Cerebellar dysfunction in MS

Samuel Pleasure

Samuel Pleasure, MD, PhD, is Professor of Neurology at UCSF. He got his MD and PhD (Neuroscience) degrees at the University of Pennsylvania and then trained in neurology and neuroscience at UCSF. He has authored numerous scientific papers on the basic mechanisms of brain development and how they relate to human neurodevelopmental disorders. He has clinical interests in epilepsy and multiple sclerosis.

Cerebellar dysfunction is a common feature in MS and is frequently among the more difficult to manage problems since it causes ataxia, dysarthria and incoordination. My assumption has always been that these symptoms are largely due to demyelination in the cerebellum or its afferent or efferent connections. A recent study in Annals of Neurology (Shields et al., February 2012) has introduced me to a new way to think about this problem in MS. The authors previously showed that Nav1.8, a voltage gated sodium channel, is ectopically expressed in Purkinje cells in the cerebellum in several models of MS and also in tissue taken from MS patients. This channel is normally not expressed in the central nervous system but rather is typically limited to the peripheral nervous system. In this study the authors examined mice that are genetically engineered to express Nav1.8 in Purkinje cells in order to test whether there are functional consequences to this misexpression. Indeed, these mice do develop motor coordination defects consistent with cerebellar dysfunction and isolated Purkinje cells from these mice have electrophysiologic defects. The authors then went on to induce EAE in mice that are genetically lacking the Nav1.8 gene and found that these mice fail to develop the typical cerebellar phenotypes seen in the EAE model used by the authors. Lastly, mice with EAE and with ectopic Nav1.8 expression in Purkinje cells responded positively to Nav1.8 antagonists with decrease in their cerebellar deficits.

What does this all mean? When taken along with other recent studies showing changes in metabotropic glutamate receptor subunit expression in the cerebellum, it implies that we are approaching a new understanding of a variety of the phenotypes seen in demyelinating disease. It seems that neurons in these diseases may be subject to a variety of changes in gene expression leading to the ectopic mixexpression of deleterious genes (when in the wrong context) such as Nav1.8 or perhaps the loss of other genes required for normal physiologic function. This may explain some of the more evanescent symptoms seen in MS that don’t seem to necessarily correlate with inflammatory activity. In addition, in some of these cases, as perhaps with Nav1.8, treatment with antagonists may be useful to treat clinical manisfestations of MS.

http://www.medscape.com

 

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