Search

Objectives: 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)., Methods: We report clinico-pathologic findings of a PERM patient with coexisting GlyR and GAD65 antibodies., Results: 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., Discussion: 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.

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare but debilitating disease within the stiff person syndrome (SPS) spectrum characterised by muscle rigidity, spasms, myoclonus, dysautonomia, and brainstem dysfunction. The exact pathogenetic mechanism is unclear, although there is an association with the presence of glycine receptor antibodies in serum and cerebrospinal fluid, and some cases are paraneoplastic. Here, we report a case of paraneoplastic, glycine receptor antibody-positive PERM associated with an otherwise subclinical monoclonal B-cell lymphocytosis (MBL) of the non-CLL phenotype, which may be, in turn, likely secondary to long-term methotrexate use [i.e., methotrexate-associated lymphoproliferative disorder (MTX-LPD)] or an underlying autoimmune disease. Treatment with multiple lines of initial induction immunomodulatory therapies, followed by maintenance rituximab, achieved long-term remission of the neurologic, haematological, and rheumatologic disease. This is, to our knowledge, the first reported association between PERM and MBL, or between PERM and MTX-LPD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jia, Amin, Kwon, Mousapasandi, Dai, Kitson, Selim and Ip.)

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is an autoimmune disorder involving the brainstem and spinal cord and is sometimes associated with thymoma. We encountered a 75-year-old woman with typical PERM features, glycine receptor antibody, and thymoma. Her neurologic symptoms improved after thymectomy, but she unexpectedly developed anasarca with massive pleural effusions and hypoalbuminemia and finally succumbed to death. The autopsy showed edema and mononuclear infiltration in the pleura but no neuropathological findings typical of PERM. Effective treatment of PERM can reverse the neuropathological signs of encephalomyelitis. The autoimmune nature of anasarca is possible but not proven.

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., (© 2018 EAN.)

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.

A 62-year-old woman with one-year history of type 1 diabetes mellitus was admitted to our hospital with progressive weakness in the lower extremities and urinary dysfunction following high fever. On admission, she had rigidity and myoclonus in the upper extremities with sensory ataxia. Cerebrospinal fluid examination revealed mild pleocytosis and oligoclonal band. Glutamic acid decarboxylase (GAD) antibodies were detected at high titer in serum, but antibodies to glycine receptor (GlyR), thyroid peroxidase, mitochondrial M2, and GM1 were also detected. She was diagnosed with progressive encephalomyelitis with rigidity and myoclonus (PERM), which probably developed on the basis of polyglandular autoimmune syndromes. The clinical symptoms began to improve after initiation of intravenous high-dose methylprednisolone. Muscle weakness might be related to GM1 antibodies. This is the first report of PERM, in which GM1 antibodies were detected with GAD and GlyR antibodies.

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., (© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.)

A 40-year-old man presented with respiratory compromise and was intubated. After tracheostomy, he was found to have ophthalmoplegia, severe limb rigidity, stimulus-sensitive myoclonus and autonomic dysfunction. For 1&emsp14;week before admission, there had been a prodromal illness with low mood, hallucinations and limb myoclonus. Serum glycine receptor antibodies were strongly positive: we diagnosed progressive encephalomyelitis with rigidity and myoclonus. Despite a relapse, he has done well following immunotherapies. The clinical syndrome of encephalomyelitis with rigidity, described in 1976, often has a severe progressive course. A minority of patients have glutamic acid decarboxylase antibodies. The association with glycine receptor antibody was first reported in 2008, and we briefly review subsequent case reports to illustrate the range of clinical features. The antibody is likely to be disease mediating, although this remains unproven. The spectrum of diagnosable and treatable antibody mediated neurological syndromes is expanding. It is vital to recognise these conditions early to reduce morbidity and mortality.

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.

Importance: Progressive encephalomyelitis with rigidity and myoclonus is characterized by rigidity, painful muscle spasms, hyperekplexia, and brainstem signs. Recently, glycine receptor alpha 1 antibodies have been described in adult patients with progressive encephalomyelitis with rigidity and myoclonus. We describe a pediatric case., Observations: A 14-month-old child developed startle-induced episodes of generalized rigidity and myoclonus, axial hyperextension, and trismus, without impairment of consciousness. Episodes occurred during wakefulness and sleep, lasted seconds, and were accompanied by moaning, tachypnea, and oxygen desaturation. Imaging, cerebrospinal fluid, endocrine, metabolic, and genetic screening findings were normal or negative. She was treated with intravenous steroids and immunoglobulins with resolution of symptoms, but she relapsed weeks later. At this time, episodes were more severe. Glycine receptor alpha 1 antibodies were found in serum (titer of 1:200, later 1:320) and cerebrospinal fluid (titer of 1:2). Treatment was restarted with intravenous steroids and immunoglobulins, with major improvement, and she began treatment with oral steroids. She had 4 milder relapses, with improvement after treatment adjustments., Conclusions and Relevance: To our knowledge, this is the first pediatric case of progressive encephalomyelitis with rigidity and myoclonus associated with glycine receptor alpha 1 antibodies, a potentially severe but treatable antibody-mediated neurological disorder.

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.

Background: The syndrome of progressive encephalopathy with limb rigidity has been historically termed progressive encephalomyelitis with rigidity and myoclonus (PERM) or stiff-person syndrome plus., Methods: The case is presented of a previously healthy 28-year-old man with a rapidly fatal form of PERM developing over 2 months., Results: 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., Conclusion: 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.