STOWE, VT. — Initiating use of anticonvulsant therapy or switching antiepileptic drugs used may trigger life-threatening dermatoses, Dirk M. Elston, M.D., said at a dermatology conference sponsored by the University of Vermont.
The dermatoses associated with antiepileptic drugs (AEDs) typically involve blistering or are exfoliative. Patients at greatest risk are those with the triad of fever, swelling, and point tenderness who have recently initiated or altered seizure medications, Dr. Elston said.
Although these conditions are rare, it is critical that neurologists be aware of their possible occurrence as well as the signs and symptoms of the potentially fatal, acute syndromes when prescribing the implicated agents, epileptologist Jacqueline French, M.D., told CLINICAL NEUROLOGY NEWS.
Neurologists can reduce the risk of these events by commencing all new medications at a low dose, avoiding rapid dose increases, steering clear of known or presumed cross-reactive agents in patients with a history of sensitivity to a particular agent, and directing patients to report all adverse events, according to Dr. French of the University of Pennsylvania in Philadelphia.
Patients may not link their rash to their epilepsy medication, and instead of reporting it to their neurologists, they may seek care from their primary care doctor or dermatologist.
During his presentation, Dr. Elston noted that the differential diagnoses for such patients should include anticonvulsant hypersensitivity syndrome, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN)—all of which can be fatal if not properly addressed. Time is critical for these patients, as their survival often depends on prompt recognition and appropriate multidisciplinary treatment, stressed Dr. Elston of Geisinger Medical Center, Danville, Pa.
The severe cutaneous manifestations noted are most commonly associated with the first-generation aromatic-ring antiepileptic agents (carbamazepine, phenobarbital, and phenytoin).
However, SJS and TEN have also been reported with the second-generation agent lamotrigine, particularly when used in combination with valproic acid.
Valproic acid when used as antiseizure monotherapy alone has a low independent association with the skin eruptions, Dr. Elston said.
A diagnosis of anticonvulsant hypersensitivity disorder should be presumed if the rash is morbilliform or scarlatiniform and is accompanied by facial edema, fever, and/or lymphadenopathy.
Additional clinical features often include hepatitis, eosinophilia, and atypical lymphocytosis.
Acute-onset rashes that present as severe mucosal erosions with epidermal detachment and widespread erythematosus macules may be either SJS or TEN. The former, associated with 5% mortality, is often defined by purpuric macules and atypical target lesions, full-thickness epidermal necrosis, mucous membrane involvement, and detachment of less than 10% of the total cutaneous surface.
Possibly a more severe variant of the same process, TEN shares the histologic features of SJS, but detachment affects more than 30% of the cutaneous surface and the mortality is significantly higher. Acute onset of intense skin tenderness also indicates TEN, Dr. Elston said.
When a diagnosis is confirmed, the most important treatment is to withdraw the anticonvulsant immediately and switch to an alternative medication for seizure control. “Doing so requires extreme care because of the high degree of cross-reactivity” among the various agents—particularly, but not exclusively, the aromatic drugs, Dr. Elston said.
“If you put a patient on an alternative antiseizure drug that has a high degree of cross-reactivity, not only is the eruption likely to recur, the course will probably be quicker and more devastating.”
Dr. French noted that when anticonvulsant therapy is withdrawn, there is no “one best” alternative medication for seizure control. “There are many options, but they depend on the patient's history and their seizure type,” she said.
While the newer-generation antiepileptic drugs have proved to be at least as effective as the older agents in most settings and are associated with fewer side effects and adverse events, care must still be taken when prescribing them to patients who have reacted to previous drugs.
Anecdotal reports linking gabapentin to recurrence of hypersensitivity syndrome, for example, suggest this second-generation drug should be avoided in patients with a previous sensitivity.
The coadministration of lamotrigine and valproate should be avoided as well, given the increased risk of TEN, according to Dr. French.
Dr. Elston noted that in addition to withdrawing the offending anticonvulsant, intravenous fluid replacement is a mainstay of therapy for these syndromes. For the more severe exfoliative conditions, symptomatic treatment is the same as for burns—debridement, dressings, growth factors, and aggressive monitoring for infection and for fluid and electrolyte disturbances.
In fact, “patients should be transferred to a burn center if possible,” he noted. Burn center care can improve mortality, primarily because of the specialized and intensive nursing support, he said.
It has been hypothesized that the severe anticonvulsant-induced skin reactions might be associated with reactivation of human herpesvirus 6.