Exacerbation of experimental autoimmune encephalomyelitis after withdrawal of phenytoin and carbamazepine.
OBJECTIVE
In vitro observations and studies in murine experimental autoimmune encephalomyelitis (EAE) have shown protective effects of sodium channel blockers on central nervous system axons and improved clinical status when treatment is continued throughout the period of observation. Several clinical studies of sodium channel blockers are under way in patients with multiple sclerosis. Here we asked whether a protective effect would persist after withdrawal of a sodium channel blocker.


METHODS
We studied a mouse model of myelin oligodendrocyte glycoprotein-induced EAE treated with phenytoin or carbamazepine.


RESULTS
Both phenytoin and carbamazepine significantly improved the clinical course of the disease. Withdrawal of phenytoin resulted in acute exacerbation, accompanied by a significantly increased inflammatory infiltrate within the central nervous system and the death of nearly 60% of EAE mice. There were no clinical worsening or deaths in control mice after withdrawal of phenytoin. Withdrawal of carbamazepine led to acute worsening of EAE symptoms, increased inflammatory infiltrate, and was associated with the death of 8% of mice.


CONCLUSIONS
These results, together with results showing effects of sodium channel blockers in immune cells, raise questions about the long-term effects of sodium channel blockers in neuroinflammatory disorders, and suggest that clinical studies of sodium channel blockers in these disorders should be planned carefully.
Black
Joel A
JA
Department of Neurology and Center for Neuroscience and Regeneration Research, Yale School of Medicine, New Haven, CT 06520, USA.
Liu
Shujun
S
Carrithers
Michael
M
Carrithers
Lisette M
LM
Waxman
Stephen G
SG
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects*; D015703:Antigens, CD / Q000378:metabolism; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002220:Carbamazepine / Q000009:adverse effects*; D002452:Cell Count / Q000379:methods; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010446:Peptide Fragments; D010672:Phenytoin / Q000009:adverse effects*; D011712:Pyramidal Tracts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index; D015222:Sodium Channels / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000209:etiology*
D000927:Anticonvulsants; D015703:Antigens, CD; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C491046:Scn8a protein, mouse; D015222:Sodium Channels; C445081:myelin oligodendrocyte glycoprotein (35-55); D002220:Carbamazepine; D010672:Phenytoin