COGNITIVE IMPAIRMENT AS A MARKER OF DIFFUSE BRAIN ABNORMALITIES IN MULTIPLE SCLEROSIS

Cognitive impairment appears to be common in the early stages of relapsing-remitting multiple sclerosis (MS), according to a study by Mathilde S.A. Deloire and colleagues. The most prominent manifestations of impairment involved attention, information processing speed, memory, inhibition, and conceptualization. Furthermore, “the severity of these deficits reflects the extent of the lesions and the severity of tissue disorganization outside lesions,” the investigators reported in the March Journal of Neurology, Neurosurgery, and Psychiatry.

A battery of neuropsychological tests was administered to 58 patients with relapsing-remitting MS and 70 healthy controls. Lesion load and atrophy indices were measured using MRI, and magnetization transfer ratio (MTR) histograms were obtained from lesions and normal-appearing white and gray matter. In addition, gadolinium-enhanced lesions were counted.

The investigators were able to match 44 patients with relapsing-remitting MS with healthy controls according to age, sex, and education. They found that patients with relapsing-remitting MS had significant cognitive deficits compared with healthy controls. Patients with relapsing-remitting MS performed worse on tests of verbal and spatial memory, attention, information processing speed, inhibition, and conceptualization. In addition, the investigators found that measures of attention and information-processing speed correlated with lesion load, mean normal-appearing white matter MTR, and the peak location of the normal-appearing gray matter MTR histogram in patients with relapsing-remitting MS.

Ms. Deloire and colleagues said that although poor cognitive performance is common in the early stages of relapsing-remitting MS, it remains subtle and does not significantly affect quality of life. They concluded that the deficits identified in their study could serve as a severity marker in the early stages of relapsing-remitting MS.

Deloire MSA, Salort E, Bonnet M, et al. Cognitive impairment as marker of diffuse brain abnormalities in early relapsing remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005;76:519-526.

EFFECTS OF EXPOSURE TO ANTIEPILEPTIC DRUGS IN UTERO SEEM TO VARY

Several recent studies evaluating the effects of exposure to antiepileptic medication in utero show mixed results. The studies appeared in the March 22 Neurology and examined the effects of exposure to drugs such as lamotrigine, valproic acid, carbamazepine, and phenytoin. According to researchers, exposure to lamotrigine was associated with a rate of birth defects comparable to that in the general population, whereas exposure to valproic acid was associated with a significantly increased risk of birth defects.

Marianne Cunnington, PhD, and Patricia Tennis, PhD, conducted a study that evaluated the effects of exposure to lamotrigine, one of several newer antiepileptic drugs. They found that among 414 first-trimester exposures to lamotrigine monotherapy, 12 cases of major birth defects were reported (2.9%); among 88 first-trimester exposures to lamotrigine polytherapy including valproic acid, 11 cases of major birth defects were reported (12.5%); and among 182 first-trimester exposures to lamotrigine polytherapy not including valproic acid, five cases of major birth defects were reported (2.7%).

Drs. Cunnington and Tennis concluded that the risk of all major birth defects following exposure to lamotrigine was similar to that in the general population.

On the other hand, results from another study, by Diego F. Wyszynski, MD, MHS, PhD, and colleagues, indicated that children exposed to valproic acid in utero were 7.3 times more likely to have a major birth defect. The investigators identified 16 cases of birth defects among 149 exposures to valproic acid (10.7%), compared with a 2.9% prevalence rate of birth defects among children exposed to other antiepileptic drugs in utero and a 1.62% prevalence rate of birth defects in the general population.

Similarly, in a third study, J. Vinten, PhD, and colleagues found that exposure to valproic acid was associated with harmful effects on neuropsychological development. The researchers evaluated 249 children ages 6 to 16 and discovered that children exposed to valproic acid had a significantly lower verbal IQ compared with children exposed to carbamazepine or phenytoin and those not exposed to an antiepileptic drug. Children exposed to valproic acid were more likely to have an IQ below 69; 22% of children exposed to valproic acid had an IQ below 69, compared with 8%, 7%, 7%, and 2% to 3% for the carbamazepine group, the polytherapy group, the nonexposed group, and the general population, respectively. According to the researchers, “the mothers’ IQ, exposure to valproic acid, and the number of tonic-clonic seizures during pregnancy were significant predictors of verbal IQ in this population.”

Patricia Penovich, MD, and Eija Gaily, MD, wrote in an accompanying editorial, “Although these studies do not provide absolute answers, they are important and needed to counsel women with epilepsy who contemplate pregnancy.” They noted that “maternal tonic-clonic status epilepticus may cause catastrophic damage to the fetal brain, and even partial seizures may produce infant distress.” Therefore, they highlighted the importance of maintaining effective antiepileptic drug therapy during pregnancy. They concluded that the risks for women with epilepsy and their children can be minimized by “careful planning of antiepileptic drug therapy before pregnancy, by supplementing with folate, and by using monotherapy with lowest effective dose of the antiepileptic drug that is most effective against seizures in that patient.”

Cunnington M, Tennis P. Lamotrigine and the risk of malformations in pregnancy. Neurology. 2005;64:955-960.
Penovich P, Gaily E. What can we say to women of reproductive age with epilepsy? Neurology. 2005;64:938-939.
Vinten J, Adab N, Kini U, et al. Neuropsychological effects of exposure to anticonvulsant medication in utero. Neurology. 2005;64:949-954.
Wyszynski DF, Nambisan M, Surve T, et al. Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology. 2005;64:961-965.

COMBINATION OF MORPHINE AND GABAPENTIN FOR NEUROPATHIC PAIN

Among patients with diabetic neuropathy or postherpetic neuralgia, a combination of gabapentin and morphine achieves better analgesia at lower doses of each drug than does either agent alone, according to Ian Gilron, MD, and colleagues. Results of their study were published in the March 31 New England Journal of Medicine.

The researchers conducted a randomized, double-blind, placebo-controlled, crossover study in which 57 patients—35 with diabetic neuropathy and 22 with postherpetic neuralgia—received placebo (lorazepam), sustained-release morphine, gabapentin, and a combination of morphine and gabapentin for five weeks each. A total of 41 patients completed the trial.

At baseline, patients completed a diary in which they rated the intensity of pain three times per day for seven consecutive days following discontinuation of treatment with previously prescribed opioids or gabapentin. During the first three weeks of each five-week treatment period, doses were escalated toward maximal tolerated doses or targeted ceiling doses, whichever were reached first. Researchers added that during the fifth week of each treatment period, doses were tapered for four days, and patients underwent a three-day washout.

According to Dr. Gilron and his colleagues, the mean daily pain (on a scale from 0 to 10, with 10 indicating more severe pain) at a maximal tolerated dose of each study drug was as follows: 5.72 at baseline, 4.49 with placebo, 4.15 with gabapentin alone, 3.70 with morphine alone, and 3.06 with gabapentin and morphine combined. The gabapentin/morphine combination was also superior to the other treatment regimens, as indicated by results from the Short-Form McGill Pain Questionnaire.

The mean maximal tolerated dose of each study drug was as follows: 45.3 mg for morphine as a single agent, compared with 34.4 mg for morphine in the gabapentin/morphine combination; 2,207 mg for gabapentin alone, compared with 1,705 mg for gabapentin in the gabapentin/morphine combination; and 1.38 mg for placebo.

The researchers noted that the most frequent adverse events associated with the gabapentin/morphine combination were constipation, sedation, and dry mouth, with a higher frequency of constipation than with gabapentin alone and a higher frequency of dry mouth than with morphine alone.

“Given the potential benefits (eg, improved efficacy and fewer adverse effects) and drawbacks (eg, adverse drug interactions) of any drug combination, trials are needed to compare other analgesic combinations with their respective single agents,” concluded the researchers.

Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005;352:1324-1334.

ASPIRIN SAFER THAN WARFARIN AND EQUALLY EFFECTIVE FOR SYMPTOMATIC INTRACRANIAL ARTERIAL STENOSIS

Aspirin should be used in preference to warfarin for the treatment of intracranial arterial stenosis, suggested Marc I. Chimowitz, MD, of Emory University School of Medicine in Atlanta. As reported in the March 31 New England Journal of Medicine, Dr. Chimowitz’s group found that aspirin was associated with fewer adverse events while resulting in equal efficacy to that of warfarin.

A total of 569 patients with transient ischemic stroke or stroke caused by angiographically verified 50% to 90% stenosis of a major intracranial artery were randomized to receive warfarin or aspirin. The initial dose of warfarin was 5 mg per day; patients underwent blood tests monthly to determine the international normalized ratio (target range, 2.0 to 3.0), which was then used to make adjustments in the dose of warfarin. The initial dose of aspirin was 650 mg twice daily, which could be lowered to a minimum dose of 325 mg per day if side effects, such as dyspepsia, developed.

According to the researchers, during a mean follow-up period of 1.8 years, the primary end point (ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke) occurred in 22.1% of patients who received aspirin and 21.8% of those who received warfarin. Adverse events in the two treatment groups included death (4.3% in the aspirin group vs 9.7% in the warfarin group), major hemorrhage (3.2% vs 8.3%, respectively), and myocardial infarction or sudden death (2.9% vs 7.3%, respectively). The rate of death from vascular causes was 3.2% in the aspirin group and 5.9% in the warfarin group. In contrast, the rate of death from nonvascular causes was 1.1% and 3.8%, respectively, said the researchers.

Dr. Chimowitz observed that using aspirin “will substantially lower the risk of major hemorrhage and eliminate the inconvenience of using warfarin. In addition, considerable savings can be achieved by avoiding the costs of warfarin, INR testing, and treatment of warfarin-associated hemorrhages.”

In an accompanying editorial, Walter J. Koroshetz, MD, noted that “the use of a nonstandard, large dose of aspirin and the absence of evidence tying the dose of aspirin to a benefit in stroke prevention make it difficult to choose an antiplatelet regimen and a dose in clinical practice.” He added that the higher occurrence rates of death due to cancer, congestive heart failure, diabetes, and cardiac causes in the warfarin group are incongruous with previous studies evaluating warfarin.

Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med. 2005;352:1305-1316.
Koroshetz WJ. Warfarin, aspirin, and intracranial vascular disease. N Engl J Med. 2005;325:1368-1370.

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