Peripheral Nerve Hyperexcitability Disorders Research Articles

N°128 – Needle EMG – An essential tool in the diagnosis of peripheral nerve hyperexcitability disorders

N°128 – Needle EMG – An essential tool in the diagnosis of peripheral nerve hyperexcitability disorders

Seronegative Isaac Syndrome Presenting as Focal Limb Stiffness Responsive to Plasma Exchange Therapy (P8-8.015)

<h3>Objective:</h3> N/A <h3>Background:</h3> Isaac syndrome is an autoimmune disorder of peripheral nerve hyperexcitability characterized by neuromyotonia, myokymia, muscles stiffness, pseudomyotonia, and pseudotetany frequently accompanied by dysautonomia and neuropathic pain. Approximately 50% of cases are associated with antibodies against contactin-associated protein-like 2 (CASPR2) or less commonly leucine-rich glioma inactivated protein 1 (LGI1), both components of the voltage-gated potassium channel (VGKC) complex. Paraneoplastic, genetic, and toxic etiologies must be considered. Management includes membrane-stabilizing drugs as well as immunotherapy in more severe cases. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> A 50-year-old woman presented with one year of left neck, shoulder, and upper extremity pain and stiffness that began one month after an upper respiratory illness. Her exam was notable for anterocollis, left shoulder elevation, impaired left shoulder abduction beyond 35–40 degrees, tonically contracted left biceps, and marked tenderness to palpation of the affected muscles. Symptomatic management with diazepam, lorazepam, baclofen, mexiletine, and trihexyphenidyl was ineffective. EMG demonstrated widespread neuromyotonic discharges throughout the proximal greater than distal left upper extremity, cervical and thoracic paraspinals, and right deltoid. Laboratory studies including CASPR2, LGI1, VGKC, GAD-65, and amphiphysin antibodies were unremarkable. Comprehensive screening for occult malignancy was unrevealing. She received partial benefit from carbamazepine, levetiracetam, cyclobenzaprine, and onabotulinumtoxinA injections, but symptoms remained debilitating. She was treated with IVIg 1g/kg Q2 weeks for three months with symptom progression to the jaw and lower extremities. She was started on plasmapheresis QOD for ten days every four weeks with rapid improvement in symptoms. <h3>Conclusions:</h3> We report a case of seronegative Isaac syndrome initially presenting with focal limb stiffness and dystonic posturing that was exquisitely responsive to plasmapheresis. This case highlights the need to consider peripheral nerve hyperexcitability syndromes in patients presenting with focal limb stiffness or painful dystonia and provides additional support for plasmapheresis as an effective treatment option for patients with debilitating symptoms. <b>Disclosure:</b> Dr. Khalil has received personal compensation in the range of $0-$499 for serving as a Resident and Fellow Council Member with American Association of Neuromuscular &amp; Electrodiagnostic Medicine. Dr. Khalil has received personal compensation in the range of $0-$499 for serving as a MS Mentorship Forum Participant with Foundation of the Consortium of Multiple Sclerosis Centers. Dr. Bradshaw has nothing to disclose.

Minipolymyoclonus: A Critical Appraisal.

Minipolymyoclonus is an intriguing clinical phenomenology that is seen in central neurodegenerative and epileptic disorders as well as in AHC disease (primary or secondary) and peripheral nerve hyperexcitability disorders. Our review highlights the knowledge gaps and controversies regarding this interesting phenomenon and highlights the unmet need for more extensive clinical, electrophysiological and radiological correlation studies on the topic. Some unsolved issues regarding the pathophysiology remain open to further debate. It is necessary to consider the clinical setting in which it occurs, the presence of other clinical signs, and the results of electrophysiological studies to navigate through this gray zone of overlap.

International veterinary canine dyskinesia task force ECVN consensus statement: Terminology and classification

Movement disorders are a heterogeneous group of clinical syndromes in humans and animals characterized by involuntary movements without changes in consciousness. Canine movement disorders broadly include tremors, peripheral nerve hyperexcitability disorders, paroxysmal dyskinesia, and dystonia. Of these, canine paroxysmal dyskinesias remain one of the more difficult to identify and characterize in dogs. Canine paroxysmal dyskinesias include an array of movement disorders in which there is a recurrent episode of abnormal, involuntary, movement. In this consensus statement, we recommend standard terminology for describing the various movement disorders with an emphasis on paroxysmal dyskinesia, as well as a preliminary classification and clinical approach to reporting cases. In the clinical approach to movement disorders, we recommend categorizing movements into hyperkinetic vs hypokinetic, paroxysmal vs persistent, exercise‐induced vs not related to exercise, using a detailed description of movements using the recommended terminology presented here, differentiating movement disorders vs other differential diagnoses, and then finally, determining whether the paroxysmal dyskinesia is due to either inherited or acquired etiologies. This consensus statement represents a starting point for consistent reporting of clinical descriptions and terminology associated with canine movement disorders, with additional focus on paroxysmal dyskinesia. With consistent reporting and identification of additional genetic mutations responsible for these disorders, our understanding of the phenotype, genotype, and pathophysiology will continue to develop and inform further modification of these recommendations.

MORVAN SYNDROME: AN INTERESTING CASE OF A RARE DISEASE

Morvan syndrome is a rare disorder of peripheral nerve hyperexcitability, autonomic and central nervous system hyperactivity. It is considered autoimmune and paraneoplastic in nature. The most common associated antibodies are voltage-gated potassium channel (VGKC) complex antibodies which target leucine-rich glioma inactivated 1(LGI-1) and contactin-associated protein 2 (CASPR-2). It is characterized by myokymia, burning pain, cramps, stiffness, weakness, hyperhidrosis, weight loss, insomnia, and hallucinations. Thymectomy, long-term immunosuppression, plasmapheresis, intravenous immunoglobulin (IVIG), steroids are the treatment options. Carbamazepine, phenytoin, amitriptyline, and benzodiazepine are useful in relieving symptoms. We report a rare case ofthis disease from western Rajasthan who presented with bilateral diffuse burning pain, cramps, insomnia, weight loss, hyperhidrosis, visual hallucinations, and continuous muscle twitching and rippling activity over the lower back paraspinal muscles. His serum VGKC antibodies were positive. He was treated with IV methylprednisolone (MPS) and IVIG and had a good response to therapy. We should look for rippling muscle movement in a high index of suspicion and should not be missed.

Inherited neuromyotonia as a phenotypic variation associated with a new mutation in the KCNQ2 gene

Background: Neuromyotonia is a disorder of peripheral nerve hyperexcitability (PNH) characterized by muscle cramps, stiffness, myokymia, delayed muscle relaxation after contraction, and hyperhidrosis. Usually cause of neuromyotonia was acquired autoimmune mechanisms against voltage-gated potassium-channel and rare cause was genetic disorders of potassium channels. Mutations are reported mostly in the KCNA1 gene and only one inherited PNH-associated mutation has been described in KCNQ2 (p.Arg207Trp).

Excessive Blinking and Ataxia in a Child With Occult Neuroblastoma and Voltage-Gated Potassium Channel Antibodies

A previously healthy 9-year-old girl presented with a 10-day history of slowly progressive unsteadiness, slurred speech, and behavior change. On examination there was cerebellar ataxia and dysarthria, excessive blinking, subtle perioral myoclonus, and labile mood. The finding of oligoclonal bands in the cerebrospinal fluid prompted paraneoplastic serological evaluation and search for an occult neural crest tumor. Antineuronal nuclear autoantibody type 1 (anti-Hu) and voltage-gated potassium channel complex antibodies were detected in serum. Metaiodobenzylguanidine scan and computed tomography scan of the abdomen showed a localized abdominal mass in the region of the porta hepatis. A diagnosis of occult neuroblastoma was made. Resection of the stage 1 neuroblastoma and treatment with pulsed corticosteroids resulted in resolution of all symptoms and signs. Excessive blinking has rarely been described with neuroblastoma, and, when it is not an isolated finding, it may be a useful clue to this paraneoplastic syndrome. Although voltage-gated potassium channel complex autoimmunity has not been described previously in the setting of neuroblastoma, it is associated with a spectrum of paraneoplastic neurologic manifestations in adults, including peripheral nerve hyperexcitability disorders.

Seronegative Neuromyotonia and Congenital Hyperinsulinism with Mutation of the Inwardly Rectifying Potassium Channel (KCNJ11) (P05.183)

Objective: We present a man with congenital hyperinsulinism due to mutation of the inwardly rectifying potassium channel (Kir6.2) and neuromyotonia. Background Patients with activating mutations in the KCNJ11 gene can have neonatal diabetes mellitus and associated DEND syndrome (developmental delay, epilepsy and hypotonia). Inactivating mutations of this ATP-sensitive potassium channel lead to congenital hyperinsulism due to insulin oversecretion from pancreatic beta-cells. Down-regulation of Kir6.2 expression in myometrium may contribute to enhanced uterine contractility with onset of labor. Neuromyotonia is a disorder of peripheral nerve hyperexcitability characterized by myokymia, muscle cramps and stiffness, usually due to autoantibodies against neuronal voltage-gated potassium channels (VGKC) or rare VGKC mutations. Design/Methods: The patient is of European descent and was born uneventfully to a family without neurologic or endocrine problems. He was hypoglycemic at birth and was eventually diagnosed with hyperinsulinism. He underwent a subtotal pancreatectomy at two months after unsuccessful medication trials and developed diabetes mellitus at 12. Around age 13, he noted muscle spasms and twitching, with difficulty relaxing his muscles after exertion and falls due to stiffness. He had no percussion or grip myotonia, muscle rippling or myokymia at rest. With hyperextension of his legs he demonstrated grouped fasciculations of the quadriceps. Results: Needle EMG captured increased neuromyotonic discharges. Antibodies against VGKC were negative. PCR and sequence analysis showed that he was heterozygous for an alanine to threonine mutation at codon 213 (p. Ala213Thr). Conclusions: Our patient has co-occurrence of congenital hyperinsulism and seronegative neuromyotonia in the setting of a known inactivating mutation in the Kir6.2 channel (KCNJ11). Inactivation of this channel decreases potassium flow into the cell and resting membrane potential. This channel is known to be expressed in the CNS; its distribution in the PNS is unknown. We speculate that KCNJ11 mutation is causally related to our patient9s peripheral nerve hyperexcitability. Disclosure: Dr. Thyerlei has nothing to disclose. Dr. Oakley has received personal compensation for activities with Neurovista as a consultant. Dr. Jayadev received personal compensation from About.com/New York Times for medical review. . . . . . . Dr. Jayadev has received personal compensation in an editorial capacity for About.com and The New York Times. Dr. Weiss has received personal compensation for activities with Walgreens, CSL Behring and Talecris Biotherapeutics as a consultant and/or speaker.

Isaac Disease: Does the Clinical Spectrum Include White Matter Disease in the Brain? (P05.160)

Objective: Presenting the phenotypic variability of hereditary Issac9s Syndrome. Background Isaac syndrome is a disorder of peripheral nerve hyperexcitability (PNH) manifesting as myokymia, muscle cramps, and neuromyotonia. It is considered to be an acquired condition with antibodies directed against voltage-gated potassium channels. More recently, hereditary cases have been described in association with episodic ataxia and benign familial neonatal epilepsy. These pedigrees have exhibited a wide phenotypic spectrum even within families with the same mutations. Until now, mutations in KCNA1 and KCNQ2 have been described in hereditary cases of Isaacs syndrome. In patients with KCNA1, neuromyotonia occurs in association with episodic ataxia and skeletal deformities. KCNQ2 mutations were initially identified in patients with benign familial neonatal epilepsy but now, peripheral nerve hyperexcitability may also occur. There are also cases of hereditary Issacs syndrome described without the presence of an identifiable mutation in either gene. We describe a three-generation family with inherited Issacs syndrome. Design/Methods: Case Report. Results: In the first 2 generations features of peripheral nerve hyperexcitability was present, and in the third generation refractory epilepsy is described in a child. The proband also has white matter changes on MRI resembling demyelinating disease. Cerebrspinal fluid studies show normal levels of IgG and oligoclonal bands. Abnormal MRI findings have not been described in Isaac syndrome before. Conclusions: The spectrum of abnormalities for Isaac syndrome may include central nervous system white matter disease, cognitive dysfunction, in addition to seizures and peripheral nerve disease with muscle spasm, twitching, and hypetrophy. Patients with white matter disease and recurrent muscle spasm and hypertrophy may be included in the spectrum of antibody mediated central nervous system disorders, such as Isaac syndrome. Family history of other neurological disease may provide important clues as to the cause of such symptoms. Disclosure: Dr. Sedarous has nothing to disclose. Dr. Lange has nothing to disclose.

Neuromyotonia masquerading as tetanus

Neuromyotonia, or Isaac’s syndrome, is a rare neuromuscular disorder of peripheral nerve hyperexcitability characterized by muscle stiffness, muscle hypertrophy, pseudomyotonia, myokymia and electromyographic evidence of myokymic or neuromyotonic discharges. A young boy with neuromyotonia is presented who was diagnosed with tetanus for severe muscle spasms, trismus and ophisthotonos. We discuss differentiation of neuromyotonia from tetanus and other disorders with similar features on clinical and electrophysiological examination.

Accuracy of repetitive nerve stimulation for diagnosis of the cramp–fasciculation syndrome

The goal of this retrospective cohort study was to test the hypothesis that the cramp-fasciculation syndrome (CFS) represents a disorder of peripheral nerve hyperexcitability and to evaluate the accuracy of repetitive nerve stimulation (RNS) for its diagnosis. A consecutive series of 108 patients were evaluated with posterior tibial RNS at 1, 2, and 5 HZ. Abnormal peripheral nerve excitability was defined by the presence of afterdischarges, cramp potentials, or continuous motor unit activity. RNS demonstrated abnormal nerve hyperexcitability in 29 of 36 subjects (81%) with CFS, defined operationally by the presence of both muscle cramps and fasciculations. Based on receiver operating characteristic (ROC) curve analysis, tibial RNS correctly classified the presence or absence of CFS in 75% of subjects. These results suggest that CFS represents a form of peripheral nerve hyperexcitability and, furthermore, that RNS is a clinically useful test for CFS.

Inherited neuromyotonia: A clinical and genetic study of a family

Neuromyotonia is a disorder of peripheral nerve hyperexcitability characterized by myokymia, muscle cramps and stiffness, delayed muscle relaxation after contraction (pseudomyotonia), and hyperhidrosis, associated with well described spontaneous electromyographic features. It is usually an acquired disorder associated with autoantibodies against neuronal voltage-gated potassium channels. However, mutations of KCNA1, encoding the K + channel subunit hKv1.1, have been reported in rare families with neuromyotonia, and mutations in KCNQ2, encoding voltage-gated potassium M channel subunit, in families with benign neonatal seizures and myokymia. We report a three-generation family with inherited neuromyotonia without evidence of immunological involvement. Genetic study excluded mutations in KCNA1, KCNA2, KCNA6 and KCNQ2 genes. Our study does not completely exclude the involvement of other genes encoding ion channels subunits in the pathogenesis of this disorder. Further studies of familial cases will shed light on the molecular basis of inherited neuromyotonia.

Clinical electrophysiological characterization of the acquired neuromyotonia phenotype of autoimmune peripheral nerve hyperexcitability

Acquired autoimmune neuromyotonia is regarded as part of the spectrum of peripheral nerve hyperexcitability disorders. We aimed to use clinical neurophysiological measurements to study the extent, distribution, and characteristics of spontaneous motor unit potentials in 11 patients with acquired neuromyotonia. Investigations revealed that most spontaneous discharges recorded were motor unit, or partial motor unit potentials of normal size. Bursts of motor unit potentials arose more commonly from distal portions of the peripheral nerve and had abnormal absolute and relative refractory periods. Spontaneous discharges in some patients occurred in semirhythmic bursts in certain muscles. No patient had neurophysiological abnormalities detectable in first-order neurons of the central nervous system when using transcranial magnetic stimulation to estimate the threshold for corticomotor excitation and determine central motor conduction time. Only patients with coexistent myasthenia gravis had neurophysiologically detectable defects in neuromuscular transmission. The pathogenic region of abnormality in peripheral nerve hyperexcitability disorders therefore seems to lie within the terminal branches of peripheral motor nerves.