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Swelling of vascular endothelial cells decreases cerebral perfusion, causing ischemia and infarction. Swelling of the epithelial cells of the choroid plexus and the endothelial cell blood-brain barrier can compromise their structural and functional integrity, thereby altering the permeability of barrier.

Axonal Protection with Sodium Channel Blocking Agents in Models of Multiple Sclerosis
Joel A. Black, Kenneth J. Smith, Stephen G. Waxman
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Abstract
Axonal degeneration in multiple sclerosis (MS) has come to be increasingly appreciated as a major contributor to nonremitting disability in MS. Significant axonal damage and loss occur with acute MS plaques, and this loss continues, albeit at an attenuated rate, in chronic inactive plaques. These observations have triggered considerable interest in identifying neuroprotective therapies that can ameliorate axonal injury and degeneration in neuroinflammatory disorders. Accumulating evidence implicates participation of voltage-gated sodium channels in Ca2+-mediated damage of central white matter axons. Indeed, blockade of sodium channels has been shown to provide protective effects for axons exposed to anoxia, trauma, and ischemia injuries. In the present chapter, we describe work from our laboratories that has examined the effects of sodium channel blocking agents on disease progression in rodent models of neuroinflammatory lesions, including experimental autoimmune encephalomyelitis (EAE), a disease that is widely utilized to model aspects of MS. The sodium channel blocking agents utilized in our studies—phenytoin, carbamazepine, flecainide, and lamotrigine—provide robust protection of spinal cord axons, preserve action potential conduction, significantly diminish immune cell infiltration, and attenuate neurological deficits in EAE. Results from these studies provided a rationale for planning and implementing clinical studies utilizing sodium channel blocking agents in patients with MS, and several clinical trials examining the efficacy of sodium channel blockade in ameliorating clinical disability in MS are currently ongoing.

Pathogenesis of axonal and neuronal damage in multiple sclerosis
Ranjan Dutta, PhD
Bruce D. Trapp, PhD
ABSTRACT Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the CNS. Approximately 2 million people worldwide have MS, with females outnumbering males 2:1. Because of its high prevalence, MS is the leading cause of nontraumatic neurologic disability in young adults in the United States and Europe. Axon loss is the major cause of irreversible disability in atients with MS. Axon damage, including transection of the axon, begins early in MS and correlates with inflammatory activity. Several mechanisms lead to axon loss, including inflammatory secretions, loss of myelinderived support, disruption of axonal ion concentrations, energy failure, and Ca2 accumulation. Therapeutic interventions directed toward each of these mechanisms need to be tested for their efficacy in enhancing axon survival and, ultimately, their ability to delay progression of neurologic disability in patients with MS.NEUROLOGY 2007;68 (Suppl 3):S22–S31

Central pontine myelinolysis or CPM for short is a neurological disease caused by severe damage of the myelin sheath of nerve cells in the brainstem, more precisely in the area termed the pons, predominately of iatrogenic etiology. It is characterized by acute paralysis, dysphagia (difficulty swallowing), and dysarthria (difficulty speaking), and other neurological symptoms.
It can also occur outside the pons.[1] The term "osmotic demyelination syndrome" is similar to "central pontine myelinolysis", but also includes areas outside the pons.[2]

Finally, magnetic resonance imaging focal areas of T2-increased signal intensity in the white matter, without corresponding to neurological impairment, were detected in 4 (27%) of 15 CAH patients by Sinforiani et al,5 in 14 (36%) of 39 patients by Nass et al,6 and in 7 (30%) of 23 patients by us (R.B., C.L., E.C., C.U., D.F., and V.C., unpublished data, 2003).

In these series, white matter abnormalities were diffuse (mostly periventricular) and focal. Diffuse white matter abnormalities could be an expression of hypotensive episodes, producing infarctions in watershed areas.6 A different explanation could be that they are the expression of myelin sufferance, interpretable as extrapontine myelinolysis, induced by the rapid correction of hyponatremia.6 Concerning focal white matter abnormalities, some of them, such as the lesions in the cerebellum6 and the corpus callosum (R.B., C.L., E.C., C.U., D.F., and V.C., unpublished data, 2003), are similar to those typical of MS.

Osmotic demyelination syndrome is a well-known clinicopathologic entity characterized by edema and demyelination in the pons and extrapontine areas [1–5]. Previous studies have noted the MRI findings of osmotic demyelination syndrome in various patient groups [3, 4]. The pathogenesis of osmotic demyelination syndrome remains unclear, but many underlying diseases are known to be associated with this condition [1, 6, 7]. The syndrome is most often seen after rapid correction of chronic hyponatremia [2, 3, 7, 8], but other diseases that cause fluid and electrolyte disturbances may also lead to myelinolysis [1, 6, 9]. In patients with end-stage renal disease, osmotic demyelination syndrome may develop as a result of the disease itself or because of osmotic changes during hemodialysis [1, 10, 11]. Dysequilibrium syndrome is one of the metabolic complications of hemodialysis that may trigger osmotic demyelination syndrome [10].

The MRI findings of osmotic demyelination syndrome in patients with end-stage renal disease have not been documented in detail. The aims of this study were to present the brain MRI findings of osmotic demyelination syndrome at the time of an episode after hemodialysis and at follow-up, and to identify possible factors that may contribute to the development of these lesions in patients with end-stage renal disease.

Abstract
Two patients with chronic alcohol abuse and central pontine myelinolysis are described. One developed a Korsakoff syndrome 2 days before admission to our hospital and the other showed signs of a incipient delirium without Korsakoff syndrome. Diagnosis of incipient central pontine myelinolysis was based on acute brain-stem dysfunction, serum electrolyte disturbances, malnutrition with vitamin B1 (thiamine), B6 (pyridoxine) and B12 (cyanocobalamin) deficiency in combination with typical neuroradiological findings. Hypokalaemia but no disturbance in serum sodium levels was found in both patients. After correction of hypokalaemia and vitamin deficiency the patients showed complete recovery of neurological and neuropsychological function. The findings are interpreted as suggesting that disturbances in serum potassium levels as well as rapid correction of hyponatraemia may be associated with pontine swelling and dysfunction which, if undetected, leads to central pontine myelinolysis.

Prevention of brain demyelination in rats after excessive correction of chronic hyponatremia by serum sodium lowering

Alain Soupart1, Raymond Penninckx1, Laurent Crenier1, Alain Stenuit1, Olivier Perier1 and Guy Decaux1
1Research Unit for the Study of Hydromineral Metabolism, Department of Internal Medicine and Laboratory of Clinical Biology, Erasmus University Hospital, and Department of Neuroanatomy, School of Medicine, Free University of Brussels, Brussels, Belgium
Correspondence: Dr A Soupart, Service de Médicine Interne, Hôpital Universitaire Erasme, route de Lennik, 808, B-1070 Brussels, Belgium.
Received 4 September 1992; Revised 17 August 1993; Accepted 19 August 1993.
Abstract
Prevention of brain demyelination in rats after excessive correction of chronic hyponatremia by serum sodium lowering. Brain myelinolysis occurs after correction of chronic hyponatremia in rats when the magnitude of increase in serum sodium (SNa) exceeds 20 to 25 mEq/liter/24 hr (the critical threshold for brain). We tested the hypothesis that after a sustained excessive correction, brain lesions (BL) could be prevented by subsequently decreasing the serum sodium below the critical threshold for brain through the administration of hypotonic fluids. After three days of severe (< 115 mEq/liter) chronic (3 days) hyponatremia, 55 rats were submitted to an excessive correction (SNa > 25 mEq/liter) by a single i.p. infusion of hypertonic saline (NaCl). This osmotic stress was maintained during 12 hours before the serum sodium decrease was initiated. Thirty-two rats reached the twelfth post-correction hour without symptoms. In group 1 after a large (SNa 32 mEq/liter) and sustained (12 hr) osmotic stress, the natremia was rapidly (2 hr) decreased by the administration of oral tap water and, at the end of the first 24 hours, the magnitude of correction was maintained below 20 mEq/liter/24 hr. All the rats fared well in this group and were free of neurologic symptoms. Mild BL were noticed in only 20% of them. On the contrary, in controls (no hypotonic fluids administration at the twelfth hour) whose serum sodium was left overcorrected, all the rats became symptomatic and 57% of them died rapidly. Brain damage developed in 100% of the surviving rats. In group 2, despite hypotonic fluids administration, the serum sodium decreased insufficiently and the correction was > 20 mEq/liter at the end of the first 24 hours (SNa 25 mEq/liter). The majority of these rats also presented a poor outcome. Finally, a group of rats developed very early (< 12 hr) neurologic symptoms (N = 23, 42%), and all of them died rapidly (< 24 hr) if the natremia was not decreased. Hypotonic fluids administration in some of these rats allowed them a longer survival, and brain analysis also demonstrated severe demyelination. This work demonstrates that the process leading to brain demyelination remains reversible in hyponatremic rats despite a sustained (12 hr) exposure to an excessive correction. Indeed, subsequent brain damage can be completely prevented in asymptomatic rats by early (12 hr) serum sodium lowering provided that the final correction was maintained below 20 mEq/liter/24 hr. Our results also show that the osmotic stress must be maintained a minimum period of time to induce brain lesions.