The cerebellar channelopathy of multiple sclerosis.

Clinical abnormalities in multiple sclerosis (MS) have traditionally been attributed to inflammation, demyelination, or degeneration of axons within the brain and spinal cord. Among those symptoms, clinical deficits due to cerebellar dysfunction, including loss of coordination, ataxia, tremor, and dysarthria, can reduce function substantially, are less likely to remit, and are more likely to be associated with progressive MS in the future. Interestingly, cerebellar signs and symptoms are sometimes seen in patients in whom structural lesions or inflammation of the cerebellum cannot be detected. These symptoms can be paroxysmal, similar to trigeminal neuralgia in patients with MS, which preferentially responds to sodium channel blockers. What is the basis for these clinical deficits? The NaV1.8 sodium channel, encoded by gene SCN10A, was initially called SNS (sensory neuron specific) because of its preferential expression within primary sensory neurons such as dorsal root ganglion (DRG) and trigeminal ganglion neurons in the healthy nervous system. NaV1.8 displays a unique functional profile that includes reduced steady-state inactivation at depolarized potentials (a property that allows NaV1.8 channels to remain available for operation at depolarized membrane potentials where other sodium channels are inactivated) as well as slow onset of inactivation followed by a rapid recovery from inactivation. As a result of these biophysical properties, NaV1.8 produces repetitive neuronal firing in response to sustained depolarization. In 2000, Black et al. described the abnormal expression of NaV1.8, which is not normally detectable in the cerebellum, within cerebellar Purkinje neurons in the brains of mice with experimental autoimmune encephalomyelitis (EAE) and in postmortem brain tissue from humans with MS. The presence of NaV1.8 channels within these cerebellar output neurons, where they are not normally present, would be expected to perturb the pattern of activity of these cells and, indeed, subsequent studies demonstrated that expression of NaV1.8 within Purkinje neurons in vitro and in mice with EAE leads to abnormal firing by these critically important cerebellar neurons. In this issue ofNeurology®, Roostaei et al. extend the evidence for a role of NaV1.8 in cerebellar dysfunction in patients with MS. With a focus on motor-behavioral and neural correlates of SCN10A polymorphisms, they assessed 161 patients with relapsing-onsetMS for clinical disability and functional status. They assessed the SCN10A polymorphisms in these patients and found a relationship between SCN10A genotype and performance on tests of functional status. This association was independent of cerebellar volume, but in a subset of 62 patients with MS assessed via resting-state fMRI, there was decreased cerebellar-functional connectivity with the thalamus and midbrain in patients carrying the single nucleotide polymorphism associated with impaired performance. Consistent with the idea that NaV1.8 is expressed in the cerebellum in MS but not in the normal cerebellum, SCN10A genotype did not have an effect on performance in a control group that did not have MS. All of this suggests that molecular mistuning of Purkinje neurons as a consequence of the abnormal presence of NaV1.8 contributes to phenotypic manifestation of MS. It may therefore be possible to reverse cerebellar symptoms in MS by treatment with drugs that block NaV1.8 channels. Because NaV1.8 plays an important role in the firing of DRG neurons, including painsignaling cells, NaV1.8 subtype selection blockers are being developed for the treatment of pain. Two of these NaV1.8 blockers have, in fact, been studied in animal models of MS, and improve clinical function, with a time course that parallels their pharmacokinetics. While the latest work by Roostaei et al. represents an important step forward, there is still much to learn about the cerebellar channelopathy that occurs in MS. Higher-resolution tests of cerebellar function might more definitively establish the details of the impact of the abnormally tuned Purkinje neurons on specific aspects of cerebellar function in MS. While Black et al. clearly demonstrated the anomalous presence of NaV1.8 in Purkinje neurons in the cerebellums of patients with MS, examined postmortem, and the Roostaei et al. article provides evidence for a role of