Progressive Myoclonus Epilepsy With Demyelinating Peripheral Neuropathy and Preserved Intellect: A Novel Syndrome

Background  The progressive myoclonic epilepsies (PMEs) are a disparate group of syndromes whose common features include disabling myoclonus, progressive cognitive decline, and seizures, typically with a relentless deterioration over time.

Objective  To report a novel PME syndrome.

Design  Case report.

Setting  Epilepsy service in a tertiary care urban medical center.

Patient  A 24-year-old man with progressive myoclonus, seizures, and unique features of preserved intellect and demyelinating peripheral neuropathy.

Main Outcome Measure  Detailed clinical assessment, electrophysiologic studies, and survey of the literature.

Results  We characterize an unusual PME phenotype with unique features of preserved intellect and electrophysiologic evidence of a generalized demyelinating peripheral neuropathic condition. An extensive diagnostic evaluation did not reveal an underlying cause, and a literature survey did not identify other, similar clinical reports.

Conclusion  We describe a novel PME syndrome with preserved intellect and demyelinating peripheral neuropathy.

The progressive myoclonus epilepsies (PMEs) are a disparate collection of diseases characterized by inexorable clinical progression, disabling myoclonus, seizures, ataxia, and (usually) devastating cognitive decline. Other specific clinical features occur in selected conditions. Despite the applicability of the descriptor progressive myoclonus epilepsy to more than 20 specific diseases,^1,2 this condition remains undiagnosed in some patients despite an extensive evaluation. Failure to establish a cause is more common in patients who present with PME with ataxia than PME without cerebellar features. We describe a single patient with a unique clinical phenotype that fits under the rubric of PME whose condition remained undiagnosed despite an extensive workup. We propose that this is a novel PME syndrome.

A 24-year-old man of French-Canadian origin was born to unrelated parents after a normal pregnancy and delivery as the eldest of 2 children. He was vaccinated against measles. He had no clinical history of syncope, asphyxia, near-drowning, or any other possible anoxic brain injury. There was no family history of seizures, epilepsy, myoclonus, ataxia, or cognitive decline. His younger sister (22 years of age) was healthy at the time of this study. A maternal uncle had a long-standing history of cryptogenic static mental retardation, which necessitated institutional care. The mother of the patient reported that he had normal development of motor, language, and social skills in childhood and that he was completely healthy until the age of 16 years. He was an avid wrestler and musician. He was academically accomplished and graduated from college magna cum laude. To our knowledge, he had never used illicit drugs and had not had any significant exposures to neurotoxins.

At the age of 16 years, he began to experience unsteadiness while walking and abrupt falls to the ground without warning or loss of consciousness. Within weeks, he had developed action-induced involuntary jerky movements of his upper limbs. By the age of 20 years, he required the use of a wheelchair because of truncal myoclonus. He was unable to turn over in bed or bathe independently. Within 3 years of the onset, the action myoclonus prevented him from using cutlery, shaving, typing, playing guitar, and writing. In addition to volitional movements, he also indicated that noise- or touch-induced startle and driving down a tree-lined avenue aggravated the myoclonus. During the 8-year history, he experienced 5 early morning brief convulsive seizures, all in the hypnopompic state. The seizures were preceded by a crescendo buildup of myoclonus and thus were myoclonic-tonic-clonic in nature. At the age of 23 years, he noticed the insidious onset of slurred speech; his speech continues to slowly deteriorate. Apart from myoclonus, no other involuntary movements have occurred. None of his symptoms are alcohol or temperature responsive. His intellect remains unchanged, and neither neuropsychiatric nor behavioral complications have been observed. Despite the electrophysiologic findings described herein (Table), he does not report any symptoms suggestive of a sensory, motor, or autonomic neuropathic condition. He does not report numbness, tingling, loss of sensation, or weakness. He experienced temporary benefit from clonazepam (up to 4 mg/d) and levetiracetam (up to 4 g/d). He did not respond to phenytoin (up to 400 mg/d) or zonisamide (up to 200 mg/d).

Eight years after the onset of myoclonus, he is bright and articulate. His speech is dysarthric with a staccato quality. Despite his neurological difficulties, the results of his most recent general physical examination were normal. He currently has prominent multifocal myoclonus that affects his fingers (minipolymyoclonus) and face, upper and lower limbs, and trunk (a video is here). The myoclonus is aggravated by action, tactile stimuli, and startle (see the online video, clip 1). He is barely able to stand because of negative truncal myoclonus, and he is unable to walk without assistance (see the online video, clip 2). The tone and strength in his limbs are normal. His upper limb reflexes are normal. Although his lower limb reflexes are brisk, they are not accompanied by clonus, spasticity, or extensor plantar responses (see the online video, clip 3). Results of testing of his primary sensory modalities were normal. Visual fixation and eye movements are normal (see the online video, clip 3). Results of his most recent ophthalmoscopic examination were normal. The myoclonus precludes accurate testing for limb ataxia, but asymmetric (right>left) dysdiadochokinesis is probably present (see the online video, clip 4).

He was extensively evaluated during an 18-month period. The results of magnetic resonance imaging of his brain and spine were normal, as was analysis of cerebrospinal fluid, including immunoelectrophoresis. A broad infectious and paraneoplastic screen was unrevealing. Electroencephalographic readings revealed a normal background without epileptiform discharges. The myoclonus was not accompanied by obvious synchronous electroencephalographic changes. A photoparoxysmal response was evident (Figure 1). Also, somatosensory-evoked potentials revealed enlarged cortical responses (Figure 2). His F-wave responses were 34.90, 81.55, 78.10, and 43.05 milliseconds for the right ulnar nerve, right peroneal nerve, right tibial nerve, and right median nerve, respectively.

Repeated electrophysiologic studies during a period of 8 years confirm the presence of diffusely slowed conduction velocities and prolonged F-wave latencies that strongly suggest either a demyelinating or dysmyelinating generalized neuropathic condition (Table) with measured parameters that remained unchanged during 3 successive studies. Extensive investigations, which included genetic testing and skin, nerve, and muscle biopsies, were performed to specifically assess for the known PMEs, hereditary ataxias, and neuropathic conditions. Specifically, testing for Unverricht-Lundborg disease, Lafora disease, myoclonic epilepsy with ragged red fibers and other mitochondrial disorders, and action myoclonus–renal failure syndrome had unrevealing results. Other notable studies with negative results were a long chain fatty acid screen, celiac disease testing, serum arylsulfatase levels, vitamin E level, creatine kinase level, serum immunoglobin levels and electrophoresis, serum phytanic acid levels, antimyelin-associated protein antibody, and anti-GAD65 antibody testing. Lastly, a detailed search of the literature did not reveal other clinical cases with the same clinical phenotype.

We describe an adult with progressive myoclonus, rare generalized seizures, limb ataxia, dysarthria, and electrophysiologic findings which suggest a demyelinating generalized neuropathic condition. We propose that this distinct clinical phenotype is a novel PME syndrome, the principal defining feature of which is demyelinating neuropathy.

In addition to the extensive evaluation that searched for a cause among the list of known PMEs, a number of features were found that distinguish this patient from others in the literature. First, there are no affected family members, which suggests either a nongenetic basis or, if monogenic, a de novo mutation, incomplete penetrance, or an X-linked or autosomal recessive mode of transmission. Second, despite an 8-year progression, his intellect is unaffected. Third, the presence of uniformly slowed peripheral nerve conduction, unchanged over time and clinically asymptomatic, adds a unique dimension to the clinical phenotype.

Five disease entities, Unverricht–Lundborg disease, Lafora disease, neuronal ceroid lipofuscinoses, myoclonic epilepsy with ragged red fibers, and sialidoses, account for most PME cases. A number of conditions may be associated with a case of peripheral neuropathy and myoclonus, including renal failure action myoclonus, mitochondrial encephalopathic syndrome (particularly myoclonic epilepsy with ragged red fibers and mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes), celiac disease, and spinocerebellar degeneration (particularly SCA6). This patient did not have evidence of these disorders.

Progressive myoclonic ataxia (Ramsay Hunt syndrome) is characterized by ataxia and myoclonus but not neuropathic symptoms.³ Cerebellar disease may be seen with primary cortical myoclonic disorders,⁴ such as familial cortical myoclonic tremor with epilepsy,⁵ but neuropathy is not a defining feature. Lastly, the spectrum of adult phenotypes associated with POLG gene mutations is expanding to include epilepsy, headache, ataxia, nystagmus, dysarthria, neuropathy, myoclonus, and late-onset ophthalmoplegia. However, in a recent series of 38 patients with POLG1 mutations,⁶ affected adults tended to have a phenotype characterized by refractory epilepsy, prominent ataxia, progressive external ophthalmoplegia, and cognitive deterioration; our patient did not have these clinical characteristics. Lastly, our patient exhibits many of the features seen in postanoxic Lance-Adams syndrome, but he has no history of anoxic brain injury.

Other diagnostic possibilities are that the patient has either an unusual phenotypic variation of a known disease or, alternatively, the coexistence of 2 diseases (peripheral neuropathy and progressive myoclonus). The diffuse uniform slowing of peripheral nerve conduction is more in keeping with a dysmyelinating process, which is likely developmental or hereditary in origin. We believe that this particular feature of the neuropathic condition makes it more likely to be causally related to the same process that underlies the progressive central features, including myoclonus and dysarthria. We know of no other clinical disease that produces this particular constellation of clinical features.

We believe that this patient shows clinical features of a novel PME syndrome. The presence of preserved intellect and a generalized demyelinating neuropathic condition in the setting of disabling myoclonus, rare seizures, and mild cerebellar signs should prompt physicians to consider this entity. Other clinical cases are needed for further study of this novel clinical syndrome.

Correspondence: Daniel Costello, MD, MRCPI, Epilepsy Service, Department of Neurology, ACC 835, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114 (djcostello@partners.org).

Accepted for Publication: October 6, 2008.

Author Contributions:Study concept and design: Costello and Siao. Acquisition of data: Costello and Siao. Analysis and interpretation of data: Costello, Chiappa, and Siao. Drafting of the manuscript: Costello. Critical revision of the manuscript for important intellectual content: Costello, Chiappa, and Siao. Statistical analysis: Chiappa. Administrative, technical, and material support: Chiappa and Siao. Study supervision: Costello.

Financial Disclosure: None reported.

Additional Contributions: We thank the patient for allowing the submission of a video recording.