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Abstract
A 40-year-old man presented with respiratory compromise and was intubated. After tracheostomy, he was found to have ophthalmoplegia, severe limb rigidity, stimulus-sensitive myoclonus and autonomic dysfunction. For 1 week before admission, there had been a prodromal illness with low mood, hallucinations and limb myoclonus. Serum glycine receptor antibodies were strongly positive: we diagnosed progressive encephalomyelitis with rigidity and myoclonus. Despite a relapse, he has done well following immunotherapies. The clinical syndrome of encephalomyelitis with rigidity, described in 1976, often has a severe progressive course. A minority of patients have glutamic acid decarboxylase antibodies. The association with glycine receptor antibody was first reported in 2008, and we briefly review subsequent case reports to illustrate the range of clinical features. The antibody is likely to be disease mediating, although this remains unproven.
The spectrum of diagnosable and treatable antibody mediated neurological syndromes is expanding. It is vital to recognise these conditions early to reduce morbidity and mortality.
- MYOCLONUS
- EYE MOVEMENTS
- CLINICAL NEUROLOGY
- NEUROIMMUNOLOGY
- MOVEMENT DISORDERS
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Introduction
Neurological disorders with antibodies against neuronal surface antigens are now well recognised, and the spectrum of these disorders has expanded over the past decade.1 While the more common variants, such as limbic encephalitis with voltage-gated potassium channel complex (VGKC-complex) antibodies and N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis are recognised regularly, rarer conditions such as progressive encephalomyelitis with rigidity and myoclonus (PERM), are less well known, although they may show typical clinical features. We present an illustrative case report and discuss the literature.
Case report
A previously well 40-year-old man, unemployed but previously working in removals, presented to the emergency department with difficulty breathing and swallowing, and with involuntary jerking. He had a 5-day history of presumed upper respiratory tract infection. After being sent home, he re-presented later that day in respiratory distress, requiring intubation. The family reported a 1-week prodrome of mood change, hallucinations and involuntary tic-like jerks. He had a history of excess alcohol consumption and cannabis use. Examination findings included large anogenital papillomatous lesions.
Over the following 2 weeks, he failed multiple attempts to wean him from ventilation and he underwent tracheostomy. Off sedation, he was awake, appropriate and cooperative, with no obvious cognitive impairment, but with profound ophthalmoplegia. He had severe rigidity in his limbs, especially the legs, such that it was impossible to move his knee or ankle joints passively. He had frequent large amplitude myoclonic jerks, both spontaneous and stimulus-sensitive, triggered by noises in the intensive care unit or attempts to move him by the nursing staff. He had profuse sweating and episodes of tachycardia.
The following blood investigations were negative or normal: vasculitis screen (anti-nuclear antibody, anti-neutrophil cytoplasmic antibody, anti-double-stranded DNA antibody, extractable nuclear antigen, rheumatoid factor, complement C3 and C4, erythrocyte sedimentation rate), serum angiotensin-converting enzyme, thyroid function tests, tumour markers, infective screen (serology for HIV, syphilis, legionella, crypotococcus, botulism, mycoplasma, borrelia) and autoantibodies (including onconeuronal, VGKC complex, NMDA receptor, thyroid peroxidase, basal ganglia, GQ1b, and glutamic acid decarboxylase (GAD)).
CT and magnetic resonance (MR) brain imaging were normal. CT imaging of the chest, abdomen and pelvis, and ultrasound of the testes showed no malignancy. The anogenital papillomatous lesions were found on excision to be benign condylomata. Cerebrospinal fluid (CSF) opening pressure was 20 cmH2O (8–20), with 11 white cells/µl (≤5) (100% monocytes) and 1 red cell/µl; normal protein and glucose; negative oligoclonal bands; negative microscopy and culture for tuberculosis, fungi and virology.
Two months after the illness onset, we treated him empirically for a presumed antibody-mediated brainstem process with intravenous immunoglobulins (IVIg). Glycine receptor antibodies were then found to be positive in stored serum (1:600) and subsequently in CSF (1:40). Further immunomodulatory treatments included oral corticosteroids and plasma exchange. We also treated him symptomatically for rigidity with an intrathecal baclofen pump and oral clonazepam. Figure 1 shows his antibody titres in blood and CSF during his illness. Videos are available from the authors on request from various points in his clinical course.
(A) Graph of serum and CSF antibody titres over time, treatments indicated. IVIG=Intravenous Immunoglobulins, PE=Plasma Exchange. (B) HEK cells expressing the alpha-1 subunit of the glycine receptor covalently tagged with eGFP are shown in the left hand panels. Serum (diluted 1:20) is incubated with these cells and detected with a red fluorescent secondary antibody (goat anti-human IgG Alexa-fluor 568). The upper centre panel shows IgG from this patient's serum binding to the eGFP-GlyRα1 expressing HEK cells while IgG from a healthy volunteer does not bind (lower centre panel). The right hand panels show a merge of the two previous panels.
He gradually responded to treatment, and at 6 months, he was weaned off ventilation and the tracheostomy was removed. His rigidity, spasms and ophthalmoplegia had improved. However, at 7 months from disease onset, he relapsed over a few days, with recurrence of rigidity, worsening ophthalmoplegia and myoclonic jerks, requiring re-intubation. On this occasion, there was no neuropsychiatric prodrome. We gave further plasma exchange, increased the corticosteroid dose, and increased the symptomatic treatments (intrathecal baclofen and clonazepam). He responded, was extubated and is undergoing neurorehabilitation. He was discharged from hospital 11 months from disease onset, and remains on prednisolone 20 mg, clonazepam and intrathecal baclofen.
Discussion
Progressive encephalomyelitis with rigidity (PERM) was initially described in 19762 as a subacute disorder characterised by muscular rigidity, stimulus-sensitive spasms, brainstem dysfunction and the pathological finding of perivascular lymphocyte cuffing and neuronal loss in the brainstem and spinal cord with relative sparing of the cortex. In the 1990s, several reports described stiffness associated with generalised myoclonus, hyperekplexia, cerebellar ataxia and autonomic dysfunction. Some authors regarded this as a more aggressive variant of stiff-person syndrome, and used the term stiff-person plus, noting that this variant responded less well to therapy and less commonly showed anti-GAD antibodies.3 ,4 PERM is now the preferred term.4
In 2008, GlyR antibodies were shown to be present in a typical PERM patient,5 and since then several further cases have been reported,6–11 (table 1) only one of whom had anti-GAD antibodies. The clinical features were fairly consistent, with core features of rigidity and painful muscle spasms. Most showed spontaneous or stimulus-sensitive myoclonus, diplopia and autonomic features such as sweating, tachycardia and urinary retention. Some had breathing and swallowing difficulties and psychiatric features. Eight of the 10 reported cases, including this case, are male.
Ten reported cases of PERM with positive glycine receptor antibodies; demographics, clinical features, investigation results, management and outcome
There were two cases with thymomas, both of whom responded well to thymectomy.6 ,12 This, together with the GAD antibodies in one PERM patient,11 supports an immune-mediated aetiology. A retrospective analysis recently found GlyR antibodies in patients with stiff-person syndrome but no features of PERM; some of these also had GAD antibodies.13
All reported patients, including this case, were extensively investigated. All had normal MR brain scans. CSF was normal or mildly inflammatory (table 1). Various inflammatory, infective and paraneoplastic causes were excluded. However, the practical neurologist will recognise that this fairly unique clinical picture, with normal imaging and a non-infective CSF, does not have a wide differential diagnosis.
Criteria for possible neuronal surface antibody-associated syndromes in the absence of antibodies to a known cell surface antigen. Note that although paraneoplastic syndromes are often associated with intracellular antigens (eg, Hu, Yo, Ma2, etc), and often do not respond to immunotherapies, finding a tumour does not exclude an immunotherapy-responsive condition.
Adapted from Zuliani et al15
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Acute or subacute (<12 weeks) onset of symptoms
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Evidence of central nervous system inflammation
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CSF inflammatory changes (pleocytosis, unmatched oligoclonal bands)
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Imaging changes suggestive of inflammation (MRI, PET)
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Inflammatory changes on biopsy
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Exclusion of other causes
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Infective
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Trauma
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Toxic
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Metabolic
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Neoplastic
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Paraneoplastic
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Demyelinating
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The prognosis is variable. Many cases showed substantial and sustained improvement with immunotherapies, usually with combinations of corticosteroids, IVIg, plasma exchange and cyclophosphamide. Ours is the second case where relapse necessitated further immunotherapy. Two cases had poor outcomes, one of death and the other of a persistent vegetative state (table 1).
Many patients have breathing difficulties during the illness, but this patient was unusual in presenting with respiratory failure. His symptoms progressed so rapidly that he required intensive care support on the day of admission, only 1 week after symptom onset.
In other, more common neurological disorders mediated by antibodies against cell-surface antigens, such as the limbic encephalitides and NMDAR-antibody encephalitis, swift immunomodulatory therapy appears to impact on prognosis, although with few clinical trials, this remains unproven. Many clinicians therefore advocate treating with immunomodulation on clinical suspicion, without awaiting antibody results that could delay treatment14; criteria for making this decision are summarised in box 1. In rare conditions such as PERM, it is vital to recognise the clinical features early to allow aggressive early treatment, which may influence hospitalisation and prognosis. As more cases are reported, the core clinical features of this condition are increasingly clear.
References
Footnotes
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Contributors This paper was written by WS, MMW and AV. The antibody testing and data was supplied by AV, PW and MRW. Figure 1 was created by PW. WS, MMW, RH and RMC were involved in the clinical care of the patient.
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Competing interests AV and the University of Oxford hold patents and receive royalties and payments for antibody assays. AV has received honoraria for speaking at various conferences. PW is a named inventor and will receive royalties for antibody assays, and has received a speaker honorarium from Biogen-idec Japan. There are no other competing interests to declare.
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Patient consent Obtained.
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Provenance and peer review Commissioned. Externally peer reviewed. This paper was reviewed by David Burn, Newcastle-upon-Tyne, UK.
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