Importance Progressive encephalomyelitis with rigidity and myoclonus is characterized by rigidity, painful muscle spasms, hyperekplexia, and brainstem signs. Recently, glycine receptor alpha 1 antibodies have been described in adult patients with progressive encephalomyelitis with rigidity and myoclonus. We describe a pediatric case.
Observations A 14-month-old child developed startle-induced episodes of generalized rigidity and myoclonus, axial hyperextension, and trismus, without impairment of consciousness. Episodes occurred during wakefulness and sleep, lasted seconds, and were accompanied by moaning, tachypnea, and oxygen desaturation. Imaging, cerebrospinal fluid, endocrine, metabolic, and genetic screening findings were normal or negative. She was treated with intravenous steroids and immunoglobulins with resolution of symptoms, but she relapsed weeks later. At this time, episodes were more severe. Glycine receptor alpha 1 antibodies were found in serum (titer of 1:200, later 1:320) and cerebrospinal fluid (titer of 1:2). Treatment was restarted with intravenous steroids and immunoglobulins, with major improvement, and she began treatment with oral steroids. She had 4 milder relapses, with improvement after treatment adjustments.
Conclusions and Relevance To our knowledge, this is the first pediatric case of progressive encephalomyelitis with rigidity and myoclonus associated with glycine receptor alpha 1 antibodies, a potentially severe but treatable antibody-mediated neurological disorder.
Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare neurological disorder, until recently classified as part of the stiff person syndrome (SPS) spectrum.1 However, PERM differs from SPS by the presence of brainstem, autonomic, and long-tract signs and its usually aggressive course. It is characterized by limb and truncal rigidity, painful muscle spasms, hyperekplexia, and brainstem involvement (eg, ocular motor disturbance, dysphagia, dysarthria).1 In most patients, the onset is subacute over weeks and the duration of illness ranges from weeks to years, often with exacerbations and remissions.1 Recently, glycine receptor alpha 1 (GlyR) antibodies have been described in some adult patients with PERM and related disorders,2-7 who generally had good outcomes if treated.2-7 Herein, we present the first report of a child with severe PERM positive for GlyR antibodies.
From presentation to diagnosis
A girl was born after an unremarkable gestation and delivery and had normal psychomotor development until age 14 months. Five days after a cold at the beginning of August 2010, she developed irritability, restless sleep, and sudden episodes of axial hyperextension, rigidity, and generalized myoclonus, mostly sensitive to auditory stimulus, without impairment of consciousness. These episodes occurred during wakefulness or sleep, lasted seconds, and were accompanied by moaning and tachypnea. Soon after, she developed laterocollis to the right, left hemifacial spasm, trismus, and urinary retention. She was admitted to her local hospital and an extensive investigation was conducted (Table 1). A provisional diagnosis of brainstem encephalitis or postinfectious condition was made and she was treated with intravenous (IV) acyclovir sodium, ceftriaxone sodium, clarithromycin, steroids, and immunoglobulins. Trismus that impaired feeding persisted, and later she developed an abnormal posture with both feet in plantar flexion as well as brisk deep tendon reflexes. The paroxysmal episodes and trismus slowly subsided and steroids were subsequently discontinued. By the end of August, off steroids, she had only abnormal posture of the left foot, could stand without assistance, and could walk a few steps with help.
Table 1. Initial Investigations
Table 1. Initial Investigations
Figure. Clinical features, treatments, and glycine receptor alpha 1 (GlyR) antibody titers. A, Time course over 750 days of the disease. The peaks convey the relative severity of the relapses based on the number and severity of symptoms. The clinical presentation and first relapse were the most severe, with widespread rigidity, myoclonus, spinal cord and brainstem signs, and intermittent need for oxygen by mouth mask. The other 4 relapses were milder, ranging from segmental dystonia to limited stimulus-sensitive myoclonus and erratic ocular movements. The GlyR antibody levels are expressed as the highest serum (eg, 1:320 at peak) or cerebrospinal fluid (CSF) (1:2) dilution that is positive. IV indicates intravenous; IVIg, IV immunoglobulins. B, Example of patient serum IgG, diluted 1:50 and detected with Alexa Fluor 568 antihuman IgG (red, middle panel) binding to the extracellular surface of live human embryonic kidney cells expressing GlyR subunit tagged with enhanced green fluorescent protein (EGFP) (green, left panel).2-7 A merge of these 2 images is shown on the right.
Table 2. Subsequent Investigations
Table 2. Subsequent Investigations
Evolution during the next 24 months
This child had a neurological syndrome that fits within the spectrum of PERM and is associated with GlyR antibodies. The disease started acutely, had periods of exacerbation, and showed a clear response to steroids and other immunotherapies. The features ranged from mild segmental dystonia, auditory sensitive myoclonus and rigidity, and spinal cord and brainstem signs (ocular motor disturbance, hemifacial spasm) to episodes of widespread severe hyperekplexia, rigidity, and myoclonus that affected her respiratory function. The GlyR antibodies were present in serum and cerebrospinal fluid, and findings on additional neurological investigations were unremarkable. We believe this to be the first report of PERM in a child and the first in a child with GlyR antibodies. The presence of erratic eye movements and myoclonus initially raised the possibility of opsoclonus-myoclonus syndrome,9 but the movements lacked the arrhythmic, chaotic, multidirectional saccades, without intersaccadic intervals characteristic of opsoclonus,9 in which GlyR antibodies were not found.7
In adult patients previously described,2-7 GlyR antibody–positive PERM can present acutely or subacutely, show exacerbations on a chronic course, or have a more insidious onset. In each case, the potentially very severe clinical manifestations contrast with the unremarkable investigation findings. Indeed, in this patient, negative test results were very important to exclude tumors, infections or other forms of autoimmune encephalitis (eg, N -methyl-D-aspartate receptor antibody),10 or postinfectious inflammation such as disseminated demyelination.11 Even so, antiviral and antimicrobial therapies were given to reduce the risks of treating potentially undiagnosed infectious diseases with steroids. As already noted in adult patients2-4,6,7 this child needed persistent immunotherapy to achieve a substantial improvement, and she still has some detectable serum GlyR antibodies. Therefore, close clinical and serological monitoring may be important and long-term immunosuppression may be required.
Progressive encephalomyelitis with rigidity and myoclonus represents a form of SPS with additional autonomic and brainstem features.1 To our knowledge, only 4 pediatric cases of SPS have been reported12-15 but the age at onset and clinical features were variable, including axial and limb muscle involvement, trismus,12,15 blepharospasm, and life-threatening respiratory spasms.15 The clinical course varied between progressive13 and fluctuating.12,15 When stated, the best treatment was a high dose of diazepam.13-15 One patient with trismus, blepharospasm, and respiratory spasms also had major improvement on steroids,15 and 3 patients12,14,15 had a good outcome. It is possible that these patients also had PERM with GlyR antibodies rather than typical SPS. The GlyR antibodies can be present in some patients with SPS, both with and without glutamic acid decarboxylase antibodies.7,16
The presence of antibodies that bind extracellularly to GlyR on the surface of transfected cells (Figure) suggests an autoantibody-mediated disease17 that will respond well to immunotherapies. In PERM, in contrast to typical SPS, both respiratory and autonomic dysfunction may be present and not easily recognized, although they could have catastrophic consequences if not monitored closely and treated. Those manifestations may have contributed to a vegetative state or death in a few patients whose GlyR antibody–positive PERM had not been diagnosed and treated appropriately.4,5 This case study highlights the importance of recognizing this potentially severe but treatment-responsive disorder that can occur in children as well as in adults.
Correspondence: Angela Vincent, FRCPath, Nuffield Department of Clinical Neurosciences, Level 6, West Wing, John Radcliffe Hospital, Oxford OX3 9DU, England (email@example.com).
Accepted for Publication: November 20, 2012.
Published Online: February 4, 2013. doi:10.1001/jamaneurol.2013.1872
Author Contributions:Study concept and design: Damásio, Santos, and Carrilho. Acquisition of data: Damásio, Leite, Coutinho, Waters, Woodhall, Santos, Carrilho, and Vincent. Analysis and interpretation of data: Damásio, Leite, Coutinho, Waters, Woodhall, Santos, Carrilho, and Vincent. Drafting of the manuscript: Damásio, Leite, and Waters. Critical revision of the manuscript for important intellectual content: Leite, Coutinho, Waters, Woodhall, Santos, Carrilho, and Vincent. Administrative, technical, and material support: Damásio, Waters, Woodhall, Santos, and Carrilho. Study supervision: Leite.
Conflict of Interest Disclosures: None reported.
Additional Contributions: Mark Rees, FRCPath, Rhys Thomas, MD, and Owain Howell, PhD, from the Institute of Life Science, College of Medicine, Swansea University performed the genetic tests for hyperekplexia genes.
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