A SEIZURE ALERT SYSTEM?

Real-time electroencephalogram (EEG) recordings can signal a seizure minutes before onset, according to a review of 26 recordings taken from patients with temporal lobe epilepsy. Although their results are preliminary, researchers are envisioning a seizure alert system that can warn patients of an imminent seizure as well as provide an opportunity for early intervention.

The study included 23 patients with refractory temporal lobe epilepsy who required continuous scalp EEG recording and video monitoring. Five patients also had intracranial electrodes that recorded activity within the amygdala, hippocampus, and the temporo-occipito–cortical junction. The researchers compared EEG dynamics between recordings taken at distant moments in time. This relative measure reduces noise and artifacts and is fast enough to be carried out in real time, they explained. Seizure onset was defined by the appearance of symptoms such as aura sensation or by electrographic criteria such as localized, sustained, rhythmic discharges greater than 2 Hz in frequency.

Changes in scalp EEG activity allowed the anticipation of a seizure in 25 of 26 cases, the researchers reported in the January 20 Lancet. Persistent deviations were recorded a mean seven minutes before the earliest clinical or overt EEG signs of the seizure, they explained. For the patients with both scalp and intracranial recordings, the time course of preictal changes prior to a seizure were similar.

The preictal changes frequently showed a "widespread topography that projected beyond the limits of the epileptogenic temporal lobe," the researchers noted. Neuroimaging studies, which have shown preictal modifications around 10 minutes before temporal-lobe seizures, have also reported large changes in blood flow in both the epileptogenic and contralateral nonepileptogenic neocortices, they pointed out, consistent with a widespread perturbation of brain perfusion before seizure onset.

The ability to anticipate seizure with scalp EEG monitoring has practical implications for patients with uncontrolled epilepsy, the researchers said. If proven reliable, this method can be used at home or in a hospital setting. Early detection and treatment, they said, can lower the medical consequences of seizures and improve patients' quality of life.

Although further study of this "transition phase" prior to a seizure may provide new insights into the pathophysiology or reveal new treatment strategies or criteria for surgical selections, direct clinical application to suppress seizures in patients with epilepsy will not be easy, observed David R. Fish, MD, in an accompanying commentary. Currently available antiepileptic therapies have only limited ability to produce immediate effects, and the patients would be subjected to lifelong EEGs, he pointed out. Nevertheless, implantable recording devices combined with intracranial drug delivery or stimulation systems could be developed, he concluded.

Suggested Reading
1. Fish D. Anticipation of epileptic seizures from standard electro-encephalographic recordings. Lancet. 2001;357:160-161.
2. Le Van Quyen M, Martinerie J, Navarro V, et al. Anticipation of epileptic seizures from standard EEG recordings. Lancet. 2001;357:183-188.

PESTICIDE EXPOSURE LINKED TO PARKINSON'S DISEASE

The combination of two widely used agricultural chemicals reproduced behavioral and neuropathologic features of Parkinson's disease in a mouse model, according to a study published in the December 15 Journal of Neuroscience.

Exposure to the combination of paraquat (an herbicide) and maneb (a fungicide) caused greater detrimental effects on the nigrostriatal dopaminergic system than either toxin alone. Multiple concurrent exposure to these agricultural chemicals appears to have additive and irreversible effects in mice, said the researchers.

This study is among the first to examine the effects of pesticide combinations. Current safety regulations are based on the effects of single toxins; but "in the real world, we're exposed to mixtures of chemicals every day," said Deborah Cory-Slechta, PhD. There is a geographic overlap in usage patterns of paraquat (1,1'-dimethyl-4,4'-bipyridinium) and maneb (manganese ethylenebis[dithiocarbamate]) on farms across the United States, the researchers pointed out, and they noted that multiple chemical residues have been found in foods.

In this study, male mice were injected with saline, paraquat (10 mg/kg), maneb (30 mg/kg), or a paraquat-maneb combination over a period of six weeks. Maneb, but not paraquat, caused an immediate reduction in locomotor activity that completely resolved within 24 hours. This effect was potentiated by combination treatment. By the end of the study, however, mice in the combination group lost the ability to recover motor activity.

Continuous exposure to the toxins increased the magnitude of pathologic effects, the researchers said. A combination of both toxins, but neither alone, reduced levels of tyrosine hydroxylase, decreased dopamine transporter immunoreactivity, and produced reactive gliosis selectively within the striatum. These findings suggest that the combination of paraquat and maneb may be an "environmental analog of the methamphetamine model of Parkinson's disease," the researchers proposed. This study offers compelling evidence that environmental factors may play a role in the etiology of Parkinson's disease, they concluded.

In a related study published in the December Nature Neuroscience, the pesticide rotenone induced behavioral and neuropathologic features of Parkinson's disease in rats. "This remarkable observation not only provides a new animal model for the study of Parkinson's disease, but will also reinvigorate interest in the possible role of exposure to pesticides and other toxins as a cause of human neurodegenerative disease," said Benoit I. Giasson and Virginia M-Y Lee in an accompanying commentary.

Long-term intravenous administration of rotenone (2 to 3 mg/kg/day) in rats produced motor deficits characteristic of Parkinson's disease including bradykinesia, postural instability, unsteady gait, and some evidence of tremor, the researchers reported. Rotenone acts on the mitochondrial complex I found uniformly throughout the brain; however, neurodegeneration was limited to the nigrostriatal dopaminergic system, they said. Histologic examination of surviving nigral neurons revealed the appearance of intracytoplasmic a-synuclein-rich inclusions similar to Lewy bodies. The researchers concluded that the substantia nigra may be vulnerable to progressive oxidative damage by rotenone exposure.

Suggested Reading
1. Betarbet R, Sherer TB, MacKenzie G, et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci. 2000;3:1301-1306.
2. Giasson BI, Lee VM. A new link between pesticides and Parkinson's disease. Nat Neurosci. 2000;3:1227-1228.
3. Thiruchelvam M, Richfield EK, Baggs RB, et al. The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson's disease. J Neurosci. 2000;20:9207-9214.

THIAZIDE DIURETICS, ANTIHYPERTENSIVES, AND RISK OF STROKE

The absence of a thiazide diuretic in antihypertensive drug regimens was associated with an 85% increased risk of ischemic stroke when compared with regimens that included the use of a thiazide diuretic, according to a population-based study of hypertensive patients published in the January 8 Archives of Internal Medicine. These results support the use of thiazide diuretics as first-line antihypertensive agents, the researchers said.

In an attempt to assess the association between antihypertensive drug therapy and incident ischemic stroke, researchers identified patients with hypertension (age 30 to 79) who had enrolled in the Group Health Cooperative of Puget Sound, a large health maintenance organization with more than 400,000 members in western Washington State. Information regarding patients' demographics, health habits, cardiovascular risk factors, and comorbidities were abstracted from medical records or obtained from telephone interviews. The pharmacy records were used to assess the type, dose, and quantity of drug dispensed. The cohort consisted of 380 treated hypertensive patients who had an ischemic stroke between July 1, 1989 and December 31, 1996, and 2,790 treated hypertensive patients without a history of stroke.

Among those without a history of cardiovascular disease, the adjusted risk of stroke was 2.03- to 2.79-fold higher among users of single-drug therapy with ß-blockers, calcium channel blockers, or angiotensin-converting enzyme (ACE) inhibitors than among users of a thiazide diuretic alone. When a thiazide diuretic was used in combination with another antihypertensive drug, the risk of stroke was similar to that of the diuretic alone. Combination therapy that did not include a thiazide diuretic, however, was associated with a 2.48-fold increase in the risk of stroke compared with the use of a thiazide diuretic alone.

Among patients with a history of cardiovascular disease, the association between diuretic use and lowered risk of ischemic stroke was less pronounced, the researchers said.

A second analysis, which adjusted for potential confounding factors, confirmed the decreased risk of stroke in thiazide diuretic users without a history of cardiovascular disease. Additional adjustment for education level, marital status, duration of treated hypertension, treated diastolic blood pressure, pretreatment diastolic blood pressure, body mass index, physical activity, glucose and potassium levels, and use of alcohol had "trivial effects" on the findings, the researchers said. The results were "virtually the same" for the use of thiazide diuretics below, at, or above the daily modal dose (25 mg for hydrochlorothiazide, 25 mg for chlorthalidone, and 5 mg for metolazone), they added.

The findings of this observational study were consistent with those of the Heart Attack Primary Prevention in Hypertension (HAPPHY) trial, the Medical Research Council trial, and the Captopril Prevention Project trial, which linked thiazide diuretics to reduced stroke risk over other antihypertensive drug therapies.

Although the mechanism is unclear, the researchers suggested that thiazide diuretics may decrease the risk of stroke by its effect on systolic blood pressure. Systolic blood pressure may be more strongly associated with the occurrence of stroke than is diastolic blood pressure, and diuretics may be more effective than other antihypertensive drugs in lowering systolic blood pressure, they proposed. Reevaluation of previous clinical trials as well as future studies are needed to clarify the role of diuretics in stroke prevention, they concluded.

Suggested Reading
Klungel OH, Heckbert SR, Longstreth WT Jr, et al. Antihypertensive drug therapies and the risk of ischemic stroke. Arch Intern Med. 2001;161:37-43.

HYPERTENSION, DIABETES MELLITUS LINKED TO COGNITIVE DECLINE IN MIDDLE AGE

Hypertension and diabetes mellitus were positively associated with cognitive decline over six years in a late middle-aged population. "It probably wasn't even enough for the participants to notice any change in their mental abilities," said lead author David Knopman, MD. "But it shows that diabetes and high blood pressure start affecting cognitive abilities as early as late middle age. If these diseases can be treated early—before age 60—it might lessen the burden of cognitive problems in later life."

The cohort of this study is the youngest in which a longitudinal association of cardiovascular risk factors with neuropsychologic decline has been documented, noted the authors. A recent study that enrolled participants between age 59 and 71 demonstrated an association between hypertension and cognitive decline over a four-year period. Similar associations have been noted in older populations (ie, the Cardiovascular Heart Study, the Honolulu Heart Study, the Rotterdam Study, the Framingham Heart Study, and the Göteborg Longitudinal Study).

The present study—Atherosclerosis Risk in Communities (ARIC)—is a population-based, multisite study of 10,963 individuals (8,729 white; 2,234 black) who were between age 45 and 64 at enrollment (between 1987 and 1989). Follow-up ranged from 3.6 to 8.8 years. Cognitive assessments included the delayed word recall test, the digit symbol subtest of the Wechsler Adult Intelligence Scale-Revised (WAIS-R), and the first-letter word fluency test. Participants were assessed for cardiovascular risk factors: hypertension, prevalent diabetes mellitus, and hyperlipidemia. Nonsteroidal anti-inflammatory drug (NSAID) use was also determined.

Diabetes at baseline was associated with greater decline in scores on both the digit symbol subtest and the word fluency test, even among participants younger than age 58. Hypertension was associated with a greater decline in digit symbol subtest scores than in other subtest scores. The study did not show an association between smoking status, carotid intima-media wall thickness, hyperlipidemia, or use of NSAIDs.

The authors noted that change on the digit symbol subtest scores was more strongly associated with risk factors than was change on the other subtest scores. "Because it is a timed test, it may be more sensitive to subcortical vascular lesions in the striatum and in cortico-cortical and cortico-subcortical pathways," they said. The study did not address the mechanism by which hypertension and diabetes mellitus impair cognition. "It could be due to microinfarctions … in the brain's white matter," suggested Dr. Knopman.

Dr. Knopman led the study while at the University of Minnesota; he is currently a neurologist at Mayo Clinic in Rochester, Minnesota.

Suggested Reading
Knopman D, Boland LL, Mosley T, et al. Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology. 2001;56:42-48.

WHO FOLLOWS DOCTORS' ORDERS?

Surprisingly, disease severity is not necessarily an important factor in adherence to (or compliance with) medical instructions, according to a recent study of 119 children with epilepsy. Rather, a combination of sociocultural factors predicted who kept scheduled appointments or took the prescribed medication. "This study found little support for several common prejudices and beliefs regarding patient adherence," researchers said in the December Epilepsia.

Families with parents who had less education, who had a lower income, who did not speak English at home, and who were recent immigrants were more likely to keep appointments and avoid unscheduled contact with physicians or medical staff, according to the study authors. Families reporting higher levels of stressful life events were also more likely to adhere to treatment, indicated the study conducted at the Children's Hospital of Los Angeles.

In contrast, seizure frequency, duration, and previous treatment failures did not contribute to treatment adherence. "In effect, adherence was equally likely in the face of long-standing refractory or severe epilepsy or new-onset epilepsy with only a few reported seizures," they observed. Seizure severity, they recognized, may indirectly affect other measures such as patient behavior.

For children exhibiting behavioral problems, both mediation and visit adherence were lower, the researchers continued. "Parents with the additional stress of managing a child who they perceive as overactive, inattentive, or uncooperative may have substantially more difficulty attending visits on schedule," they speculated.

In an attempt to provide a complete picture of the motivations for treatment adherence, the researchers created a model that grouped individual measures of medical, behavioral, and psychosocial data into conceptual domains. For example, the acculturation domain took into account education, nativity, nationality, and primary language. In addition, they evaluated adherence using three separate measures. Parental reports of medication adherence did not reflect adherence as judged by patient serum anticonvulsant levels, the researchers pointed out. Similarly, patients who kept their appointments were no more likely to have appropriate serum drug levels than were those who did not keep appointments. This underscores the need for using multiple measures to "capture the full spectrum of clinically meaningful indicators," the researchers said.

Nonadherence to therapy affects a broad range of illnesses, the researchers said, and they advised physicians to consider sociocultural and environmental factors in addition to medical factors when prescribing treatment.

NR