A case of glycine-receptor antibody-associated encephalomyelitis with rigidity and myoclonus (PERM): clinical course, treatment and CSF findings

Abstract

Over several months a 58-year-old man developed muscle stiffness, myoclonus and experienced several sudden falls caused by sensory and acoustic stimuli. On neurological examination, a severe startle reaction could be triggered by unexpected noises and there was stiffness, especially of the back and lower limb muscles, with myoclonus, lower limb paraparesis, muscle rigidity and increased tendon reflexes without further pyramidal signs. He was not able to walk without help. He also exhibited a mild pontine syndrome with disturbed smooth pursuit eye movements and diplopia. Electrophysiological studies revealed ubiquitous early recruitment and continuous motor unit activity as described for stiff person syndrome by Meinck and Thompson [1]. Cerebral MRI scans were normal. Antibodies against glutamic acid decarboxylase (GAD), amphiphysin, CYFRA 21-1, CEA, Ri, Hu, Yo, MA1, MA2, CV2 and CRMP5 could not be detected in serum. Neuron-specific enolase (NSE) enzyme concentrations were not raised. An extensive cancer search including 18-F-FDG-PET, abdominal ultrasound, X-ray of the chest and bronchoscopy was negative. However, serum glycine receptor (GlyR) antibodies were detected by a cell-based assay (Fig. 1) [2]. Initial lumbar puncture revealed oligoclonal IgG bands and 45 lymphocytes/ll (normal: \4 cells/ll) in the cerebrospinal fluid (CSF). GlyR antibodies could also be found in the patient’s CSF. Gamma-aminobutyric acid (GABA) and glutamate levels in CSF were measured by HPLC, with electrochemical detection after precolumn o-phthaldialdehyde sulphite derivatization, in the patient’s CSF and control samples from 10 subjects (4 males, 6 females); age range 35–83 years (mean 54 years) undergoing diagnostic lumbar puncture as part of their investigations. Their CSF analyses were normal and neurological disorders were excluded. All lumbar punctures were done between 11.00 am and 2.00 pm. Their GABA levels were 42.7 ± 14.2 nmol/l. As shown in Fig. 2, before any treatment the patient’s GABA level was higher (89.0 nmol/l) than upper limit of the control range (mean ? 3SDs, 85.3 nmol/l). Glutamate levels were also lower (initial: 0.33 lmol/l; after 18 months: 0.35 lmol/l) than controls (0.49 ± 0.2 lmol/l) although not significantly different. The neurological symptoms ameliorated after an initial therapy of six plasmaphereses followed by oral corticosteroids (1 mg/kg body weight). The GABAA receptor agonist clonazepam led to a further improvement of muscle stiffness and rigidity. Only a mild pontine symptom with diplopia persisted. CSF GABA levels fell over the treatment period to 28.5 nmol/l (18 months after initial lumbar puncture). GlyR antibody titers also declined but were still just detectable in the serum at 12 months (Fig. 1). Once the improvement had stabilised for 18 months, we tried to wean the steroids. After 2 weeks without steroids the patient developed again neurological symptoms with a left internuclear ophthalmoplegia, and without signs on the MRI. Steroids were therefore increased to 0.5 mg/kg and a steroidsparing drug, azathioprine (2 mg/kg), was introduced. Under this regime the patient is now without symptoms. Up to now, medical examinations are being done every 6 months. A. Piotrowicz (&) A. Thumen A. Moser Neurochemical Research Group, Department of Neurology, University of Lubeck, Ratzeburger Allee 160, 23538 Lubeck, Germany e-mail: agnieszka.piotrowicz@neuro.uni-luebeck.de