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Abstract
Background Glycine receptor antibodies (GlyR-ab) were reported in a patient with progressive encephalomyelitis with rigidity and myoclonus (PERM).
Methods Three additional patients were clinically described. GlyR-ab was detected with a cell-based assay of HEK293 cells transfected with the α1 subunit of the GyR.
Results A 33-year-old woman presented with diplopia, dysphagia and gait ataxia that improved in 5 weeks. Then, she developed a typical stiff-person syndrome (SPS) that resolved with corticosteroids, but relapsed 17 months later with a stiff limb syndrome. After treatment with intravenous immunoglobulins (IVIG), she has been asymptomatic for 8 years. A 60-year-old man developed, dysphagia, diplopia, left facial palsy and right trigeminal hypoaesthesia in a few days, followed by muscular rigidity, corticospinal signs, myoclonic jerks and severe dysautonomia. He developed seizures and suffered a cardiac arrest that left him in a persistent vegetative state. A 48-year-old man presented with leg rigidity and frequent spells of trismus, muscle spasms followed by opisthotonus and diaphoresis. The symptoms were antedated by pruritus of the left scapulae, right arm and T11–T12 dermatome. At the same time he became progressively more aggressive with emotional irritability. He also developed dysgeusia (metallic taste) and severe concurrent behavioural changes and diurnal hypersomnia. Only the rigidity and the spasms improved after therapy.
Conclusions The clinical picture associated with GlyR-ab is wider than the classical view of PERM. GlyR-ab should be examined in patients with core symptoms of muscle rigidity and spasms atypical for SPS.
- Autoantibodies
- encephalomyelitis
- glycine receptor
- stiff-person syndrome
- clinical neurology
- neuroimmunology
- stiff man syndrome
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- Autoantibodies
- encephalomyelitis
- glycine receptor
- stiff-person syndrome
- clinical neurology
- neuroimmunology
- stiff man syndrome
Introduction
Progressive encephalomyelitis with rigidity was initially described as a subacute disorder characterised by muscular rigidity, stimulus-sensitive spasms, brainstem dysfunction and pathological findings of perivascular lymphocyte cuffing and neuronal loss in the brainstem and spinal cord.1 2 Generalised myoclonus, hyperekplexia, cerebellar ataxia and autonomic dysfunction were described in several reports, and the term ‘progressive encephalomyelitis with rigidity and myoclonus’ (PERM) was used to describe this syndrome.3–5
Glutamic acid decarboxylase antibodies (GAD-ab) have been reported in PERM patients with a slightly lower frequency than in stiff-person syndrome (SPS).6 Whether or not PERM is a completely different syndrome or a particular severe form of SPS is presently unknown.6 Recently, glycine receptor (GlyR) antibodies (GlyR-ab) were described in a patient with PERM and characteristic findings of hyperekplexia,7 and subsequently in a another PERM patient who had a thymoma.8 Careful clinical description of the patients with novel antibodies is important to recognise if there is a common clinical phenotype that could be caused by a specific immunological mechanism. The aim of the current report is to describe the clinical features of three new patients with GlyR-ab.
Methods
Patients were analysed for the presence of GlyR-ab because they presented rigidity and spasms of central origin plus other symptoms described in PERM. GlyR-ab were detected by binding to HEK293 cells transfected with the α1 subunit of the GlyR as previously described.7 Binding of serum (1:20) was scored visually by two observers using a scale from 0 to 4. Scores >1 have been found in 26 of 170 sera (15%) sent for GlyR-ab testing, and in 1.2% of 600 patients sent for NMDAR or AQP4 antibody testing.
Case reports
Patient 1
A 33-year-old woman, with autoimmune thyroiditis, presented in September 1999 with subacute onset of brainstem symptoms, diplopia, dysphagia and gait ataxia that improved spontaneously in 5 weeks. In January 2000, she progressively developed rigidity of lower limbs with painful spasms, involuntary jerks and contracture of both ankles and urinary retention. Brain and spinal MRI and cerebrospinal fluid (CSF) examination was normal with negative oligoclonal bands. EMG demonstrated involuntary continuous motor unit activity and abnormal exteroceptive reflexes. Onconeural antibodies (Hu, Yo, Ri, Tr, CV2, Ma2, amphiphysin) and GAD-ab were negative. A progressive complete recovery was obtained with corticosteroids, diazepam and baclofen. She relapsed with stiffness and painful spasms predominantly of the right leg in November 2001. She was treated with a course of intravenous immunoglobulin (IVIG) (0.4 g/kg/day×5 days) and restarted with symptomatic therapy. By May 2002, she returned to work, and she has been asymptomatic for 8 years. GlyR-ab were found positive, with a score of 3.5 in serum stored from 2001 (CSF was not available for analysis). A follow-up serum sample obtained in 2009 was low positive with a score of 1.
Patient 2
A 60-year-old man complained of progressive dysphagia. Five days later, he began to experience brief attacks of rigidity of his legs with painful spasms and back pain. Two days later, the spasms became more frequent; he noticed diplopia and right facial numbness that prompted his admission. The family had also noted emotional irritability, anxiety and behavioural changes in the last month. On examination, he was anxious with no evidence of cognitive deterioration. There was a mild paresis of the VI and VII left cranial nerves, right trigeminal hypoaesthesia and dysarthria. He had difficulties in swallowing, and the tongue was weak. The rigidity and spasms of the legs were spontaneous and easily elicited by sensory stimuli accompanied by diaphoresis and tachycardia. Routine haematological, biochemical and CSF analysis, CSF oligoclonal bands, whole body CT and brain MRI were normal or negative. EMG demonstrated involuntary continuous motor unit activity. Onconeural antibodies and GAD-ab were negative, but GlyR-ab were present in serum and CSF (both at score 3.5). In the ensuing days, the brainstem symptoms worsened, and he developed spastic paraparesis with bilateral Babinski signs and ankle clonus. There was also severe stimuli-sensitive multifocal myoclonus. Seven days after admission, he developed repetitive right and left motor seizures, with severe autonomic instability (profuse sweating, mydriasis, tachycardia, high blood pressure and hyperthermia) followed by a cardiac arrest. He was intubated and ventilated but did not recover, and he has remained in a persistent vegetative state and ventilator-dependent.
Patient 3
A 48-year-old man presented in September 2009 with 2 months of pruritus that involved the left scapula, right arm and right T11–T12 dermatome. At the same time, he became progressively more aggressive and developed emotional irritability, dysgeusia (metallic taste) and severe diurnal hypersommia. Over the ensuing weeks, he presented progressive rigidity in the right leg, severe trismus elicited by yawning or deglutition that prevent him to drink or eat, and frequent spells of trismus, axial rigidity with leg spasms that were followed by an opisthotonic posture and accompanied by facial flushing and diaphoresis of brief duration. These spells were easily elicited by sensory stimuli. Neurological examination revealed an alert patient with normal cognitive status. There was diffuse rigidity of the right leg with hyper-reflexia and Babinski response. A light touch caused dysesthesia in the areas with pruritus. Sensory, but not auditory, stimuli (tactile cutaneous and pharyngeal) elicited the spells described above.
Routine haematological, biochemical and CSF analysis, CSF oligoclonal bands, whole-body CT, brain and spinal MRI scans were normal or negative. An EMG performed while he was on treatment did not show continuous motor unit activity. Onconeural antibodies and GAD-ab were negative. GlyR-ab were present in the serum and CSF (score 3). Treatment with diazepam and gabapentin provided an immediate complete relief of the spasms. The patient received 10 monthly courses of IVIG and oral corticosteroids. He showed a partial improvement with resolution of his leg rigidity but persistence of the pruritus, dysgeusia, hypersomnia, masseter spasms with yawn, and behavioural changes.
Discussion
We have reported on three patients with GlyR-ab who exhibited CNS hyperexcitability associated with muscular rigidity and superimposed spasms. However, the full clinical picture was not uniform. The three patients had normal brain and spinal cord MRI and CSF examination, and the autoimmune origin of the syndrome remained unclear until GlyR-ab were determined. GlyR-ab have now been found in >20 patients with PERM or related syndromes, and in <2% of patients with other immune-mediated neurological disorders (MIL, PW, AV in preparation).
The first patient had transient brainstem symptoms before developing a typical picture of SPS in the first relapse (with the exception of the urinary disturbances) and a stiff limb syndrome in the second.9 Transient brainstem symptoms have been reported in PERM (4, patients 5 and 6) and in stiff limb syndrome.9 Stiff limb syndrome is characterised by stiffness and painful limb spasms, usually of the calf and foot. Since the initial descriptions, the syndrome has been reported with and without GAD-ab,10 11 and almost 40% of the patients develop brainstem symptoms that are usually transient and show a relapsing and remitting course.9 Unlike the present patient, we did not observe any evidence of brainstem involvement in our series of patients with stiff limb syndrome and GAD-ab.12 Further studies in GAD-ab negative patients with stiff limb syndrome will be important to see if GlyR-ab could be markers of a more widespread clinical phenotype.
The second patient developed a more typical syndrome of PERM with rapidly progressive brainstem symptoms followed by lower-limb rigidity, corticospinal signs, myoclonic jerks and severe dysautonomia. Later, he developed seizures, a relatively unusual feature in PERM in line with the pathological reports that show that the inflammatory infiltrates and neuronal loss are confined to the lower brainstem and spinal cord.1 5 GlyR are ligand-gated chloride channels that facilitate inhibitory neurotransmission in the brainstem and spinal cord, where they are mainly distributed.13 GlyR are localised in some specific nucleus in the brainstem whose dysfunction may result in the symptoms reported in PERM. GlyR-ab could downregulate GlyR in the hippocampus and favour the development of seizures as in our patient 2. Indeed, an epileptogenic drug, cyclothiazide, is an inhibitor of GlyR in the hippocampus.14
The third patient presented with a clinical syndrome resembling tetanus with trismus, muscle spasms, opisthotonos and diaphoresis. He presented with behavioural changes (described also in the second patient), sleep disturbance and sensory symptoms defined as pruritus with a dermatomal distribution. Sensory symptoms often preceding the rigidity and spasms is not rare in patients with PERM.5 However, the perception of the sensory disturbance as pruritus is unusual. Neurogenic pruritus is described in patients with focal lesions of the spinal cord, and it was the presenting symptom in a patient with paraneoplastic SPS associated with amphiphysin antibodies.15
To conclude, although our patients were initially selected for the presence of rigidity and spasms of central origin, our report emphasises that the clinical features associated with GlyR-ab are wider than the classical view of PERM, and likely not well recognised yet. Pending future study, analysis of GlyR-ab should be indicated in patients who fulfil the criteria of PERM and also in those with core symptoms of muscle rigidity and spasms, additional symptoms not seen in SPS and absent GAD-ab.
References
Footnotes
Funding Supported in part by grants PI030028 Fondo de Investigaciones Sanitarias, Madrid, Spain (FG).
Competing interests AV and the Department of Clinical Neurology in Oxford receive royalties and payments for antibody assays.
Patient consent Obtained.
Ethics approval Ethics approval was provided by the Hospital Clínic.
Provenance and peer review Not commissioned; externally peer reviewed.