Lockjaw in stiff-person syndrome with autoantibodies against glycine receptors

A 37-year-old man was admitted to our hospital in 1998 with severe contraction of both masseter muscles, which made him unable to open his mouth. He could only drink using a straw fitting through a tooth gap. Spasms of the facial and masseter muscles had started in 1993 and transiently improved after treatment with benzodiazepines. The patient’s history included treatment of back and joint pain in 1990 and several admissions to psychiatry for “conversion neurosis.” At one time, his wife was suspected of poisoning him with an insecticide because of residues of parathion in his serum. Neurologic workup including brain and spinal cord MRI, lumbar puncture, extensive blood tests, and nerve conduction studies were normal. EMG showed profuse activity of the masseter muscle that increased when the mouth was passively opened. The masseter inhibitory reflex (MIR), performed according to Aramideh and Ongerboer de Visser, revealed lack of the late silent period (SP2) even at high stimulus intensities, while the early silent period (SP1) was present (figure 1A). With a tentative diagnosis of autoantibodymediated stiff-person–like disorder, plasmapheresis was initiated. After the third treatment, the patient was able to open his mouth and to eat normally. EMG showed normal muscle activity. Both SP1 and SP2 of the MIR were now present (figure 1B). However, after 2 months, lockjaw reappeared. Again, plasmapheresis led to complete recovery. For 1 year, plasmapheresis was repeated every 6 weeks, because this was the interval when lockjaw recurred. Corticosteroids (methylprednisolone 1,000 mg/d for up to 5 days), azathioprine (150 mg/d), and IV immunoglobulins (Igs) (53 30 g, equaling 2 g/kg body weight) were ineffective and unable to prolong the intervals. In 1999, spasms of the right body and sudden falls occurred. Again, plasmapheresis led to fast improvement. Consecutive treatment with mycophenolate mofetil, cyclophosphamide, and rituximab was not effective. Immunoadsorption using a protein A– coated column was regularly performed since then, and a Cimino fistula was installed in the patient’s left forearm for reliable vascular access. Still, lockjaw was the main symptom, remitting rapidly after immunoadsorption and recurring a few weeks later (video at Neurology.org/nn). If an interval of 4 weeks for immunoadsorption was maintained, lockjaw could be prevented. Whenever the interval was prolonged—like most recently because of a strike of train drivers in May 2015, which made it impossible for the patient to attend our department for immunoadsorption— lockjaw and falls reoccurred. Limb spasms and dystonic malposition of the right fingers 3 to 5 are present most of the time, but myoclonus, other brainstem symptoms, and hyperekplexia have not occurred so far. Assays for autoantibodies against anti-glutamate decarboxylase or anti-amphiphysin were negative, as was tumor screening. Patient serum did not bind to sections of human, rat, or mouse nervous tissue but did bind to freshly dissociated mouse hippocampal neurons. In 2014, anti-glycine receptor (GlyR) a autoantibodies were detected in the patient’s serum and purified IgG by binding assays using unfixed human embryonic kidney 293 cells transfected with GlyR a1, a2, and a3 (figure 2). Binding to a1, a2, and a3 subunits suggests that GlyR autoantibodies recognize an epitope common to all a subunits. Similar reactivity to all a subunits that, however, did not relate to the overall autoantibody titers has been described in a recent study. In fact, the use of unfixed cells has been reported to be more sensitive compared to fixed cells in the detection of GlyR a1 autoantibodies. GlyR a1 autoantibodies have been described in patients with progressive encephalomyelitis with rigidity and myoclonus (PERM), a more severe variant of stiff-person syndrome, and also in 12% of patients with stiff-person syndrome. In a larger cohort of GlyR a antibody–positive patients, the majority showed the typical clinical picture of PERM; only 2 patients had stiff-person syndrome. Trigeminal, facial, and bulbar symptoms, including trismus, were reported at the onset of disease in 47% and in 57% during the course of disease. Trismus was also predominant in an adult in this study, resulting in an inability to eat. However, all patients described so far presented with additional signs and symptoms,