HUNTINGTON’S STUDY PROVIDES USEFUL LEAD, BUT NO NEW TREATMENT

A large-scale clinical trial testing the efficacy of two experimental treatments for Huntington’s disease failed to demonstrate significant improvement for patients. However, one of the drugs, coenzyme Q₁₀, did slow the progress of the disease, leading investigators to pronounce, “we’ve got something to chase.”

The trial, conducted by the Huntington Study Group under the guidance of Karl Kieburtz, MD, Professor of Neurology at the University of Rochester Medical Center, involved 347 patients in stage I or II of Huntington’s disease. The results were published in the August 14 Neurology. Patients were divided into four groups for a randomized, double-blind test of the efficacy of remacemide hydrochloride and coenzyme Q₁₀ on functional decline as measured by the Total Functional Capacity Scale. During the 30-month trial, one group received remacemide hydrochloride in 200-mg doses three times per day, the second received coenzyme Q₁₀ in 300-mg doses two times per day, the third received a combination of both drugs, and the fourth group received placebo.

After adjustment for variables, patients receiving remacemide as well as those receiving placebo “worsened by 2.74 units on the Total Functional Capacity scale.” While remacemide had “no appreciable effect on functional decline,” there was a suggestion that it might decrease chorea, though this was not verified to any degree of statistical significance.

Coenzyme Q₁₀ also failed to show a significant decrease in functional decline. However, after the first year of treatment, patients receiving coenzyme Q₁₀ “worsened at a slower rate (2.40 versus 2.74 units) and also showed a slower cognitive decline on two additional scales.”

A tangential trial, also published in the August 14 Neurology, showed coenzyme Q₁₀ supplementation to have a positive effect on myopathic coenzyme Q₁₀ deficiency. Two brothers who presented with “nonspecific myopathy, necrotic fibers, fiber hypotrophy, marked lipid accumulation in type I fibers, and reduction of respiratory chain activity” were treated with coenzyme Q₁₀ by S. Di Giovanni, MD, and colleagues from the Institute of Neurology at Catholic University, Rome. Initial daily doses of 150 mg, increased and maintained at 200 to 300 mg for eight months, resolved lipid storage, normalized levels of coenzyme Q₁₀, and increased the production of mitochondrial enzymes.

The study conducted by Dr. Di Giovanni’s group seems to support the theory that coenzyme Q₁₀ can indeed have an efficacious impact on the impairment of mitochondrial function such as is seen in Huntington’s disease. However, as C. W. Shults, MD, and A. H. V. Schapira, MD, observed in an accompanying editorial, there remain “issues to be resolved.”

The Huntington Study Group’s trial was inconclusive. While coenzyme Q₁₀ clearly has a retarding effect on the functional and cognitive impairment associated with Huntington’s disease, the results were deemed “not sufficient to warrant a recommendation for coenzyme Q₁₀ as a treatment” by the investigators. Dr. Kieburtz’s group cited an uncertainty as to whether their results could be repeated and sustained, as well as the “prohibitive financial costs” of the medication. Drs. Shults and Schapira applauded the investigators’ “appropriately conservative interpretation” and supported their position that further insights into the potential of coenzyme Q₁₀ in combating neuromuscular disease are both necessary and warranted.

Suggested Reading
1. Huntington Study Group. A randomized, placebo-controlled trial of coenzyme Q₁₀ and remacemide in Huntington’s disease. Neurology. 2001;57:397-404.
2. Di Giovanni S, Mirabella M, Spinazzola A, et al. Coenzyme Q₁₀ reverses pathological phenotype and reduces apoptosis in familial CoQ₁₀ deficiency. Neurology. 2001;57:515-518.
3. Shults CW, Schapira AHV. A cue to queue for CoQ? Neurology. 2001;57:375-376.

RESONANT RESULTS IN ANGIOGRAPHY OF TIGHT CAROTID STENOSIS

Because carotid endarterectomy is most effective in reducing the risk of ischemic stroke only in patients with severe carotid stenosis (80% to 99% stenosis), it is critical that imaging strategies be capable of distinguishing more than 80% stenosis from lesser degrees. Intra-arterial angiography is the acknowledged standard for such imaging, but it carries a risk of a permanently disabling stroke in patients with mild cerebrovascular disease that increases relative to degree of stenosis. Magnetic resonance angiography is an increasingly employed alternative, but its accuracy of reporting has been called into question in cases involving severe carotid stenosis.

According to J. M. Wardlaw, MD, “the greatest proportion of significant errors” between intra-arterial and magnetic resonance arteriograms occurs “in the tight stenosis/occlusion range.” Dr. Wardlaw and colleagues at the Department of Clinical Neurosciences of Western General Hospital, Edinburgh, UK, published the results of their investigation in the July Journal of Neurology, Neurosurgery, and Psychiatry. Forty-four patients referred for intra-arterial angiography were also administered magnetic resonance angiography. All patients had already undergone Doppler ultrasound showing a carotid stenosis of 70% or greater on the symptomatic side. There were no exclusion criteria beyond those contraindications standard to magnetic resonance imaging.

Two neurologists and two neuroradiologists read the magnetic resonance angiography results individually and blindly. Intra-arterial angiography results were read individually by two independent observers who were blind to symptoms and magnetic resonance angiography results. All observers agreed that there was no signal gap present in magnetic resonance angiography in 20 patients and that there was a signal gap in 11. In the remaining 12 patients, there was disagreement among observers about the presence of a signal gap.

Analysis determined that patients with signal gap coordinated with a range of 67% to 99% stenosis on intra-arterial angiography, with a mean 90% stenosis for those magnetic resonance angiography showing “definite signal gap.” The two measurements were most consistent in the range of 75% to 85% stenosis, but only if signal gaps were seen. The researchers added that magnetic resonance angiography “consistently overestimated the percentage stenosis,” leading them to assert that “signal gaps should be viewed cautiously, rather than automatically classifying them as tight stenoses.”

Additionally, the greatest proportion of clinically significant errors (7%) was recorded in the “tight stenosis” range. However, because “not all of the 7% will have a bad outcome caused by the wrong decision,” and some of the perceived magnetic resonance angiography errors may in fact reflect intra-arterial angiography misreadings, the researchers concluded that, weighed against the relative risks, magnetic resonance angiography is “overall probably safer.” They deferred a final judgment until a randomized clinical trial could be conducted.

Suggested Reading
Wardlaw JM, Lewis SC, Humphrey P, et al. How does the degree of carotid stenosis affect the accuracy and interobserver variability of magnetic resonance angiography? J Neurol Neurosurg Psychiatry. 2001;71:155-160.

STROKE LOCATION AND SUBTYPE ASSOCIATED WITH RISK OF SEIZURES

Lesion location and stroke subtype were found to be “strong determinants” of early seizure and status epilepticus risk in the setting of acute stroke, according to Daniel L. Labovitz, MD, and colleagues at Columbia University’s College of Physicians and Surgeons. Dr. Labovitz presided over a study designed to determine “the prevalence and determinants of seizures and status epilepticus within seven days of stroke onset.” Based on their results, he declined to recommend that the contraindication to the use of anticonvulsant therapies during stroke be lifted.

The researchers drew their cohort of 904 patients with incident first stroke from the Northern Manhattan Stroke Study. Data were collected through medical record review for “all hospitalized and nonhospitalized cases of first stroke in subjects older than 20 from July 1,1993 to June 30, 1997.” There were 704 cases of infarct, 150 cases of intracerebral hemorrhage, and 50 cases of subarachnoid hemorrhage.

Results were published in the July 24 Neurology. Early seizure, defined as any seizure occurring within seven days of stroke onset, was found in 37 patients. Seizure occurred at stroke onset in 15 patients, within 24 hours in 17 patients, and between 24 hours and seven days in five patients. Risk of early seizure was significantly elevated in patients with lobar intracerebral hemorrhage (14.3%) and in subarachnoid hemorrhage (8.0%) as compared with infarct (3.1%). Age, sex, race/ethnicity, hypertension, diabetes mellitus, current tobacco use, and alcohol abuse were not found to be predictors of early seizure.

Status epilepticus occurred in 10 patients, representing only 1.1% of the cohort but 27% of the early seizure suß-cohort. Neither intracerebral nor subarachnoid hemorrhages were significant predictors of status epilepticus when compared to infarct, though risk was elevated for lobar versus deep lesions.

Additionally, early seizure, lesion type and location, and age older than 69 were “all significant predictors of death within 30 days” of stroke onset. The relationship between early seizure and 30-day mortality persisted after adjustment for the other variables, prompting the researchers to suggest that early seizure increased the risk of death within 30 days, independent of underlying conditions. Despite their conclusions, however, they argued that, in the absence of data demonstrating the effectiveness of anticonvulsant therapies in the treatment of early seizure, prophylaxis with such medications during stroke should remain discontinued unless “the occurrence of a seizure might precipitate a lethal event.”

Suggested Reading
Labovitz DL, Hauser WA, Sacco RL. Prevalence and predictors of early seizure and status epilepticus after first stroke. Neurology. 2001;57:200-206.

HOW COMMON IS SINOVENOUS THROMBOSIS IN CHILDREN?

Sinovenous thrombosis in children affects primarily neonates and results in neurologic impairment or death in approximately half the cases, according to findings published in the August New England Journal of Medicine. The increasing rate with which sinovenous thrombosis is being diagnosed in children, and the lack of literature on children with sinovenous thrombosis, prompted the founding of a special registry designed to increase the understanding of the disorder’s epidemiology so that appropriate therapies can be developed.

Not all imaging is effective in diagnosing the disorder, but the usefulness of anticoagulant therapy in treating these patients is maintained, the study revealed.

The Canadian Pediatric Ischemic Stroke Registry was initiated in 1992 at the 16 pediatric tertiary care centers in Canada. According to the registry’s parameters, data were included on children (newborn to 18 years) with symptoms and radiographic confirmation of sinovenous thrombosis. The registry also obtained comprehensive prospective epidemiologic data on stroke, including sinovenous thrombosis, in children.

Large, population-based studies of the epidemiology of sinovenous thrombosis during childhood are needed, the authors believe, as extrapolating the results of studies of adults to children is of little value because of considerable age-related differences in the hemostatic, vascular, and neurologic systems. During the first six years of the registry, 160 consecutive children with sinovenous thrombosis were enrolled; the incidence was 0.67 cases per 100,000 children per year, and neonates were the most commonly affected age-group. Of those enrolled, 58% of children had seizures, 76% had diffuse neurologic signs, and 42% had focal neurologic signs.

There were age-related differences in the neurologic manifestations of sinovenous thrombosis, and specific risk factors were identified, including head and neck disorders (in 29%), acute systemic illnesses (in 54%), chronic systemic diseases (in 36%), and prothrombotic states (in 41%). Venous infarcts and the occurrence of seizures both predicted a poor neurologic outcome.

Antithrombotic agents were administered to 53% of the children overall, to 36% of the neonates, and to 66% of the non-neonates. Most children were treated for three months, and none died or had neurologic deterioration due to hemorrhagic complications. Anticonvulsant therapy was required by 74% of the neonates, as compared with 42% of the non-neonates. Neurologic deficits were present in 38% of the children, most commonly motor impairment, cognitive impairment, developmental delay, speech impairment, and visual impairment. Of the children, 8% died; half of the deaths were due to sinovenous thrombosis.

The registry was able to accumulate standardized data on the long-term neurologic outcome for 89% of the children. Although the long-term neurologic outcome of sinovenous thrombosis in children is not certain, this study’s findings were consistent with estimates that after a little more than two years, 77% of neonates and 52% of non-neonates are neurologically normal.

The registry also allowed the researchers to compare the accuracy of different radiographic tests used to diagnose sinovenous thrombosis in children. They found that computed tomography (CT) scans detected the disorder in only 84% of the children who also underwent magnetic resonance imaging (MRI) and magnetic resonance venography (MRV). Indeed, it has been suggested that CT scans may also have false-positive results in neonates. “At this time, the optimal technique for establishing the diagnosis in children is MRI with MRV,” the authors wrote.

Their research also suggests that anticoagulant therapy is not associated with serious hemorrhage in selected patients and that such therapy warrants further evaluation, particularly in neonates.

NR