Progressive encephalomyelitis with rigidity and myoclonus and glycine receptor antibodies

Sarah J Crisp MBBChir PhD (

Dr. Crisp of University of Cambridge has no relevant financial relationships to disclose.

)
Angela Vincent MBBS (Dr. Vincent of Oxford University received consulting fees and royalties from Athena Diagnostics, and royalties from Euroimmun AG as a patent holder.)
Francesc Graus MD PhD, editor. (

Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.

)
Originally released May 8, 2020; Expires May 8, 2023

This article includes discussion of progressive encephalomyelitis with rigidity and myoclonus (PERM) and glycine receptor antibodies, stiff-person syndrome plus, and jerking stiff man syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a potentially treatable but often life-threatening neurologic disorder. PERM is characterized by progressive muscular rigidity and spasms, myoclonus and hyperekplexia with prominent brainstem signs, long-tract signs, and autonomic dysfunction. In approximately half of patients with PERM, 1-glycine receptor autoantibodies can be detected in serum and/or CSF. The discovery of glycine receptor autoantibodies has revolutionized the treatment of patients with PERM because it is now clear that, despite the severity of the disorder, at least some patients respond to immunomodulatory therapies.

Key points

 

• Approximately half of patients with PERM and a minority of patients with stiff-person spectrum disorders have detectable glycine receptor autoantibodies in the serum and/or CSF; some patients have coexisting glutamic acid decarboxylase 65 (GAD65) antibodies.

 

• Most remaining patients with PERM are “seronegative” or have GAD65 antibodies alone.

 

• PERM can be paraneoplastic but most cases occur in individuals without an underlying malignancy; approximately one third have other autoimmune disorders.

 

• Most patients improve with immunomodulatory therapies, though complete neurologic recovery may not occur.

 

• A significant minority of patients relapses following initial treatment.

 

• Glycine receptor antibodies have also been reported in other neurologic disorders where their clinical significance is less clear.

Historical note and terminology

Following the first descriptions of stiff-person syndrome (Moersch and Woltman 1956), PERM was recognized as a distinct clinical presentation within the stiff-person disorder spectrum, characterized by the unequivocal involvement of the brainstem (Whiteley et al 1976). The possibility of distinct underlying pathogenic mechanisms in PERM compared with classical stiff-person syndrome was put forward in 1999 (Brown and Marsden 1999). However, the relatively rapid and relentless progression of PERM led to the widespread belief that the disorder had a paraneoplastic or neurodegenerative basis (Bateman et al 1990), although notably malignancies were only detected in a minority of cases. The discovery of autoantibodies to glycine receptors in some patients with PERM has led to a shift in understanding of the pathophysiological mechanisms of disease (Hutchinson et al 2008; Carvajal-Gonzalez et al 2014). It is now clear that many patients with PERM have an autoimmune disorder and immunomodulatory treatment results in neurologic improvement in many cases.

Glycine receptor autoantibodies were first detected in a patient with PERM in 2008 (Hutchinson et al 2008). This patient presented with acquired spontaneous and stimulus-sensitive myoclonus, then went on to develop a more florid clinical syndrome with gaze palsies and severe truncal and lower limb rigidity. It was the similarity of his initial presentation to patients with hereditary hyperekplexia (most commonly caused by mutations in the alpha-1 subunit of the glycine receptor) and the discovery of autoantibodies to neuronal surface antigens occurring in association with acquired CNS disorders (Crisp et al 2016; Dalmau and Graus 2018) that prompted the search for glycine receptor autoantibodies. The index case made a substantial recovery following treatment with corticosteroids, plasmapheresis, intravenous immunoglobulins, and cyclophosphamide. The first series of patients with glycine receptor autoantibodies identified 33 out of 45 patients with high-titer glycine receptor autoantibodies having a clinical diagnosis of PERM and retrospective analysis of a separate cohort of 52 patients with stiff-person spectrum disorders identified a further 11 cases with glycine receptor autoantibodies, 5 of whom had PERM (Carvajal-Gonzalez et al 2014). Glycine receptor autoantibodies were also identified in some patients with other acquired neurologic syndromes including other stiff-person spectrum disorders, brainstem encephalitis, encephalitis with seizures, and optic neuritis. The range of neurologic presentations reported in patients found to harbor glycine receptor antibodies has continued to broaden, though the strongest clinical association is with PERM. Laboratory studies have demonstrated the direct pathogenicity of glycine receptor autoantibodies purified from patients with PERM and stiff-person spectrum disorders (Crisp et al 2019).

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