Progressive Encephalomyelitis with Rigidity and Myoclonus with GlyR Antibodies

By Nathan Schleinkofer, MD

Synopsis: This is a retrospective observational study of patients with a clinical diagnosis of progressive encephalomyelitis with rigidity and myoclonus (PERM) and glycine receptor (GlyR) antibodies identified at a specialized neuroimmunology laboratory, as well as an accompanying systematic literature review. The goal of the study was to describe the clinical features and long-term outcome of patients with GlyR antibody-mediated PERM.

Source: Guasp M, Saiz A, Ruiz-Vives M, et al. Progressive encelphalomyelitis with rigidity and myoclonus with glycine receptor antibodies. Neurol Neuroimmunol Neuroinflamm. 2025;12(6):e200473.

The term progressive encephalomyelitis with rigidity and myoclonus (PERM) originally was introduced in 1994 to describe a syndrome of subacute muscle stiffness, rigidity, and spasms resembling stiff-person syndrome (SPS), as well as brainstem signs including diplopia, bulbar symptoms, autonomic symptoms, and gaze palsies. PERM generally is considered a variant of SPS, given the presence of antibodies against glutamic acid decarboxylase (GAD) in the initial case series. However, in 2008, there was a case report of a patient with PERM and anti-glycine receptor (GlyR) antibodies. Since then, GlyR antibodies have increasingly been associated with PERM, and antibody-transfer models have supported their direct role in the pathogenesis of the syndrome, suggesting a clinical entity that is separate from SPS-spectrum disorders.

The laboratory’s records were analyzed to identify patient samples with GlyR antibodies in the serum or cerebrospinal fluid (CSF), of which there were 44. Demographic, diagnostic, treatment, and follow-up information was gathered. Patients were included in the study if they were older than 15 years of age, had a clinical presentation consistent with PERM, GlyR antibodies, and follow-up data at 12 months or more. Patients not fitting these criteria, having GAD antibodies or other neuronal cell-surface antibody positivity, or having a clinical course suggestive of SPS with overlapping symptoms of PERM, were excluded. Twenty-two patients ultimately were included in the study. A systematic review of the literature on PubMed also was conducted, with 116 studies identified and, ultimately, 19 patients whose data fit the inclusion/exclusion criteria.

The median age of patients was 58 years and the majority were male (88%). Twenty-four percent of cases were preceded by an infection and 22% were associated with malignancy; thymoma, Hodgkin lymphoma, and lung cancer were the most common. Symptom onset was rapid, with an average of one to four weeks between onset and hospitalization. Brainstem symptoms tended to present first, mostly dysphagia followed by trismus, respiratory distress, and/or cranial nerve palsies. Muscle stiffness/spasms and myoclonus presented days after the bulbar symptoms, with up to 57% of patients having these symptoms on admission. Importantly, these were the main presenting symptoms in 22% of patients. Other reported symptoms included dysesthesias, hallucinations, dysautonomia, and cacosmia with dysgeusia. Overall, 61% of patients developed the triad of stiffness, myoclonus, and muscle spasms in addition to brainstem symptoms that are characteristic of PERM.

Clinically, more than half of patients required admission to an intensive care unit (ICU). CSF pleocytosis was the most common abnormality at 62% of patients. Positive CSF oligoclonal bands also were identified in 37% of patients. Electromyography (EMG) in 58% of patients showed continuous motor unit firing of agonist and antagonist muscles. All patients received immunotherapy, such as glucocorticoids, immunoglobulins, or plasma exchange, with 39% also receiving rituximab or cyclophosphamide. By the time of discharge, 77% of patients had improved (defined by a decrease of one point on the modified Rankin Scale [mRS]), with a median nadir score of 5 and median discharge score of 3. There was not a statistically significant difference in improvement between patients who received cyclophosphamide or rituximab and those who did not.

At follow-up, eight patients had died as the result of complications from PERM, with older age being the only variable associated with increased risk of death. Twenty-eight percent of patients had relapses within the 12-month follow-up period. At 24 months, 70% of patients had a good outcome (mRS score < 3), with increased age and ICU admission identified as risk factors for having a bad outcome.

Commentary

The goal of the study was to describe the clinical features and long-term outcome of patients with GlyR antibody-mediated PERM and how it differs from SPS. In this study population, patients were more likely to be male and older than patients with SPS. These patients with PERM had a rapid onset of brainstem and muscle symptoms, with additional symptoms of hallucinations, dysesthesias, and cacosmia with dysgeusia. The symptoms were severe, and more than half of patients required ICU-level care. Notwithstanding, the majority improved with immunotherapy and no discreet benefit from second-line therapies was observed. This description of PERM with associated GlyR antibodies helps distinguish it from the related SPS-spectrum disorders and highlights the need for rapid diagnosis and management, given the severity of the disorder.

Nathan Schleinkofer, MD, is Clinical Neurophysiology-EMG Fellow, New York Presbyterian-Weill Cornell Medical Center.