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A 39-year-old woman presented to the emergency department with a 3-week history of worsening spasms in her axial and lower limb muscles and new-onset urinary retention. Sudden episodes of painful involuntary spasms first appeared in her abdominal muscles 2 weeks after a cold. Soon after, spasms spread to all of her axial muscles and both lower limbs. These paroxysmal episodes lasted a few seconds, occurred up to 20 times a day, and were exacerbated by external stimuli. There was no impairment of consciousness during the attacks. A review of her previous records revealed a diagnosis of Hashimoto thyroiditis 1 month earlier. She had no history of tobacco, alcohol, or drug use.
She had hyperhidrosis and tachypnea on admission. Neurological examination results disclosed an abnormal mental status. Cranial nerve examination results demonstrated slow saccades. Motor system examination results revealed a symmetric and severe hypertonia and rigidity throughout her trunk and all 4 extremities. Further notable occurrences were severe spasms (Figure, A; Video 1) and patella clonus associated with brisk deep tendon reflexes (Video 2). She demonstrated marked myoclonus on tactile and acoustic stimulation. Extensor plantar responses were present bilaterally.
A, Patient experiencing spasms. B, Electromyography examination of the patient.
Severe spasms and rigidity of axial muscles and lower limbs lasting seconds and occurring more than 20 times day.
Patellar clonus in response to deep tendon reflex testing.
Laboratory results were significant for an elevated level of thyroperoxidase antibodies (50.85 IU/mL; normal, <5.16 IU/mL) and thyroglobulin antibodies (88.35 ng/mL; normal: <4.11 ng/mL; to convert to micrograms per liter, multiply by 1). Cerebrospinal fluid testing results revealed normal protein level and cell counts, as well as absent oligoclonal bands or evidence of infection. Her paraneoplastic panel results were negative. Cranial and spinal magnetic resonance imaging yielded no abnormalities. Needle electromyography (EMG) results showed a continuous firing of normal motor unit potentials at rest within the axial and lower limb muscles (Figure, B; Video 3). A routine electroencephalogram (EEG) showed mild background slowing without periodic discharges. Computed tomography scan results of the thorax, abdomen, and pelvis were negative. An electrocardiogram showed sinus tachycardia.
Electromyography results show continuous firing of normal motor unit potentials at rest in the rectus abdominis.
Progressive myoclonic epilepsies (PMEs)
Faciobrachial dystonic seizures
Creutzfeldt-Jakob disease (CJD)
Progressive encephalomyelitis with rigidity and myoclonus (PERM)
D. Progressive encephalomyelitis with rigidity and myoclonus (PERM)
The patient’s severe clinical features included rigidity and painful spasms as well as persistent myoclonus that was associated with typical EMG features. These findings are highly suggestive of PERM. The diagnosis was further supported by positive serum testing results for anti–glutamic acid decarboxylase (GAD65) antibodies (>29.43 mg/dL; normal: <0.15 mg/dL; to convert to micromoles per liter, multiply by 67.967). Testing results for anti–glycine receptor (GlyR) and antiamphiphysin antibodies were negative.
First described by Whiteley et al,1 PERM represents a more severe clinical spectrum of stiff person spectrum disorder.2 In this patient, PERM can be distinguished from classic stiff person syndrome by prominent brainstem features, including myoclonus, oculomotor disorder, and a disturbance of respiratory rhythm. Her diffuse neurological symptoms, including encephalopathy (altered mental status), autonomic dysfunction (tachycardia and hyperhidrosis), and spinal cord involvement (urinary retention), also fit within the spectrum of PERM.
Worsening myoclonus and encephalopathy could be indicative of progressive myoclonic epilepsies (PMEs), which are a group of genetic disorders with an overall poor prognosis. They typically present in late childhood or adolescence and rarely affect adults. Moreover, rapidly progressive presentations over weeks and a lack of epileptiform discharges on EEG made PMEs unlikely in this patient. Faciobrachial dystonic seizures are characterized by repetitive abnormal stereotypic movements that typically affect the ipsilateral face and arm and are associated with leucine-rich glioma-inactivated 1 antibodies. Creutzfeldt-Jakob disease would be consistent with rapidly progressive dementia and myoclonus. Positive assays for neuronal autoantibodies have occasionally been described in CJD but at very low titers of uncertain significance.3 In this patient, the lack of typical MRI abnormalities and absence of periodic sharp wave complexes on EEGs decreased the likelihood of CJD. Real-time quaking-induced conversion test (with 100% specificity for CJD) could be used in cases of diagnostic confusion.
Immune-mediated pathomechanisms that target proteins mainly expressed by inhibitory synapses have been associated with stiff person spectrum disorder.4 Autoantibodies that have been identified include GAD65, GlyR, amphiphysin, dipeptidyl peptidase-like protein 6, gephyrin, γ-aminobutyric acid-A receptor (GABAAR), and GABA receptor associated protein (GABARAP).5 In PERM patients, GlyR antibodies were the most frequent antibodies identified in approximately half of cases, followed by GAD antibodies and rare amphiphysin or dipeptidyl peptidase-like protein 6 antibodies.2 Notably, there remains a subgroup of seronegative cases. Thus, although positive autoantibody serology results serve as a strong indicator of PERM, it is not a requirement for the diagnosis, which relies on the clinical manifestations plus EMG features.5 The etiology of PERM can be either paraneoplastic or autoimmune mediated.6 Documented malignancy is often associated with amphiphysin antibodies and less frequently with GAD antibodies.7 In this patient, further neoplasia screening results, including positron emission tomography scan and mammogram, were unremarkable. Autoimmune disorders frequently coexist in patients with positive results for GAD antibodies, primarily type 1 diabetes and thyroid disease.8 This patient received a diagnosis of Hashimoto thyroiditis before her first symptoms occurred. Thus, the presence of a concomitant autoimmune condition and GAD antibodies suggests an autoimmune pathomechanism.
Management of PERM is focused on immunotherapy, symptomatic treatment, and tumor screening and treatment.9 Prognosis is highly variable among patients; patients with GAD65 antibodies generally had a worse prognosis than patients with GlyR antibodies.5 Continuous monitoring and maintenance therapy are important as PERM typically has high likelihood of relapse and residual disability.
Progressive encephalomyelitis with rigidity and myoclonus may comprise different diseases associated with various immunological features. While laboratory studies support the pathogenicity of GlyR autoantibodies that target cell surface antigens,9 the pathogenicity of GAD antibodies is controversial given that they direct against intracellular synaptic proteins. It is possible that GAD antibodies may mediate a similar transiently exposed antigen effect like amphiphysin antibodies and impair GABAergic inhibition.10
The patient was treated with intravenous immunoglobulin (0.4 g/kg/d) for 5 days, intravenous methylprednisolone (500 mg/d) for 5 days with an oral prednisone taper, and intravenous diazepam (60 mg/d) for 5 days followed by a taper within 3 weeks. Oral clonazepam (6 mg/d) was used as maintenance therapy. On 6-month follow up, she demonstrated marked improvement with undetectable serum GAD antibodies. There was no evidence of malignancy over the 1-year follow-up.
Corresponding Author: Sheng Chen, MD, PhD, Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (email@example.com).
Published Online: March 9, 2020. doi:10.1001/jamaneurol.2020.0175
Conflict of Interest Disclosures: None reported.
Additional Contributions: We thank the patient for granting permission to publish this information. We also thank Robert L. Macdnoald, MD, PhD, Vanderbilt University, for comments on the manuscript. He was not compensated for his contributions.
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Shen D, Zhou H, Chen S. Spasms and Myoclonus in a Young Woman With Hashimoto Thyroiditis. JAMA Neurol. Published online March 09, 2020. doi:10.1001/jamaneurol.2020.0175
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