Behavioral & Cognitive Disorders
Dementia associated with amyotrophic lateral sclerosis
Aug. 11, 2023
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Peripheral nerve hyperexcitability syndromes are a group of disorders that share clinical and electrodiagnostic features of motor nerve instability. However, their clinical presentations and phenotypes are varied. Common symptoms of peripheral nerve hyperexcitability syndromes, including muscle stiffness, twitches, and spasms, are also shared with certain central nervous system and myopathic conditions. Cramp-fasciculation syndrome, Isaacs syndrome, and Morvan syndrome are the most accepted terms, though terminology has been confusing. More recent investigations have led to an understanding of the autoimmune mechanisms of these rare conditions; their specific associated antibodies, including voltage-gated potassium channel-complex antibodies; and associated neoplasms. The evaluation of peripheral nerve hyperexcitability syndromes requires familiarity with the spectrum of symptoms associated with them, recognition of their diagnostic electrodiagnostic features, an understanding of their autoimmune pathogenesis, and the application of the optimal treatment.
• Symptoms of Isaacs syndrome include muscle stiffness, muscle twitches/clinical myokymia, and autonomic symptoms. Morvan syndrome is similar to Isaacs syndrome but with additional encephalopathy symptoms.
• EMG findings in peripheral nerve hyperexcitability syndromes include fasciculation potentials and myokymic and neuromyotonic discharges. Stimulus-induced after-discharges (SIAD) on motor nerve conduction studies may also be seen.
• Antibodies to voltage-gated potassium channel (VGKC)-complex proteins directed against contactin-associated protein-2 (CASPR2) or leucine-rich glioma-inactivated 1 (LGI1) may be elevated in peripheral nerve hyperexcitability syndromes.
• Isaacs and Morvan syndromes may be associated with malignancy, including thymoma and small cell lung carcinoma. VGKC-complex antibody seropositive patients may have a higher incidence of malignancy.
• Peripheral nerve hyperexcitability syndromes respond to treatment with membrane-stabilizing drugs, such as carbamazepine, phenytoin, and gabapentin.
• In severe cases, immunomodulatory treatment is necessary. Plasma exchange or infusion of intravenous immunoglobulin provide relief, which may be supplemented by corticosteroids or immunosuppressive therapy.
In 1888 and 1895, Kny and Schutze, respectively and independently, described continuous muscle twitches and quoted the term “myokymia” (myo = muscle, kyma = wave in Greek).
In 1890, Augustin Morvan described “la chorée fibrillaire” associated with autonomic dysfunction and severe insomnia.
In 1948, Denny-Brown and Foley first described generalized myokymia and identified the electrical correlate of this activity consisting of continuous, irregular discharges from different motor units (04).
In 1961, Isaacs described a clinical syndrome in which generalized myokymia was a prominent component. He later showed that the myokymia was not eliminated by blockade of the peripheral nerve but that it could be eliminated by curare, and he suggested that motor activity originated from the distal segments of peripheral nerves (10; 11).
In 1965, Mertens and Zschocke coined the term “neuromyotonia” to highlight the peripheral nerve origin of the myotonia-like muscle discharges (16).
More recently, the terminology and clinical phenomenology of peripheral nerve hyperexcitability syndromes, which significantly overlap, have been confusing. The medical literature has used multiple terms to describe peripheral nerve hyperexcitability syndromes, including idiopathic generalized myokymia, acquired neuromyotonia, Armadillo syndrome, syndrome of continuous muscle fiber activity, la chorée fibrillaire, and quantal squander. To add to this confusion, the electrophysiological terms, including myokymia, neuromyotonia, continuous muscle fiber activity, continuous motor neuron discharges, and neurotonia, are used interchangeably and in an inconsistent fashion.
Despite the presence of several distinguishing clinical and electrophysiological features of peripheral nerve hyperexcitability syndromes, a significant overlap exists among the three main peripheral nerve hyperexcitability syndromes: Isaacs syndrome, Morvan syndrome, and cramp-fasciculation syndrome.
(Figure reprinted with permission from: Termsarasab T, Thammongkolchai T, Katirji B. Stiff person syndrome and related disorders. Springer: New York, 2020.)
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