Progressive encephalomyelitis with rigidity and myoclonus: glycine and NMDA receptor antibodies

Abstract

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.

Figure 1. Neuropathology of glycine receptor/NMDA receptor–associated encephalomyelitis

(A) Coronal section at the level of the anterior hippocampus shows a slit-like third ventricle (arrow) reflecting swelling due to edema and inflammation of the hypothalamic region (B). Most of the lymphocytic inflammation was perivascular (B, arrow). However, T lymphocytes also extended into the parenchyma (C, CD3 stain). Direct contact between T cells and neurons can be observed at high-power magnification (D, E, arrows). T cells attached to a pyramidal (D) and granule neuron (E) of the hippocampus (CD3 stain) are shown. These cells were mostly of CD8 subtype (D, inset). Selective attack of individual Purkinje cells by T cells/microglia was also seen in the cerebellum (F, G). A microglial nodule replacing a Purkinje cell was noted (F, arrow) and the striking outline of 2 Purkinje cells, including proximal dendrites, by activated microglia (CD68 stain) (G, arrow). There was complete sparing of another adjacent Purkinje cell (G, arrowhead).

Figure 2. Glycine receptor (GlyR) and NMDA receptor (NMDAR) antibodies

HEK cells transfected with EGFP-tagged GlyR cDNA (GlyR-EGFP; A) or cotransfected with NMDARs (NR1 and NR2B subunits) plus EGFP (NMDAR and EGFP; B). EGFP fluorescence shown in green. Patient immunoglobulin G (IgG) binding shown in red: score of 3 for GlyR antibody and 2 for NMDAR antibody (scoring system as in Irani et al.). Patient IgG did not bind to HEK cells transfected with EGFP only (C).