Article Text
PDF
Abstract
Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a subtype of stiff-person syndrome (formerly stiff-man syndrome). It is rare and disabling, and characterised by brainstem symptoms, muscle stiffness, breathing issues and autonomic dysfunction. We describe a 65-year-old man who presented with odynophagia together with tongue and neck swelling, followed by multiple cranial nerve palsies culminating in bilateral vocal cord paralysis with acute stridor. He subsequently developed progressive generalised hypertonia and painful limb spasms. Serum antiglycine receptor antibody was strongly positive, but antiglutamic acid decarboxylase and other antibodies relating to stiff-person syndrome were negative. We diagnosed PERM and gave intravenous corticosteroids and immunoglobulins without benefit; however, following plasma exchange he has made a sustained improvement.
- clinical neurology
- stiff man syndrome
- intensive care
- spasticity
- ENT
Statistics from Altmetric.com
Introduction
Stiff-person syndrome (previously known as stiff-man syndrome) is a rare autoimmune neurological disorder characterised by axial and limb muscle stiffness with cocontraction of antagonistic muscle groups and painful muscle spasms.1–3 Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a variant of stiff-person syndrome, distinguishable by additional involvement of brainstem structures and the autonomic nervous system, as well as a different autoantibody profile.4–6 We report a gentleman with antiglycine receptor (GlyR) antibody positive PERM, presenting with sequential cranial nerve dysfunction and stridor, responding to plasma exchange.
Case report
A 65-year-old man presented to the emergency department with odynophagia and swelling over the left side of his neck, 2 weeks after recovering from an upper respiratory tract infection. Ear, nose and throat (ENT) assessment identified a swollen and bruised tongue with limited protrusion, a mildly swollen uvula and normal vocal cord movements. Blood investigations were unremarkable, including serum vitamin B12, folic acid, iron profile, ACE, antinuclear antibodies and antineutrophil cytoplasmic antibody. He was diagnosed with glossitis and started on intravenous metronidazole, cefuroxime and dexamethasone.
The swelling persisted and 2 days later he developed right hypoglossal nerve palsy. CT scan of the neck with contrast and MR scan of the brain were normal. Histology from three biopsied tongue ulcers showed non-specific changes with no infection, dysplasia or malignancy. CT scan of thorax, abdomen and pelvis identified two small liver cysts with benign features. The tongue swelling subsided, and his swallowing improved steadily. His oral intake improved and he was discharged from ENT.
Two weeks later, he developed horizontal diplopia on right lateral gaze and left-sided facial weakness. Examination identified one-and-a-half syndrome (right conjugate horizontal gaze palsy and right internuclear ophthalmoplegia), left lower motor neuron seventh nerve palsy and new onset atrial fibrillation, for which he was started on warfarin. He again developed swallowing difficulties, confirmed by speech therapists and ataxia with veering to the right on walking. He developed dysphagia, nausea and recurrent vomiting. Nerve conduction studies showed a moderate length-dependent, sensorimotor polyneuropathy which was presumed to be incidental to his presentation. We did not arrange electromyography at the time owing to anticoagulation. MR scan of brain with contrast showed no posterior fossa ischaemic changes, leptomeningeal or parenchymal enhancement. Cerebrospinal fluid analysis was unremarkable. Serum onconeural antibodies including Hu, Yo and Ri were negative.
One month later, he presented a third time with sudden breathlessness. ENT examination with direct laryngoscopy identified bilateral vocal cord paralysis causing significant stridor. CT pulmonary angiogram excluded emboli but identified pulmonary oedema. He was admitted to critical care, mechanically ventilated, and underwent tracheostomy. A percutaneous endoscopic gastrostomy tube was inserted to manage his worsening dysphagia. With the rapid evolution of symptoms and signs, we considered an autoimmune disorder. We gave an empirical 3-day course of intravenous methylprednisolone (1 g per day) followed by high-dose oral prednisolone, and a 5-day course of intravenous immunoglobulins, but with no tangible improvement.
He subsequently developed progressive hypertonia in all four limbs and trunk associated with painful limb spasms and minimal joint flexion, preventing him from sitting up. The hypertonia of his abdominal rectus and external oblique muscles was severe, resembling the guarding seen in an ‘acute abdomen’. There was no elicitable hyperekplexia to sudden noise or movement. Serum antibody titres were negative for antibodies against glutamic acid decarboxylase, amphiphysin, glutamate, leucine-rich glioma inactivated 1, contactin-associated protein 2 and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 1 and 2 but anti-GlyR antibody titre was strongly positive, consistent with PERM.
We initially gave escalating doses of baclofen (10 mg three times daily, increased gradually to 30 mg three time daily) and benzodiazepines (clonazepam 1 mg two times daily). This led to gradual resolution of muscle spasms and improvement in tone, such that within 3 weeks he could sit up and walk 10 metres with bilateral support, after having been immobile for 5 months. However, a month later, he again developed increased rigidity and myoclonic movements despite muscle relaxants. His eye movements normalised except for persistent nystagmus on left lateral gaze, possibly as a delayed response to immunotherapy. With the relapse occurring within a month despite previously delivered immunosuppressive therapies, he underwent five sessions of plasma exchange. Four weeks later he was walking 20 m with a frame several times a day and was discharged home. Over subsequent months, his condition remained stable despite gradually weaning his oral corticosteroids. Swallowing improved steadily and his gastrostomy tube was removed. More recently his tracheostomy tube has also been removed and he can now walk without assistance. In the subsequent 18 months, he has not required further immunotherapy or experienced any further relapses.
Discussion
Stiff-person syndrome has several variants, including classic stiff-person syndrome, partial stiff-person syndrome (stiff-limb syndrome), paraneoplastic stiff-person syndrome and PERM. PERM is the least common, with an estimated incidence of 1 per million per year. It comprises approximately 0.1% of stiff-person syndrome cases, with fewer than 100 published cases, but is probably underdiagnosed and under-reported.3 Whiteley et al first described PERM as a variant of stiff-person syndrome characterised by a subacute progressive course with hyperekplexia (excessive startle), painful spasms, breathing problems, autonomic and brainstem dysfunction. They also noted postmortem changes of neuronal loss in the brainstem and spinal cord and perivascular lymphocyte cuffing, with cortical sparing.4 PERM has been generally associated with a poorer prognosis than other forms of stiff-person syndrome, although advances in therapies have improved outcomes.5 7 8
PERM is associated with the presence of high serum titres of antibodies against the GlyR.3 6 Hutchinson et al first described these in a phenotypical PERM patient; they suspected the antibodies were directly pathogenic to the GlyR, concentrated in the pontine region and spinal cord. The disruption of the normal inhibitory glycinergic mechanism of the nucleus reticularis pontis caudalis results in hyperekplexia; a classic feature of PERM.6 9
Anti-GlyR antibody associated PERM was not initially thought to be paraneoplastic; however, Carvajal-González et al found that 9 out of 52 antibody-positive cases had a diagnosis malignancy at some point in their lives.7 The literature suggests a paraneoplastic incidence rate of 20%, including thymoma, Hodgkin’s lymphoma and cancers of lung, kidney and breast.8 Although anti-GlyR antibodies are a marker for PERM, they are not highly specific. McKeon et al found only 10 of 81 stiff-person syndrome patients (12.3%) had positive anti-GlyR antibodies; however, only one was diagnosed with PERM (other nine cases included five classic stiff-person syndrome patients and four with other variants).10 Furthermore, anti-GlyR antibodies may occur in people with multiple sclerosis, cerebellar ataxia and optic neuritis.11
Patients with PERM often present with difficulty breathing, however, only two other reported cases have had stridor during the investigative stages. Kikuchi et al described a 19-year-old initially diagnosed with refractory asthma who eventually developed stridor and board-like rigidity and was diagnosed with PERM based on continuous motor unit discharges identified on electromyogram.12 De Blauwe et al described a 66-year-old woman who developed stridor requiring intensive care. Serum anti-GlyR antibodies were identified and her condition was considered paraneoplastic secondary to breast cancer; she responded to plasma exchange.13
There are no established management guidelines for PERM due to the small number of cases. Muscle stiffness and spasms are frequently managed using high doses of baclofen and benzodiazepines, supported by observational data.2 3 Consequently, high doses of baclofen and benzodiazepines may mask typical electromyographic findings suggesting PERM, resulting in diagnostic ambiguity. Intravenous immunoglobulins, plasma exchange and B-cell depletion using rituximab have all been used to suppress the presumed causative antibody-mediated process. The efficacy of intravenous immunoglobulins in stiff-person syndrome patients was supported by the results of a randomised, blinded, cross-over study; however, 30% of patients did not respond to intravenous immunoglobulins and required other immunomodulatory treatment.14 In 2014, a systematic review by Pagano et al found that almost half (42%) of stiff-person syndrome patients improved following plasma exchange.15 Furthermore, Stern et al reviewed the management of 10 anti-GlyR positive PERM cases and found that treatment in all cases overlapped the above approach taken in stiff-person syndrome, with similarly encouraging results.16
Key points
Progressive encephalomyelitis with rigidity and myoclonus (PERM) is the least common phenotype of stiff-person syndrome.
PERM can present with sequential cranial nerve palsies, including stridor.
Antiglycine receptor antibody is an important diagnostic tool for diagnosing PERM, though it is not specific.
Plasma exchange is a reasonable treatment option for patients with PERM.
Further reading
McKeon A, Robinson MT, McEvoy KM, et al. Stiff-man syndrome and variants: clinical course, treatments, and outcomes. Arch Neurol 2012;69:230–8. doi:10.1001/archneurol.2011.991
Carvajal-González A, Leite MI, Waters P, et al. Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes. Brain 2014;137:2178–92. doi:10.1093/brain/awu142
Ethics statements
Patient consent for publication
References
Footnotes
Contributors The case was identified by AP. All authors were involved in the management of the patient. All authors contributed towards reporting the case.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned. Externally peer reviewed by Emma Tallantyre, Cardiff, UK.