Positive symptoms in multiple sclerosis: their treatment with sodium channel blockers, lidocaine and mexiletine

Sakurai, Masaki; Kanazawa, Ichiro

doi:10.1016/s0022-510x(98)00322-0

Cited by 99 publications

(54 citation statements)

References 22 publications

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“…A very high dose of antagonist would be needed to close sufficient numbers of voltage-gated potassium channels to have a measurable effect on the cumulative g L in the membrane. If, as it seems, the traditional use of sodium channel blockers as treatments for positive clinical phenomena in MS has a rational basis (36,37), we propose that regulation of g L might also take part in the axonal compensation mechanism and might be an effective pharmacotherapy target.…”

Section: Discussionmentioning

confidence: 96%

Imbalance of ionic conductances contributes to diverse symptoms of demyelination

Coggan

Prescott

Bartol

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Fast axonal conduction of action potentials in mammals relies on myelin insulation. Demyelination can cause slowed, blocked, desynchronized, or paradoxically excessive spiking that underlies the symptoms observed in demyelination diseases. The diversity and timing of such symptoms are poorly understood, often intermittent, and uncorrelated with disease progress. We modeled the effects of demyelination (and secondary remodeling) on intrinsic axonal excitability using Hodgkin-Huxley and reduced Morris-Lecar models. Simulations and analysis suggested a simple explanation for the breadth of symptoms and revealed that the ratio of sodium to leak conductance, g Na /g L , acted as a four-way switch controlling excitability patterns that included spike failure, single spike transmission, afterdischarge, and spontaneous spiking. Failure occurred when this ratio fell below a threshold value. Afterdischarge occurred at g Na /g L just below the threshold for spontaneous spiking and required a slow inward current that allowed for two stable attractor states, one corresponding to quiescence and the other to repetitive spiking. A neuron prone to afterdischarge could function normally unless it was switched to its "pathological" attractor state; thus, although the underlying pathology may develop slowly by continuous changes in membrane conductances, a discontinuous change in axonal excitability can occur and lead to paroxysmal symptoms. We conclude that tonic and paroxysmal positive symptoms as well as negative symptoms may be a consequence of varying degrees of imbalance between g Na and g L after demyelination. The KCNK family of g L potassium channels may be an important target for new drugs to treat the symptoms of demyelination. O ligodendrocytes and Schwann cells tightly wrap axons at regular intervals to form the myelin sheath that allows for rapid axonal conduction. Neuropathies involving axonal demyelination are characterized by the unraveling of this insulation and can affect both the central nervous system, as in the case of multiple sclerosis (MS), and the peripheral nervous system, as in Guillain-Barré syndrome.Causes of demyelination include immunologic disease processes, as well as lesions such as traumatic nerve damage, nonpenetrating spinal cord injuries, and chronic nerve compression (1-4). Regardless of the precise etiology, clinical presentation often involves negative (loss-of-function) symptoms, including loss of motor control (i.e., paresis) and sensory deficits such as blindness and numbness, as well as positive (gain-of-function) symptoms, including muscle spasms, tactile allodynia, and chronic pain that is constant or paroxysmal (1, 4-7). Which muscles or sensory modalities are affected depends on where in the nervous system the demyelinating lesions develop, but changes in conduction velocity alone are clearly insufficient to explain the breadth of symptoms observed, especially the positive ones. In particular, MS often produces confounding symptoms that can present intermittently, resolving and retu...

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Section: Discussionmentioning

confidence: 96%

Imbalance of ionic conductances contributes to diverse symptoms of demyelination

Coggan

Prescott

Bartol

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Des impulsions ectopiques générées au site de démyélinisation sont vues comme responsables de symptômes «positifs» chez les patients SP comme des convulsions toniques douloureuses, des dysesthésies, la spasticité et la névralgie faciale. 7 La physiopathologie de ce désordre soulève d'importantes questions cliniques sur l'emploi de l'anesthésie neuraxiale chez ces patients. Premièrement, quels sont les effets des anesthésiques locaux sur les fibres démyélinisées ?…”

Section: Anesthésie Neuraxiale Etunclassified

“…Ectopic impulses generated at the site of demyelination are considered responsible for "positive" symptoms experienced by MS patients such as painful tonic seizures, dysesthesias, spasticity and trigeminal neuralgia. 7 The pathophysiology of this condition raises important clinical questions regarding the practice of neuraxial anesthesia in these patients. First, what are the effects of local anesthetics on demyelinated fibres?…”

mentioning

confidence: 99%

“…8 Moreover, systemically administered local anesthetics can alleviate the positive symptoms associated with demyelination, such as paresthesias, and spasticity, allegedly by blocking the propagation of ectopic impulses. 7 Both iv lidocaine and oral mexiletine have been used successfully to treat these symptoms in patients with MS. 7 The administration of intrathecal local anesthetics for the purpose of spinal anesthesia has also been reported to unmask previously silent demyelinated plaques, by precipitating the appearance of negative MS symptoms. 9 Levesque reported a case of acute onset of previously undiagnosed MS presenting as oculomotor paralysis following spinal anesthesia performed for a minor orthopedic procedure.…”

mentioning

confidence: 99%

“…These symptoms, whether unmasked by systemically or intrathecally administered local anesthetics, are typically transient and reversible, and do not imply worsening of the underlying condition, unlike a true disease relapse or exacerbation, ultimately defined by appearance of new demyelinated areas. 7 Second, is the quality of neuraxial blockade any different in MS patients? Should we expect a greater intensity or duration of blockade in MS patients?…”

mentioning

confidence: 99%

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