Anti-glycine Receptor Antibodies Research Articles

Autoantibodies related to ataxia and other central nervous system manifestations of gluten enteropathy

Gluten ataxia and other central nervous system disorders could be linked to gluten enteropathy and related autoantibodies. In this narrative review, we focus on the various neuro-logical manifestations in patients with gluten sensitivity/celiac disease, immunological and autoimmune mechanisms of ataxia in connection to gluten sensitivity and the autoantibodies that could be used as a biomarker for diagnosing and following. We focused on the anti-gliadin antibodies, antibodies to different isoforms of tissue transglutaminase (TG) (anti-TG2, 3, and 6 antibodies), anti-glycine receptor antibodies, anti-glutamine acid decarboxylase antibodies, anti-deamidated gliadin peptides antibodies, etc. Most studies found a higher prevalence of these antibodies in patients with gluten sensitivity and neurological dysfunction, presented as different neurological disorders. We also discuss the role of a gluten-free diet on the clinical improvement of patients and also on imaging of these disorders.

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.

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.

Brain and Muscle Metabolic Changes by FDG-PET in Stiff Person Syndrome Spectrum Disorders.

Objective: To report clinical characteristics and fluorodeoxyglucose positron emission tomography (FDG-PET) findings in the brain and muscles of individuals with stiff person syndrome (SPS) spectrum disorders (SPSSDs).Methods: Retrospective cohort study from 1997 to 2018 at Johns Hopkins Hospital identified 170 individuals with SPS or cerebellar ataxia (CA) associated with anti-glutamic acid decarboxylase (anti-GAD)-65 antibodies. Fifty-one underwent FDG-PET, with 50 involving the body and 30 with dedicated brain acquisition. The clinical and immunological profiles were extracted via medical record review. The brain scans were analyzed quantitatively using the NeuroQ software, with comparison with an averaged normal database. The body scans were reviewed qualitatively by a blinded nuclear medicine radiologist.Results: Mean age of symptom onset was 41.5 years (range 12–75 years). Majority were female (68%) and White (64%). Of the patients, 82% had SPS (majority being classic phenotype), and 18% had CA. Three had a paraneoplastic process. Forty-seven had serum anti-GAD, two with anti-amphiphysin, and one with anti-glycine receptor antibodies. Brain metabolic abnormalities were seen in both SPS and CA, with significant differences between the groups noted in the right superior frontal cortex, right sensorimotor cortex, left inferior parietal cortex, bilateral thalami, vermis, and left cerebellum. Of the patients, 62% demonstrated muscle hypermetabolism, most commonly bilateral, involving the upper extremities or axial muscles. Neither brain nor muscle metabolism was correlated with functional outcomes nor treatments.Conclusions: Metabolic changes as seen by FDG-PET are present in the brain and muscle in many individuals with SPSSD. Future studies are needed to assess whether FDG-PET can help aid in the diagnosis and/or monitoring of individuals with SPSSD.

West Nile Virus infection triggering autoimmune encephalitis: Pathophysiological and therapeutic implications

BackgroundA contributing factor in triggering autoimmune phenomena is pathogen infections. Here we describe a case that expands the spectrum of infection-associated autoimmune encephalitis and discuss plausible pathogenetic mechanisms. DesignCase report and in silico analysis. ResultsA patient with West Nile Virus infection developed autoimmune encephalitis with positive anti-glycine receptor antibodies. Combination therapy with corticosteroids and intravenous immunoglobulin resulted in the resolution of encephalitis signs and symptoms. An in silico analysis unveiled certain sequence similarities between viral antigens and receptor sequence fragments suggesting a molecular mimicry autoimmunization process. ConclusionsOur case indicates that West Nile Virus infections can trigger autoimmune encephalitis. Our finding expands the spectrum of autoimmune conditions that can develop following an infection. Whether the autoimmunization process is due to molecular mimicry or due to the expansion of natural autoantibody clones merits further investigation.

Follow-up of patients with epilepsy harboring antiglycine receptor antibodies

ObjectiveThe long-term follow-up of patients with epilepsy harboring autoantibodies against the glycine receptor (also glycine receptor antibodies or GlyR-Ab) is not well-known. Our aim was to investigate the 5-year prognosis and treatment response of patients with epilepsy who were seropositive for GlyR-Ab. MethodsClinical features; electroencephalogram (EEG), neuroradiological, and neuropathological findings; and treatment responses of patients with epilepsy with GlyR-Ab seropositivity were investigated. ResultsThirteen (5.46%) of 238 patients with epilepsy were GlyR-Ab positive: focal epilepsy of unknown cause (FEoUC) was diagnosed in four (7.27%) out of 55 patients, mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) in five (4.5%) out of 111 patients, epileptic encephalopathy (EE) in two (4%) out of 50 patients, and status epilepticus (SE) in two (9.09%) out of 22 patients. None of the patients developed any other neurological symptoms or cancer during the 5-year follow-up. Seven of them had seizures that were resistant to antiepileptic drug (AED). Immunotherapy was used in two patients (with FEoUC and EE) improving seizure control. Three patients with MTLE-HS benefited from epilepsy surgery, and another patient with EE showed spontaneous remission. ConclusionGlycine receptor antibodies are detected in a wide spectrum of epileptic disorders with unclear pathogenic significance. Two GlyR-Ab seropositive patients with AED-resistant epilepsy treated with intravenous immunoglobulin (IVIg) showed clear benefit from immunotherapy. Future studies will be valuable in determining the role of screening patients with drug-resistant epilepsy for GlyR-Ab in order to identify patients who may benefit or respond to immunotherapy.

Antiglycine receptor antibody related disease: a case series and literature review.

Background and purposeAntibodies to glycine receptors (GlyR‐Abs) were first defined in progressive encephalopathy with rigidity and myoclonus (PERM) but were subsequently identified in other clinical presentations. Our aim was to assess the clinical associations of all patients identified with GlyR‐Abs in Queensland, Australia, between April 2014 and May 2017 and to compare these to cases reported in the literature.MethodsA literature review identified the clinical features of all published GlyR‐Ab‐positive cases through online databases. A case series was undertaken via collection of clinical information from all patients diagnosed or known to immunology, pathology or neurological services in Queensland during the study period of 3 years.ResultsIn all, 187 GlyR‐Ab‐positive cases were identified in the literature. The majority (47.6%) had PERM, 22.4% had epilepsy, but the remaining 30% included mixed phenotypes consisting of cerebellar ataxia, movement disorders, demyelination and encephalitis/cognitive dysfunction. By contrast, in our series of 14 cases, eight had clinical presentations consistent with seizures and epilepsy and only three cases had classical features of PERM. There was one case each of global fatiguable weakness with sustained clonus, laryngeal dystonia and movement disorder with hemiballismus and tics. The rate of response to immune therapy was similar in all groups.ConclusionAntibodies to glycine receptors are linked to a spectrum of neurological disease. The results of the literature review and our case series suggest a greater relationship between GlyR‐Abs and epilepsy than previously reported.

Clinical Spectrum of Stiff Person Syndrome: A Review of Recent Reports.

Background“Classic” stiff person syndrome (SPS) features stiffness, anti-glutamic acid decarboxylase (anti-GAD) antibodies, and other findings. Anti-GAD antibodies are also detected in some neurological syndromes (such as ataxia) in which stiffness is inconsistently present. Patients with otherwise “classic” SPS may either lack anti-GAD antibodies or be seropositive for others. Hence, SPS cases appear to fall within a clinical spectrum that includes conditions such as progressive encephalomyelitis with rigidity and myoclonus (PERM), which exhibits brainstem and autonomic features. We have compiled herein SPS-spectrum cases reported since 2010, and have segregated them on the basis of likely disease mechanism (autoimmune, paraneoplastic, or cryptogenic) for analysis.MethodsThe phrases “stiff person syndrome”, “PERM”, “anti-GAD antibody syndrome”, and “glycine receptor antibody neurological disorders” were searched for in PubMed in January 2015. The results were narrowed to 72 citations after excluding non-English and duplicate reports. Clinical descriptions, laboratory data, management, and outcomes were categorized, tabulated, and analyzed.ResultsSixty-nine autoimmune, 19 paraneoplastic, and 13 cryptogenic SPS-spectrum cases were identified. SPS was the predominant diagnosis among the groups. Roughly two-thirds of autoimmune and paraneoplastic cases were female. Anti-GAD antibodies were most frequently identified, followed by anti-amphiphysin among paraneoplastic cases and by anti-glycine receptor antibodies among autoimmune cases. Benzodiazepines were the most commonly used medications. Prognosis seemed best for cryptogenic cases; malignancy worsened that of paraneoplastic cases.DiscussionGrouping SPS-spectrum cases by pathophysiology provided insights into work-up, treatment, and prognosis. Ample phenotypic and serologic variations are present within the categories. Ruling out malignancy and autoimmunity is appropriate for suspected SPS-spectrum cases.

Seropositive PERM associated with leucocytoclastic vasculitis

Background: Progressive encephalomyelitis, rigidity, and myoclonus (PERM) is a variant stiff-person plus syndrome consisting of brainstem and pyrimidal dysfunction, muscular rigidity, stimulus-evoked spasms, and dysautonomia. Continuous motor-unit activity from ectopic anterior horn cell discharges underlies the myotomal hyperactivity. Case Report: A 51-year-old man with an 8-year history of “spasmodic” mid and low back pain presented with increasing stiffness, hyperekplexia-induced opisthotonus-like posturing, urinary retention, long-tract motor signs, and diplopia. He had a recent history of biopsy-confirmed leucocytoclastic vasculitis-associated diffuse maculopapular rash. He responded well to IVIg treatment manifested by improved 1) gait fluidity, 2) bowel and bladder function 3) tolerance to startle, and 4) vision. Results: Serological testing revealed positive anti-glycine receptor antibodies. Anti-glutamic acid decarboxylase and voltage-gated K+-channel antibodies were absent. A chest CT was unremarkable. Conclusions: This is the second case of seropositive PERM in Canada and the first associated with leucocytoclastic vasculitis. Pathologic findings in PERM reveal perivascular lymphocytic cuffing in the rhombencephalon and spinal cord. Glycine receptor localization correlates with neurologic dysfunction. Mid-brain involvement may underlie the autonomic dysfunction but evidence of direct glycinergic inhibition of the external urethral sphincter in Onuf’s nucleus may be responsible for urinary retention.

Sporadic hyperekplexia presenting with an ataxic gait

We describe a 62-year-old man with a sporadic form of hyperekplexia who presented with an unsteady gait, present since the age of 47. His clinical examination revealed an insecure broad-based gait and difficulty with tandem walking but no other abnormalities. For nearly a decade the patient was misdiagnosed with an idiopathic ataxia. A video electroencephalogram combined with an electromyogram during sudden auditory stimulus demonstrated an excessive startle response. An extensive work-up ruled out all the known causes of symptomatic hyperekplexia including anti-glycine receptor antibodies. Treatment with clonazepam markedly reduced the threshold and intensity of the startle response, enabling him to recover independence. Hyperekplexia is frequently associated with an awkward and hesitating gait, but these gait abnormalities might be confused with other causes of gait disorders if one is not aware of this disease. We report this patient to highlight that a correct diagnosis of hyperekplexia is crucial, because its treatment may change quality of life.

Anti-Glycine Receptor Antibody Mediated Progressive Encephalomyelitis with Rigidity and Myoclonus Associated with Breast Cancer

We describe a 66-year-old woman who presented with a dramatic course of PERM. Anti-glycine receptor antibodies were found. She stabilized after plasma-exchange and partly recovered. Eighteen months later, a diagnosis of smouldering breast cancer with bone marrow metastasis was made. There are indications that this tumor was already present at first presentation. An overview of PERM and anti-glycine receptor antibodies is given.

抗グリシン受容体抗体関連疾患の臨床スペクトラム

Anti-glycine receptor (anti-GlyR) antibodies were first reported in 2008 in a case of progressive encephalomyelitis with myoclonus and rigidity (PERM), which is a variant of stiff-person syndrome (SPS). After that, the antibodies have been studied extensively. At least 40 patients have been reported or presented until May 2013. We reviewed 28 patients (median age 47 years, range 1 to 75 years), whose clinical data are available. Seventeen patients (60%) were male. We classified clinical phenotype into PERM (17), classic SPS (5), variant SPS (5), and others (1: progressive optic atrophy). Nine patients (32%) had ant-GAD antibodies. Accompanied diseases included thyroiditis (5), diabetes mellitus (3), thymoma (3), and Addison's disease (2). Twenty-one patients (75%) treated with immunotherapy or thymectomy improved, but two of six patients without immunotherapy died or developed cardiac arrest. The clinical features suggested that antibody-mediated inhibition of the GlyR on the brainstem nuclei or spinal inhibitory interneurons may cause continuous firing of α motor neurons and paroxysmal excessive response to a variety of afferent impulses, leading to increased stiffness, brainstem signs, trismus, myoclonus, painful spasms or hyperekplexia. Phenotype associated with the anti-GlyR antibodies may be broader than previously thought, but among those PERM is the most common phenotype.

GLYCINE RECEPTOR ANTIBODY MEDIATED PROGRESSIVE ENCEPHALOMYELITIS WITH RIGIDITY AND MYOCLONUS (PERM) PRESENTING WITH RESPIRATORY COMPROMISE IN A 40-YEAR-OLD MALE

A 40-year-old man was intubated after presenting with respiratory compromise. After tracheostomy, he was found to have an ophthalmoplegia, severe limb rigidity, stimulus sensitive myoclonus, and autonomic dysfunction. A history...

Relapsing Anti-Glycine Receptor Antibody Mediated Encephalitis with Rigidity and Myoclonus (P01.235)

Relapsing Anti-Glycine Receptor Antibody Mediated Encephalitis with Rigidity and Myoclonus (P01.235)

PROGRESSIVE ENCEPHALOMYELITIS, RIGIDITY, AND MYOCLONUS: A NOVEL GLYCINE RECEPTOR ANTIBODY

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare disorder of subacute onset presenting as limb and truncal rigidity, muscle spasms, brainstem signs, and hyperekplexia.1 Life-threatening, it is part of the spectrum of stiff-person syndrome (SPS) with anti-glutamic acid decarboxylase (GAD) antibodies in up to 80% of patients.1 It may also be paraneoplastic with anti-amphiphysin antibodies.2 Mutations in the α1 subunit of the glycine receptor gene GLRA1 have been identified in hereditary hyperekplexia.3 Glycine receptors are concentrated in the caudal pontine brainstem and spinal cord; in PERM, hyperekplexia (brainstem myoclonus or excessive startle)4 implies disruption of the normal inhibitory glycinergic mechanism in the caudal pons where the nucleus reticularis pontis caudalis mediates the startle reflex. We report a patient with typical severe PERM associated with a novel anti-glycine receptor antibody. ### Clinical summary. A 54-year-old man presented in January 2001 with 3 weeks of left flank tingling and 2 weeks of worsening brief frequent violent jerks, spontaneous and triggered by sensory and auditory stimuli; his upper limbs would abduct and flex and his trunk and legs extend. Neurologic examination was otherwise normal; he was intubated and ventilated. The CSF contained 60 lymphocytes × 109/L, the CSF IgG index was 0.72 (n < 0.7), oligoclonal bands negative. Cranial and spinal MRI scans with gadolinium were normal. After …