TWO SEIZURES ARE A SUFFICIENT CRITERION FOR EPILEPSY

Two seizures are a sufficient criterion for the definition of epilepsy, according to a report in the August Annals of Neurology. However, a diagnosis of epilepsy does not necessitate the initiation of antiepileptic drug therapy, said the authors.

The prospective study followed 407 children (age 1 month to 19 years) with a first unprovoked seizure who were seen between October 1983 and August 1992 at the private practices of the authors—the Montefiore Medical Center, the Jacobi Medical Center, or the North Central Bronx Hospital. The children were followed by telephone interview at least every three months to ascertain seizure recurrence. They were followed for a mean of 9.6 years.

Seizure recurrence (the median time to recurrence was 6.2 months) was experienced by 45% of the children. The cumulative risk for a second seizure was 29%, 37%, 43%, and 46% at one, two, five, and 10 years, respectively. The authors found that 72% of those who experienced a second seizure experienced a third, 58% experienced at least four seizures, and 29% experienced at least 10 seizures. Thus, the authors calculated that after two seizures the risk of subsequent seizures rises to more than 70%. The cumulative risk of additional seizures after a third seizure is 66%, 70%, and 81% at one, two, and five years, respectively. As the risk of further seizures does not change after the third seizure, this supports the definition of epilepsy as the occurrence of two or more unprovoked seizures, said the authors.

The early identification of subjects who will go on to have many seizures is important for their management, as they may be candidates for antiepileptic drug therapy or for more aggressive treatment, noted the authors. In this cohort, 13% of the children had 10 or more seizures. However, previously published studies have shown that most children with a single unprovoked seizure do not experience a second seizure.

Although antiepileptic drug treatment reduced the risk of recurrence for the first three months (44% of children with recurrent seizure were treated), it was not associated with a benefit after more than three months. The authors also noted that "in our observational study, treatment did not influence the risk of having 10 or more seizures." However, they added that children with remote symptomatic seizures were more likely than children with cryptogenic first seizures to receive treatment after a first recurrence; children were also more likely to receive treatment after a first recurrence if it occurred within six months than if it occurred later.

The authors suggested that physicians considering antiepileptic drug therapy should weigh the relative risks of further seizures against the risks of such therapy. The risks of antiepileptic drug therapy "are quite different in children than in adults" noted the authors.

Editorialist Michael Duchowny, MD, emphasized that "the optimal management of seizure-prone children hinges as much on accurately determining underlying cause as characterizing seizure type and localizing anatomic origin." However, although etiology (and the risk of seizure recurrence) is useful in the selection of a therapy, "the benefit of early medical therapy may actually be short-lived, since there is no evidence to suggest that immediate treatment induces either earlier or sustained remission." Dr. Duchowny noted that although the study by Dr. Shinnar and colleagues contributes to the data on childhood epilepsy, having multiple seizures still does not define the choice of initial response to therapy, the odds of remission of established epilepsy, or prediction of medical intractability.

Suggested Reading
Duchowny M. Seizure recurrence in childhood epilepsy: "the future ain't what it used to be." Ann Neurol. 2000;48:137-139.
Shinnar S, Berg A, O'Dell C, et al. Predictors of multiple seizures in a cohort of children prospectively followed from the time of their first unprovoked seizure. Ann Neurol. 2000;48:140-147.

PATTERNS OF BRAIN ACTIVATION MAY PREDICT ALZHEIMER'S DISEASE

Functional magnetic resonance imaging (MRI) may help identify patterns of brain activation during tasks that require memory. Patterns of activation and genetic risk are potentially useful in predicting future cognitive decline, said the authors of a study in the August 17 New England Journal of Medicine.

The study was designed to determine the relation between brain activity during tasks that require memory and apolipoprotein (APOE) genotype. Apolipoprotein has three allelic variants (APOE*E2, APOE*E3, and APOE*E4). While APOE*E4 is associated with an increased risk for Alzheimer's disease, APOE*E2 may offer protection against the disease, noted the authors. Although APOE*E4 is associated with an increased risk for Alzheimer's disease, APOE genotyping per se, is not an accurate predictor for whether people will develop the disease.

The authors hypothesized that, in combination with APOE genotype, MRI could be used to predict decline in memory. Structural MRI could show medial temporal or cerebral atrophy, and functional imaging "may reveal more subtle alterations in brain function, perhaps before the emergence of mild memory impairment," explained the authors. Functional MRI reveals signal intensity linked to cerebral blood flow during cognitive or memory tasks. Thus, the authors hypothesized that a difficult task requiring memory would cause an increase in signal intensity in presymptomatic subjects at risk for Alzheimer's disease.

Potential subjects were recruited through advertisements. After screening, 30 neurologically normal subjects were included in the cohort, 16 of whom had the APOE*E4 allele (14 were heterozygous [APOE*E3/APOE*E4] and two were homozygous [APOE*E4/APOE*E4]) and 14 of whom were homozygous for the APOE*E3 allele (APOE*E3/APOE*E3). Memory was assessed with three standardized tests: the Consistent Long-Term Retrieval section of the Buschke-Fuld Selective Reminding Test, the Logical Memory portion of the Wechsler Memory Scale, and the Benton Visual Retention Test. Brain activity was assessed while the subjects memorized pairs of unrelated words and attempted to remember them during subsequent recall periods. The authors noted that memorizing unrelated pairs of words is particularly sensitive for the identification of damage to the medial temporal lobe.

The carriers of the APOE*E4 allele had lower scores on the delayed-recall test than did the carriers of the APOE*E3 allele. However, the APOE*E4 carriers also had a greater extent and intensity of activation in the left inferior frontal region, the right prefrontal cortex, the transverse temporal gyri bilaterally, and the left posterior temporal and inferior parietal regions. The increases were greater in the left hemisphere than in the right, added the authors. "The most plausible explanation for this pattern of response is that subjects at genetic risk for Alzheimer's disease use greater cognitive effort to achieve the same level of performance as subjects who are not at genetic risk," they said.

Suggested Reading
Bookheimer S, Strojwas M, Cohen M, et al. Patterns of brain activation in people at risk for Alzheimer's disease. N Engl J Med. 2000;343:450-456.

SPEED OF PROGRESSION FROM PROBABLE TO DEFINITE MULTIPLE SCLEROSIS

Following a diagnosis of probable multiple sclerosis, most patients with positive brain imaging will progress rapidly to clinically definite multiple sclerosis, according to a study in the July Archives of Neurology.

The seven-year prospective study was led by Anat Achiron, MD, and Yoram Barak, MD, of Bat Yam, Israel. It included 163 patients who were experiencing their first neurologic symptoms suggestive of multiple sclerosis and in whose brains magnetic resonance imaging (MRI) showed at least three demyelinating lesions. In this cohort, 83.4% of experienced at least one relapse and were thus defined as having clinically definite multiple sclerosis. In that subset, 57.6% had their first relapse within one year and 80% had it within three years. The 27 subjects who did not experience relapse were classified as having clinically probable multiple sclerosis. The authors noted that polysymptomatic involvement and a higher Expanded Disability Status Scale score at onset were significant risk factors for developing definite multiple sclerosis within one year.

The early diagnosis of multiple sclerosis is becoming of increasing importance, they said. They suggest that therapeutic management of multiple sclerosis be initiated after the first attack to reduce the rate of progression to clinically definite multiple sclerosis.

In an accompanying editorial, Elliot M. Frohman, MD, and Michael Racke, MD, of the University of Texas Southwestern Medical Center in Dallas, and Stanley van den Noort, MD, of Irvine, California, agreed that therapy should be initiated after the first episode of inflammatory demyelination to decrease the rate of progression to clinically definite multiple sclerosis. Such therapy would address clinically silent damage such as epitope spreading, diversification of T-cell memory responses, demyelination, axonal loss, and neurodegeneration, said the editorialists.

They noted, however, that Drs. Achiron and Barak may not have made a valid comparison between the effect of corticosteroid treatment in their study and the effect in other clinical trials, because corticosteroid treatment was delivered only to patients with more clinically severe multiple sclerosis.

The difficult decision to initiate therapy upon diagnosis of clinically definite multiple sclerosis may become easier, suggested Drs. Frohman, Racke, and van den Noort; two studies of the benefit of treatment for monosymptomatic multiple sclerosis are underway. Also, the authors believe that "the criteria for the diagnosis of multiple sclerosis may be expanded to include those [patients] with characteristic monosymptomatic demyelinating syndromes when ancillary evidence on MRI exists for previous disease activity."

Suggested Reading
Achiron A, Barak Y. Multiple sclerosis—from probable to definite diagnosis: a 7-year prospective study. Arch Neurol. 2000;57:974-979.
Frohman E, Racke M, van den Noort S. To treat or not to treat: the therapeutic dilemma of idiopathic monosymptomatic demyelinating syndromes. Arch Neurol. 2000;57:930-932.

A LOW-FAT DIET DOES NOT APPEAR TO IMPEDE NEUROLOGIC DEVELOPMENT IN CHILDREN

Despite worries of possible adverse effects of a low-saturated-fat, low-cholesterol diet on growth and development, children who adhered to such a diet showed neurologic development "at least as good as that of children in the control group," according to a prospective study in the August 23 issue of JAMA. Introducing nutritional principles of a low-fat diet to the care of young children can lessen age-associated increases in serum cholesterol and is compatible with normal psychosocial health, the researchers proposed.

A total of 1,062 seven-month-old infants were enrolled in the Special Turku Coronary Risk Factor Intervention Project (STRIP). Participants were randomly assigned to receive either normal health education counseling (controls) or counseling aimed at limiting the child's fat intake to 30% to 35% of daily energy, with a saturated:monounsaturated:polyunsaturated fatty acid ratio of 1:1:1 and a cholesterol intake of less than 200 mg/d. In practice, mothers in both groups continued breastfeeding for a mean five months, and solid foods were introduced at three to five months. All of the children were weaned by 13 months, the researchers noted. Dietary intake, growth, and serum lipid concentrations were regularly monitored, and a subset of 496 children underwent neurologic testing at five years of age.

The absolute and relative intakes of fat, saturated fatty acids, and cholesterol were consistently lower in the children of the counseled group than in the control children, the researchers reported. The children whose caregivers were counseled also consumed more linoleic and alpha-linolenic acids, they said, noting that these polyunsaturated fatty acids "are important for cognitive development and visual function." Correspondingly, serum cholesterol concentration was 3% to 6% lower throughout the trial period in the children whose caregivers were counseled.

The percentage of children who failed individual neurologic tests ranged from 0.4% to 35.9%. However, when the test results were combined into three major areas of cognition (speech and language; gross motor function and perception; and visual motor skills), the percentages of failures were quite uniform. Several details in performance may be uncovered using more extensive neuropsychologic testing, the researchers said, and they pointed out that it was impossible to perform more detailed testing in a trial this large.

It has been argued that fat-modified diets can be detrimental to a growing central nervous system. "Because 75% of brain growth is completed by age three years, the ability of the brain to recover from early nutritional deficiencies is limited," they said. "Growth has been affected in a few children who received extremely restricted, energy-deficient, unsupervised diets," the researchers acknowledged, but they pointed out that this study recommended a diet that "provides adequate amounts of energy and essential nutrients."

Individualized counseling that aims at reducing the consumption of saturated fat is effective and does not restrict the growth of children in their first five years, the researchers said. However, it remains to be seen whether adherence to a low-fat diet in childhood can indeed prevent atherosclerosis in adulthood.

Suggested Reading
Rask-Nissila L, Jokinen E, Terho P, et al. Neurological development of 5-year-old children receiving a low-saturated fat, low-cholesterol diet since infancy: a randomized controlled trial. JAMA. 2000;284:993-1000.

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