclose. Mr. Comisac has nothing to disclose. Alexandra Balshi has nothing to disclose. Danielle Obando has nothing to disclose. Sarah Snoops has nothing to disclose. The institution of Dr. Fitzgerald has received research support from NIH. The institution of Dr. Fitzgerald has received research support from National MS Society. Dr. Newsome has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Autobahn. Dr. Newsome has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Newsome has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Newsome has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Newsome has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Newsome has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Greenwich Biosciences. Dr. Newsome has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bristol Myers Squibb. Dr. Newsome has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon Therapeutics. The institution of Dr. Newsome has received research support from Biogen. The institution of Dr. Newsome has received research support from Genentech/Roche. The institution of Dr. Newsome has received research support from Department of Defense. The institution of Dr. Newsome has received research support from Patient Centered Outcomes Research Institute. The institution of Dr. Newsome has received research support from National MS Society. The institution of Dr. Newsome has received research support from The Stiff Person Syndrome Research Foundation. Dr. Newsome has received personal compensation in the range of $5,000-$9,999 for serving as a Clinical adjudication committee member for clinical trial with medDay Pharmaceuticals. Dr. Newsome has received personal compensation in the range of $10,000-$49,999 for serving as a Lead PI for Clinical Trial with Roche.

Successful Autologous Hematopoietic Stem Cell Transplant in a Case of Stiff Person Spectrum Disorder with a positive Glycine Receptor antibody (P4-5.019)

<h3>Objective:</h3> To present a case of glycine receptor (GlyR) antibody-positive Stiff Person Syndrome Spectrum Disorder (SPSD) treated with autologous hematopoietic stem cell transplant (aHSCT). <h3>Background:</h3> SPSD is an autoimmune disease with progressive neurologic symptoms and in some cases severe disability. The exact pathophysiology of SPSD is unknown and treatment response to immunotherapy is variable. Autoantibodies against glutamic acid decarboxylase epitope 65 (GAD65) and GlyR antibody are commonly associated with SPSD. While large studies using aHSCT are currently lacking and greatly needed, this is a promising treatment approach for refractory SPSD with the potential of significant symptom improvement and perhaps clinical remission from disease. While cases of successful aHSCT in GAD65+ SPSD have been reported, to our knowledge only one other GlyR antibody-positive patient in the setting of progressive encephalomyelitis with rigidity and myoclonus (PERM) has been described. <h3>Design/Methods:</h3> Case report <h3>Results:</h3> A 59-year-old patient with GlyR antibody-positive SPSD was treated with immunotherapy including IVIG, plasma exchange (PLEX), Rituximab, and Mycophenolate Mofetil but continued to have neurological disability. Despite an initial response to PLEX with improved stiffness, muscle spasms, dysautonomia, and mobility, this improvement was not sustained. The patient continued to progress over two years despite immunotherapy, leading to the decision for aHSCT. Nine months after aHSCT, he showed significant clinical amelioration. Comparison of pre- to 21 weeks post-aHSCT findings included a 25-foot walk time reduction from 28.4 seconds to 15 seconds and a stiffness index reduction from 4/6 to 2/6. The patient also had improved gait, phonation, and reduced pain. <h3>Conclusions:</h3> We report a case of symptomatic improvement, evidenced by reduced walk time and stiffness index, after aHSCT in an anti-GlyR positive SPSD patient. Nine months after the transplant the patient had further improved symptoms, indicating aHSCT as a beneficial therapy for this patient and potentially others with similar presentations. <b>Disclosure:</b> Mrs. I Celli has nothing to disclose. Dr. Nash has nothing to disclose. Ms. McMenamin has nothing to disclose. Dr. Garza has nothing to disclose. The institution of Dr. Von Geldern has received research support from Novartis. The institution of Dr. Von Geldern has received research support from National MS Society. Dr. Von Geldern has received personal compensation in the range of $0-$499 for serving as a DSMB member with NIH, NINDS. Dr. Von Geldern has a non-compensated relationship as a editorial board member with MS and Related Disorders Journal that is relevant to AAN interests or activities. George Georges has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Magenta Therapeutics. George Georges has received personal compensation in the range of $0-$499 for serving as a Consultant for Company. George Georges has received personal compensation in the range of $0-$499 for serving as a Consultant for Talaris Therapeutics. George Georges has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Jasper Biotech. The institution of George Georges has received research support from NIH/NIAID. The institution of Dr. Piquet has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. The institution of Dr. Piquet has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Piquet has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Piquet has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Piquet has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Sands Anderson PC. The institution of Dr. Piquet has received research support from Rocky Mountain MS Center. The institution of Dr. Piquet has received research support from Novartis. The institution of Dr. Piquet has received research support from Abbvie. The institution of Dr. Piquet has received research support from Roche/Genentech. The institution of Dr. Piquet has received research support from NYU. Dr. Piquet has received publishing royalties from a publication relating to health care. Dr. Piquet has received publishing royalties from a publication relating to health care. Dr. Piquet has received personal compensation in the range of $10,000-$49,999 for serving as a Litigative Consultant with US-Dept HHS/DICP.

Severe dysautonomia in glycine receptor antibody-positive progressive encephalomyelitis with rigidity and myoclonus (PERM): A case report

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a severe form of stiff-person spectrum disorder. We report a 59-year-old man who presented with progressive encephalomyelitis causing diplopia, bulbar palsy, severe dysautonomia, followed by stiffness and myoclonic cluster. Laboratory tests showed mild pleocytosis, with markedly elevated plasma levels of norepinephrine, epinephrine, and arginine vasopressin. Glycine-receptor antibodies were identified in both serum and CSF. Despite a poor response to methylprednisolone, immunoglobulins, and plasma exchange, α-blocker stabilized dysautonomia. Dysautonomia is presumed to be due to antibody-mediated disinhibited sympathetic hyperactivity; however, this case suggests that concomitant use of α-blocker with immunotherapy may ameliorate dysautonomia.

S2777 A Rare Case of Progressive Encephalomyelitis With Rigidity and Myoclonus Related to Hepatitis E Virus

Introduction: We present an unusual case of progressive encephalomyelitis with rigidity and myoclonus (PERM) caused by hepatitis E viral illness. Case Description/Methods: A 42-year-old male with a past medical history of left nephrectomy donation, hypertension, and chronic kidney disease presents with sudden onset of numbness of his tongue. He complains of intermittent dizziness (positional), hearing changes (including voices and music) as well as double/blurry vision, global fatigue, and visual hallucinations. The patient denies any extremity weakness, difficulty swallowing, or headache. No facial droop is noted, but right eye droop is noted. The patient is ambulating with a steady gait. The patient has elevated liver enzymes (AST 178, ALT 616) with elevated alkaline phosphatase (ALP 323). The patient has no recent exposures or ingestion. He is diagnosed with PERM following the onset of symptoms managed with high-dose steroid therapy and plasmapheresis. Symptoms persisted with dysphagia requiring feeding tube placement, tracheostomy, along with progressively worsening transaminase levels with ALP 742, AST 342, ALT 1,062. Hepatology was consulted with negative autoimmune work-up, hepatitis B and C screening. Hepatitis E IgM was obtained and found to be positive. A liver biopsy was obtained showing mild portal tract inflammation with ductal reaction, focal pericentral macrophages, and hepatocyte dropout reflective of viral hepatitis. He was recommended to start ribavirin 200 mg twice daily given persistently elevated transaminase levels. Repeat evaluation with HEV testing after two months of therapy was negative. Treatment for the PERM included steroids, intravenous immunoglobulin, plasmapheresis, and rituximab with improvement in symptoms. Most recent liver enzymes were normal on ribavirin treatment. Discussion: PERM is a rare disorder characterized by muscular rigidity, muscle spasms, abnormal posture, and is caused by inflammation in the brainstem and spinal cord. PERM can be diagnosed clinically or if the patient is positive for anti-HEV IgM and has symptomatology characteristic of stiff-person plus syndrome. Symptoms can be explained by the interruption of glycinergic synaptic transmission in the spinal cord and brainstem. Antibodies present against glycine receptors in the serum and CSF suggest antibody-mediated pathogenesis, possibly responsive to immunotherapy. Ribavirin is commonly prescribed for HEV clearance and amelioration of HEV-associated neurologic symptoms.

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.

Stiff-Person Syndrome

Stiff-person syndrome (SPS) is a neurological disorder characterized by fluctuating muscle rigidity and painful spasms that occur spontaneously or are triggered by diverse stimuli. Partial or segmental forms of the disorder, such as stiff-limb syndrome (SLS) and the more severe disease called progressive encephalomyelitis with rigidity and myoclonus (PERM), are usually considered within the spectrum of SPS. SPS responds to immunotherapies, and several autoantigens have been identified. Most patients with SPS have high titers of antibodies against glutamic acid decarboxylase (GAD), the enzyme that limits the rate of the synthesis of γ-aminobutyric acid (GABA), and up to 15% have antibodies against the glycine receptor α-subunit.

Systemic delivery of human GlyR IgG antibody induces GlyR internalization into motor neurons of brainstem and spinal cord with motor dysfunction in mice.

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a life-threatening condition often associated with highly raised serum antibodies to glycine receptors (GlyRs); these bind to the surface of large neurons and interneurons in rodent brain and spinal cord sections and, in vitro, inhibit function and reduce surface expression of the GlyRs. The effects in vivo have not been reported. Purified plasma IgG from a GlyR antibody-positive patient with PERM, and a healthy control (HC), was injected daily into the peritoneal cavity of mice for 12days; lipopolysaccharide (LPS) to open the blood-brain barrier, was injected on days 3 and 8. Based on preliminary data, behavioural tests were only performed 48h post-LPS on days 5-7 and 10-12. The GlyR IgG injected mice showed impaired ability on the rotarod from days 5 to 10 but this normalized by day 12. There were no other behavioural differences but, at termination (d13), the GlyR IgG-injected mice had IgG deposits on the neurons that express GlyRs in the brainstem and spinal cord. The IgG was not only on the surface but also inside these large GlyR expressing neurons, which continued to express surface GlyR. Despite the partial clinical phenotype, not uncommon in passive transfer studies, the results suggest that the antibodies had accessed the GlyRs in relevant brain regions, led to antibody-mediated internalization and increased GlyR synthesis, compatible with the temporary loss of function.

Stiff person spectrum disorders: An illustrative case series of their phenotypic and antibody diversity

Stiff person spectrum disorders (SPSD) are a broad group of immune-mediated disorders. Clinical presentations include classical stiff person syndrome (SPS), focal SPS, and progressive encephalomyelitis with rigidity and myoclonus (PERM). The most frequently associated antibodies are anti-GAD65, anti-GlyR, anti-amphiphysin, and anti-DPPX. Immunotherapy is the primary treatment modality. We present an illustrative case series of three patients: anti-GlyR antibody-mediated PERM presenting as rapidly progressive dementia; anti-amphiphysin antibody-mediated SPS; and SPS presentation with anti-Zic4 antibodies, spasmodic laryngeal stridor and fluctuating eyelid ptosis. Clinical characteristics, CSF findings, neurophysiological features, adequate immunological assays and a high suspicion index are essential for prompt diagnosis and management.

Glycine receptor autoantibodies disrupt inhibitory neurotransmission.

Chloride-permeable glycine receptors have an important role in fast inhibitory neurotransmission in the spinal cord and brainstem. Human immunoglobulin G (IgG) autoantibodies to glycine receptors are found in a substantial proportion of patients with progressive encephalomyelitis with rigidity and myoclonus, and less frequently in other variants of stiff person syndrome. Demonstrating a pathogenic role of glycine receptor autoantibodies would help justify the use of immunomodulatory therapies and provide insight into the mechanisms involved. Here, purified IgGs from four patients with progressive encephalomyelitis with rigidity and myoclonus or stiff person syndrome, and glycine receptor autoantibodies, were observed to disrupt profoundly glycinergic neurotransmission. In whole-cell patch clamp recordings from cultured rat spinal motor neurons, glycinergic synaptic currents were almost completely abolished following incubation in patient IgGs. Most human autoantibodies targeting other CNS neurotransmitter receptors, such as N-methyl-d-aspartate (NMDA) receptors, affect whole cell currents only after several hours incubation and this effect has been shown to be the result of antibody-mediated crosslinking and internalization of receptors. By contrast, we observed substantial reductions in glycinergic currents with all four patient IgG preparations with 15 min of exposure to patient IgGs. Moreover, monovalent Fab fragments generated from the purified IgG of three of four patients also profoundly reduced glycinergic currents compared with control Fab-IgG. We conclude that human glycine receptor autoantibodies disrupt glycinergic neurotransmission, and also suggest that the pathogenic mechanisms include direct antagonistic actions on glycine receptors.

Autoimmune movement disorders

Autoimmune movement disorders (AMD) are increasingly recognized and include a wide spectrum of hyperkinetic, hypokinetic, sleep related and ataxic presentations. These range from chorea, tics, dystonic jerks, myoclonus, and neuromyotonia to hypo and akinetic rigid syndromes. The latter varieties encompass parkinsonism, stiff person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM). Ataxic syndromes include episodic ataxia associated with CASPR2 and post Herpes zoster cerebellitis and other rare paraneoplastic syndromes. The AMD have a broad spectrum of clinical phenotypes which are increasingly being recognized. They may present as an isolated movement disorder or as part of a wider clinical syndrome usually with encephalitic illnesses. They may follow infections, parainfectious, as in Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS) and Sydenham chorea, or associate with an underlying occult malignancy (Leucine rich Glioma1 inactivated, Voltage Gated Potassium Channel Antibodies) associated Limbic encephalitis with brachio facial dystonic jerks and seizures linked with ovarian and testicular teratomas. In many instances no underlying cause is found, and ongoing research is revealing new markers and aetiologies for what was labelled idiopathic in the past. The autoimmune basis of these disorders is shown by the presence of antibodies or specific groups of CD8 cytotoxic cells mostly detected in the serum, cerebrospinal fluid and other tissues. Furthermore, their response to immunotherapies supports this notion and are the mainstay of current treatments. The latter include corticosteroids, therapeutic plasma exchange (TPE, PLEX), target specific biologicals (specific monoclonal antibodies mostly against B cells markers such as Ritixumab, anti CD20). Symptomatic therapies for the movement themselves and the associated presentation such as seizures, sleep and mood disturbances. The target antigens are diverse as mentioned above. They usually present subacutely and may deteriorate rapidly or follow a relapsing remitting course. Early positive recognition of these disorders is crucial as they are potentially treatable and in some case curable. This will avoid or reduce morbidity and improve long term outcomes.

104 Silent multilevel vertebral fractures in a severe case of glycine receptor antibody-positive progressive encephalomyelitis with rigidity and myoclonus (PERM)

IntroductionAutoimmune encephalitides are a heterogenous and potentially devastating group of disorders. Antibodies to glycine receptor (GlyR) are rare and increasingly reported in patients with progressive encephalomyelitis with rigidity and myoclonus (PERM). PERM patients develop early brainstem and autonomic dysfunction, and if untreated, can be fatal. We aim to discuss the complications and treatments in this PERM case and review the literature on management of PERM.MethodsWe report a case of PERM currently undergoing treatment in our hospital.ResultsMr GT is a 46-year-old male who presented with a prodromal phase of altered sensation and acute cerebellar signs. He rapidly deteriorated with bulbar dysfunction and developed generalised muscle rigidity and hyperreflexia. Infective work-up, cerebrospinal fluid analysis, magnetic resonance imaging of brain and spine were initially normal. He was started on first line immunosuppressants for a clinical diagnosis of autoimmune encephalitis. Despite sedation in intensive care, generalised myoclonus and truncal extensor spasms were severe and presented on-going management difficulties. A computed tomography scan of his abdomen to exclude malignancy revealed incidental findings of vertebral fractures at multiple thoracic and lumbar levels. He was subsequently administered rituximab and demonstrated some signs of recovery. GlyR antibody positive results from Oxford University Hospital consequently confirmed his diagnosis.ConclusionThis is the fourth reported GlyR antibody-positive PERM case in Australia and the first description to our knowledge with intractable rigidity and myoclonus leading to vertebral fractures. Awareness and screening for this complication may assist in management of patients with PERM.

A Rare Case of Non-Neoplastic Anti-GAD Positive Cerebellar Ataxia and Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM), Responsive to IVIG Therapy (P2.2-044)

A Rare Case of Non-Neoplastic Anti-GAD Positive Cerebellar Ataxia and Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM), Responsive to IVIG Therapy (P2.2-044)

Anti-glutamic acid decarboxylase (GAD) positive cerebellar Ataxia with transitioning to progressive encephalomyelitis with rigidity and myoclonus (PERM), responsive to immunotherapy: A case report and review of literature

We present a case of a 65-year-old African American male, immunosuppressed on Tacrolimus, who initially presented with cerebellar ataxia and rapidly developed Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM) with positive anti-glutamic acid decarboxylase (GAD65) antibodies, no underlying malignancy, and normal neuroimaging. PERM is a rare spectrum of Stiff Person Syndrome (SPS), which is strongly associated with anti-GAD antibodies and characterized by flare-ups and remissions of encephalopathy, myelopathy and rigidity with myoclonus. PERM is diagnosed clinically and has been successfully treated with both Intravenous Immunoglobulin (IVIg) and plasmapheresis. Our patient was successfully treated with IVIg. On day 14 after starting IVIg treatment, his neurological symptoms started to improve and ultimately returned to baseline.

F59. Spasmodic reflex myoclonus-an characteristic electrophysiological manifestation for the diagnosis of Stiff-person syndrome

Introduction Stiff person syndrome (SPS) is a rare disease entity and the pivotal clinical features contain progressive course of fluctuating stiffness of the low back and lower limbs. Progressive encephalomyelitis with rigidity and myoclonus (PERM) is one of the unique variants of stiff person syndrome, and it was characterized with rigidity, stimulus-sensitive spasms, myoclonus, autonomic disturbance, and brainstem signs. These features resemble those of hyperekplexia. The accurate diagnosis of SPS is difficult but is crucial for the in time intervention with immunotherapy for life saving. In addition to the detection of responsible antibody, clinical electrophysiological manifestation, spasmodic reflex myoclonus, would be of great help in establishing the diagnosis. Methods Multichannel surface electromyogram (sEMG) and accelerometer recordings were conducted over the lumbar paraspinalis, rectus abdominalis, quadriceps, and hamstring muscles. Stimulus sensitive phenomenon was illustrated with accelerometer tapped over the pinprick. The signals were processed and digitized with CED power1401 with Spike2. The band pass for sEMG was set from 80 Hz to 1000 Hz. Results The results demonstrated that episodes of spontaneous onset of spasm of the low trunk and legs lasted about seconds to minutes. Stimuli with nose tip tapping, would elicit vigorous jerks with dissemination of long lasting muscle spasm of the neck, paraspinal muscle, rectus abdominalis muscle, to quadriceps and hamstring muscles in a descending spreading pattern. The unique electrophysiological manifestations illustrate the characteristic feature of spasmodic reflex myoclonus. The surface EMG recording also showed the phenomena of habituation, in which a trend of amplitude decrescendo from the first toward the third EMG responses were observed during consecutive auditory stimulus. The serum levels of anti-glutamic acid decarboxylase 65 antibodies was 164 IU. Conclusion The unique EMG pattern can help identify SPS. The clinical features of spasmodic reflex myoclonus are similar to hyperekplexia. However, there are some differences between the two phenomena. Unlike hyperekplexia, the spasmodic reflex myoclonus can be habituated after repetitive stimulation in the SPS patient. Furthermore, the initial myoclonic bursts of spasmodic reflex myoclonus were not present in hyperekplexia and the EMG burst duration was much shorter of the hyperekplexia as compared with that of spasmodic reflex myoclonus. These neurophysiological features discern spasmodic reflex myoclonus from hyperekplexia and are helpful in making diagnosis of SPS.

Stiff-Person Syndrome and Related Autoantibodies

Stiff-person syndrome (SPS) is a disorder characterized by fluctuating muscle rigidity and painful spasms that occur spontaneously or are triggered by diverse stimuli. Partial or segmental forms of the disorder, such as stiff-limb syndrome (SLS) and a more severe disease called progressive encephalomyelitis with rigidity and myoclonus (PERM), are usually considered within the spectrum of SPS. SPS responds to immunotherapies, and several autoantigens have been identified. Most patients with SPS have a high-titer of antibodies against glutamic acid decarboxylase (GAD), the rate-limiting enzyme for the synthesis of γ-aminobutyric acid (GABA), and up to 15% have antibodies to the glycine receptor α-subunit. This review explains milestones in defining SPS including autoantibodies.

Glycine receptor modulating antibody predicting treatable stiff-person spectrum disorders.

BackgroundGlycine receptor alpha-1 subunit (GlyRα1)-immunoglobulin G (IgG) is diagnostic of stiff-person syndrome (SPS) spectrum but has been reported detectable in other neurologic diseases for which significance is less certain.MethodsTo assess GlyRα1-IgGs as biomarkers of SPS spectrum among patients and controls, specimens were tested using cell-based assays (binding [4°C] and modulating [antigen endocytosing, 37°C]). Medical records of seropositive patients were reviewed.ResultsGlyRα1-IgG (binding antibody) was detected in 21 of 247 patients with suspected SPS spectrum (8.5%) and in 8 of 190 healthy subject sera (4%) but not CSF. Among 21 seropositive patients, 20 had confirmed SPS spectrum clinically, but 1 was later determined to have a functional neurologic disorder. Sera from 9 patients with SPS spectrum , but not 7 controls, nor the functional patient, caused GlyRα1 modulation (100% specificity). SPS spectrum phenotypes included progressive encephalomyelitis with rigidity and myoclonus (PERM) (8), classic SPS (5), stiff limb (5), stiff trunk (1), and isolated exaggerated startle (hyperekplexia, 1). Neuropsychiatric symptoms present in 12 patients (60%) were anxiety (11), depression (6), and delirium (3). Anxiety was particularly severe in 3 patients with PERM. Objective improvements in SPS neurologic symptoms were recorded in 16 of 18 patients who received first-line immunotherapy (89%, 9/10 treated with corticosteroids, 8/10 treated with IVIg, 3/4 treated with plasma exchange, and 1 treated with rituximab). Treatment-sparing maintenance strategies were successful in 4 of 7 patients (rituximab [2/3], azathioprine [1/1], and mycophenolate [1/3]).ConclusionsGlyRα1-modulating antibody improves diagnostic specificity for immunologically treatable SPS spectrum disorders.Classification of evidenceThis study provides Class IV evidence that GlyRα1-modulating antibody accurately identifies patients with treatable SPS spectrum disorders.