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

AIMS: 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. METHODS: 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 12 days; lipopolysaccharide (LPS) to open the blood-brain barrier, was injected on days 3 and 8. Based on preliminary data, behavioural tests were only performed 48 h post-LPS on days 5-7 and 10-12. RESULTS: 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. CONCLUSIONS: 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.

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

BACKGROUND AND PURPOSE: Antibodies 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. METHODS: A 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. RESULTS: In 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. CONCLUSION: Antibodies 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 and immunological characteristics of the spectrum of GFAP autoimmunity: a case series of 22 patients.

OBJECTIVE: To report the clinical and immunological characteristics of 22 new patients with glial fibrillar acidic protein (GFAP) autoantibodies. METHODS: From January 2012 to March 2017, we recruited 451 patients with suspected neurological autoimmune disease at the Catholic University of Rome. Patients' serum and cerebrospinal fluid (CSF) samples were tested for neural autoantibodies by immunohistochemistry on mouse and rat brain sections, by cell-based assays (CBA) and immunoblot. GFAP autoantibodies were detected by immunohistochemistry and their specificity confirmed by CBA using cells expressing human GFAPα and GFAPδ proteins, by immunoblot and immunohistochemistry on GFAP-/- mouse brain sections. RESULTS: Serum and/or CSF IgG of 22/451 (5%) patients bound to human GFAP, of which 22/22 bound to GFAPα, 14/22 to both GFAPα and GFAPδ and none to the GFAPδ isoform only. The neurological presentation was: meningoencephalomyelitis or encephalitis in 10, movement disorder (choreoathetosis or myoclonus) in 3, anti-epileptic drugs (AED)-resistant epilepsy in 3, cerebellar ataxia in 3, myelitis in 2, optic neuritis in 1 patient. Coexisting neural autoantibodies were detected in five patients. Six patients had other autoimmune diseases. Tumours were found in 3/22 patients (breast carcinoma, 1; ovarian carcinoma, 1; thymoma, 1). Nineteen patients were treated with immunotherapy and 16 patients (84%) improved. Histopathology analysis of the leptomeningeal biopsy specimen from one patient revealed a mononuclear infiltrate with macrophages and CD8+ T cells. CONCLUSIONS: GFAP autoimmunity is not rare. The clinical spectrum encompasses meningoencephalitis, myelitis, movement disorders, epilepsy and cerebellar ataxia. Coexisting neurological and systemic autoimmunity are relatively common. Immunotherapy is beneficial in most cases.

Redefining progressive encephalomyelitis with rigidity and myoclonus after the discovery of antibodies to glycine receptors.

PURPOSE OF REVIEW: This review highlights the recent discovery of antibodies to glycine receptor (GlyR-Ab) and discusses the relationship between these antibodies and neurological disorders. RECENT FINDINGS: Since the initial description in 2008 of antibodies to glycine receptors (GlyR-Abs) in a patient with progressive encephalomyelitis with rigidity and myoclonus (PERM), these antibodies have been found in PERM and in some patients with a variety of stiff person spectrum (SPS) or related disorders. Patients with GlyR-Abs often improve with aggressive immunotherapy, and antibody titres correlate with disease severity. Around 25% of patients have another autoimmune condition and 10-20% have an underlying malignancy. GlyR-Abs bind to extracellular determinants, are mainly Immunoglobulin G1 subclass and induce GlyR internalization in Human embryonic kidney 293 cells, suggesting pathogenicity. The spectrum of neurological disease associated with GlyR-Abs has not been fully characterized, and lower titres may not be syndrome specific, but GlyR-Abs, like antibodies to other neuronal cell-surface antigens, define immunotherapy-responsive disease and are likely to be pathogenic. This distinguishes them from the glutamic acid decarboxylase antibodies that can also be found at high titres in patients with classical stiff person syndrome which is more often chronic and relatively resistant to immunological treatments. SUMMARY: Irrespective of the clinical features, GlyR-Abs are helpful in the diagnosis of patients who very often have a subacute, progressive and life-threatening disorder which shows a favourable response to immunotherapy.

Focal status epilepticus and progressive dyskinesia: A novel phenotype for glycine receptor antibody-mediated neurological disease in children.

BACKGROUND: Antibody-associated disorders of the central nervous system are increasingly recognised in adults and children. Some are known to be paraneoplastic, whereas in others an infective trigger is postulated. They include disorders associated with antibodies to N-methyl-d-aspartate receptor (NMDAR), voltage-gated potassium channel-complexes (VGKC-complex), GABAB receptor or glycine receptor (GlyR). With antibodies to NMDAR or VGKC-complexes, distinct clinical patterns are well characterised, but as more antibodies are discovered, the spectra of associated disorders are evolving. GlyR antibodies have been detected in patients with progressive encephalopathy with rigidity and myoclonus (PERM), or stiff man syndrome, both rare but disabling conditions. CASE REPORT: We report a case of a young child with focal seizures and progressive dyskinesia in whom GlyR antibodies were detected. Anticonvulsants and immunotherapy were effective in treating both the seizures and movement disorder with good neurological outcome and with a decline in the patient's serum GlyR-Ab titres. CONCLUSION: Glycine receptor antibodies are associated with focal status epilepticus and seizures, encephalopathy and progressive dyskinesia and should be evaluated in autoimmune encephalitis.

[Two cases of acute onset of focal cortical reflex myoclonus following acute aseptic meningoencephalitis with positive anti-glutamate receptor autoantibody].

Patient 1 was a 40-year-old man, who suffered from right leg myoclonus 1 week after an episode of fever and headache. Myoclonus disappeared 4 months after administration of clonazepam. Patient 2 was a 42-year-old man, who suffered from right leg myoclonus, attacks of speech arrest and a generalized tonic-clonic seizure. His symptoms disappeared after steroid-pulse therapy, but right leg myoclonus and episodic impairment of consciousness recurred within a month. He underwent another steroid-pulse therapy and his symptoms disappeared. In both patients, cerebrospinal fluid (CSF) study showed pleocytosis and elevated protein level, electrophysiological study showed cortical reflex by stimulation of the right tibial nerve, and brain MRI showed the high intensity area in the left parietal lobe. In addition, on electroencephalogram (EEG) spikes at vertex preceded myoclonic jerk of the right tibialis anterior muscle in both patients. These findings indicate that focal cortical reflex myoclonus was accompanied by acute central nervous system (CNS) infection. Furthermore, in both patients, autoantibody against glutamate receptor subunits ε2 was detected both in serum and CSF, which also suggest that autoimmune mechanism contributed in the pathophysiology of acute development of focal cortical reflex myoclonus.

Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes.

The clinical associations of glycine receptor antibodies have not yet been described fully. We identified prospectively 52 antibody-positive patients and collated their clinical features, investigations and immunotherapy responses. Serum glycine receptor antibody endpoint titres ranged from 1:20 to 1:60 000. In 11 paired samples, serum levels were higher than (n = 10) or equal to (n = 1) cerebrospinal fluid levels; there was intrathecal synthesis of glycine receptor antibodies in each of the six pairs available for detailed study. Four patients also had high glutamic acid decarboxylase antibodies (>1000 U/ml), and one had high voltage-gated potassium channel-complex antibody (2442 pM). Seven patients with very low titres (<1:50) and unknown or alternative diagnoses were excluded from further study. Three of the remaining 45 patients had newly-identified thymomas and one had a lymphoma. Thirty-three patients were classified as progressive encephalomyelitis with rigidity and myoclonus, and two as stiff person syndrome; five had a limbic encephalitis or epileptic encephalopathy, two had brainstem features mainly, two had demyelinating optic neuropathies and one had an unclear diagnosis. Four patients (9%) died during the acute disease, but most showed marked improvement with immunotherapies. At most recent follow-up, (2-7 years, median 3 years, since first antibody detection), the median modified Rankin scale scores (excluding the four deaths) decreased from 5 at maximal severity to 1 (P < 0.0001), but relapses have occurred in five patients and a proportion are on reducing steroids or other maintenance immunotherapies as well as symptomatic treatments. The glycine receptor antibodies activated complement on glycine receptor-transfected human embryonic kidney cells at room temperature, and caused internalization and lysosomal degradation of the glycine receptors at 37°C. Immunoglobulin G antibodies bound to rodent spinal cord and brainstem co-localizing with monoclonal antibodies to glycine receptor-α1. Ten glycine receptor antibody positive samples were also identified in a retrospective cohort of 56 patients with stiff person syndrome and related syndromes. Glycine receptor antibodies are strongly associated with spinal and brainstem disorders, and the majority of patients have progressive encephalomyelitis with rigidity and myoclonus. The antibodies demonstrate in vitro evidence of pathogenicity and the patients respond well to immunotherapies, contrasting with earlier studies of this syndrome, which indicated a poor prognosis. The presence of glycine receptor antibodies should help to identify a disease that responds to immunotherapies, but these treatments may need to be sustained, relapses can occur and maintenance immunosuppression may be required.

Progressive encephalomyelitis with rigidity and myoclonus: a new variant with DPPX antibodies.

OBJECTIVE: To describe a novel and distinct variant of progressive encephalomyelitis with rigidity and myoclonus (PERM) associated with antibodies directed against dipeptidyl peptidase-like protein 6 (DPPX), a regulatory subunit of the Kv4.2 potassium channels on the surface of neurons. METHODS: Case series describing the clinical, paraclinical, and serologic features of 3 patients with PERM. A recombinant, cell-based indirect immunofluorescence assay with DPPX-expressing HEK293 cells was used to detect DPPX antibodies in conjunction with mammalian tissues. RESULTS: All patients presented with a distinct syndrome involving hyperekplexia, prominent cerebellar ataxia with marked eye movement disorder, and trunk stiffness of variable intensity. Additional symptoms comprised allodynia, neurogenic pruritus, and gastrointestinal symptoms. Symptoms began insidiously and progressed slowly. An inflammatory CSF profile with mild pleocytosis and intrathecal immunoglobulin G synthesis was found in all patients. High DPPX antibody titers were detected in the patients' serum and CSF, with specific antibody indices suggestive of intrathecal synthesis of DPPX antibodies. Response to immunotherapy was good, but constant and aggressive treatment may be required. CONCLUSION: These cases highlight the expanding spectrum of both PERM and anti-neuronal antibodies. Testing for DPPX antibodies should be considered in the diagnostic workup of patients with acquired hyperekplexia, cerebellar ataxia, and stiffness, because such patients might benefit from immunotherapy. Further studies are needed to elucidate both the entire clinical spectrum associated with DPPX antibodies and their role in pathogenesis.

N-methyl-D-aspartate receptor antibody-associated movement disorder without encephalopathy.

N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is a well-recognized clinico-immunological syndrome that presents with a movement disorder, cognitive decline, psychiatric symptoms, and epileptic seizures. A pure monosymptomatic presentation is rare; however, some patients present predominantly with a movement disorder in the absence of encephalopathy. Here, we describe three paediatric patients with an NMDAR antibody-mediated movement disorder: a 5-year-old female with acute onset hemichorea, a 10-year-old female with generalized chorea, and a 12-year-old male with abdominal myoclonus. These patients did not develop the characteristic encephalopathy syndrome seen in NMDAR encephalitis, but all three had other associated subtle cognitive deficits. The patients demonstrated good responses to immunotherapy.

Antiglycine receptor antibody and encephalomyelitis with rigidity and myoclonus (PERM) related to small cell lung cancer.

A 39-year-old man (a lifetime non-smoker) presented with a locked left jaw and leg myoclonus. Clinical and electromyographic findings were in keeping with progressive encephalomyelitis with rigidity and myoclonus (PERM) syndrome. A thoracic CT scan demonstrated a 19 mm right hilar nodule, which was proven to be small cell lung cancer on bronchoscopic biopsy. Serological evaluation of the patient's plasma revealed antibodies against glycine receptors (serology negative for anti-GAD, anti-Yo, anti-Hu, anti-Ri, antiamphiphysin, anti-Ma2/Ta, anti-CRMP5 and anti-NMDA receptor). After his cancer was treated with chemotherapy and intravenous immunoglobulins (IVIg), neurological symptoms resolved but returned several months later without any evidence of cancer recurrence. Symptoms were refractory to corticosteroids and IVIg therapy. Rituximab was then initiated, which led to a dramatic and sustained resolution of symptoms. To our knowledge, this is the first case of PERM related to antiglycine receptor antibodies from paraneoplastic syndrome, which resolved with rituximab.

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.

Antiglycine-receptor encephalomyelitis with rigidity.

BACKGROUND: Glycine receptor antibodies (GlyR-ab) were reported in a patient with progressive encephalomyelitis with rigidity and myoclonus (PERM). METHODS: Three additional patients were clinically described. GlyR-ab was detected with a cell-based assay of HEK293 cells transfected with the α1 subunit of the GyR. RESULTS: A 33-year-old woman presented with diplopia, dysphagia and gait ataxia that improved in 5 weeks. Then, she developed a typical stiff-person syndrome (SPS) that resolved with corticosteroids, but relapsed 17 months later with a stiff limb syndrome. After treatment with intravenous immunoglobulins (IVIG), she has been asymptomatic for 8 years. A 60-year-old man developed, dysphagia, diplopia, left facial palsy and right trigeminal hypoaesthesia in a few days, followed by muscular rigidity, corticospinal signs, myoclonic jerks and severe dysautonomia. He developed seizures and suffered a cardiac arrest that left him in a persistent vegetative state. A 48-year-old man presented with leg rigidity and frequent spells of trismus, muscle spasms followed by opisthotonus and diaphoresis. The symptoms were antedated by pruritus of the left scapulae, right arm and T11-T12 dermatome. At the same time he became progressively more aggressive with emotional irritability. He also developed dysgeusia (metallic taste) and severe concurrent behavioural changes and diurnal hypersomnia. Only the rigidity and the spasms improved after therapy. CONCLUSIONS: The clinical picture associated with GlyR-ab is wider than the classical view of PERM. GlyR-ab should be examined in patients with core symptoms of muscle rigidity and spasms atypical for SPS.