AN HIV ETIOLOGY FOR A TREATMENT-RESPONSIVE ALS VARIANT?

A form of amyotrophic lateral sclerosis (ALS) is believed to be mediated by the human immunodeficiency virus (HIV-1). Characterized by an early onset and an unusually rapid extension of the disease, this variation of ALS has been shown to improve or even resolve after treatment with antiretroviral drugs.

Antoine Moulignier, MD, and colleagues at the Adolphe de Rothschild Foundation in Paris reported the results of their retrospective study on six cases of HIV-1–associated ALS-mimic syndrome in the September 25 Neurology. The patients, five white homosexual men and one African woman, mean age 34, were assessed to rule out causes for the motor neuron disease other than HIV-1 infection. Anti-HIV therapy was initiated; follow-up lasted at least two years in five of the six patients.

There was a “positive association between a healthier immune system induced by anti-HIV therapy, a reduction of HIV viral load, and neurologic improvement” in the ALS-mimic syndrome symptoms. Dr. Moulignier postulated that “the ALS-like disorder was probably driven by increased levels of viral replication in the central nervous system or the cerebral spinal fluid and improved with the clearance of HIV-1 RNA.” The cases suggest that the association between some motor neuron diseases and HIV infection is indeed pathogenic, he added.

An additional study by D. J. L. MacGowan, MD, et al from Beth Israel Medical Center, New York, followed a 32-year-old woman presenting with a rapidly progressive ALS-mimic syndrome. She was found to be HIV positive, and other causes for the motor neuron disease symptoms were eliminated. Three weeks after presentation, the patient was “anarthric, bed-bound, quadriparetic, and required enteral nutrition.” Treatment was initiated with three antiretroviral drugs (nelfinavir, zidovudine, and lamivudine). Six months later, the patient was “walking with assistance, could swallow and speak normally, and had regained all lost weight.” Four years later, her examination was normal. The results of Dr. MacGowan and colleagues’ work were also published in the September 25 Neurology.

According to Burk Jubelt, MD, from the SUNY Upstate Medical University, Syracuse, and Joseph R. Berger, MD, of the University of Kentucky Medical Center, Lexington, both studies support the possibility of a viral etiology for some forms of ALS. In their accompanying editorial, however, Drs. Jubelt and Berger noted that alternatives are still possible. “One could argue that an unknown, opportunistic virus that directly infects motor neurons caused these ALS syndromes, which then improved after immunologic recovery attending antiretroviral therapy,” they observed. Drs. Jubelt and Berger called for “continued investigations” into these possibilities, but agreed that “when a patient presents with the classic clinical signs of ALS, a viral cause should be considered because HIV-ALS syndromes are treatable.”

Suggested Reading
1. Moulignier A, Moulonguet A, Pialoux G, Rozenbaum W. Reversible ALS-like disorder in HIV infection. Neurology. 2001;57:995-1001.
2. MacGowan DJL, Scelsa SN, Waldron M. An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy. Neurology. 2001;57:1094-1097.
3. Jubelt B, Berger JR. Does viral disease underlie ALS? Lessons from the AIDS pandemic. Neurology. 2001;57;945-946.

AED-RELATED BONE DISEASE UNRECOGNIZED BY MANY NEUROLOGISTS

Most neurologists do not consider the problem of antiepileptic drug (AED)–related bone disease to be of clinical importance, and so they rarely administer prophylactic calcium and vitamin D supplements for their patients. However, of the few physicians who do screen patients and find bone disease, most either treat their patients or refer them to specialists, according to a study in the September Archives of Neurology.

Cassandra Valmadrid, MD, and colleagues proposed two reasons why some neurologists might not focus on AED-induced bone disease: lack of familiarity with the relevant literature and uncertainty as to whether skeletal effects of AEDs are clinically important. In their study, the researchers evaluated the practice patterns of 404 pediatric and 624 adult neurologists regarding their methods of screening for bone disorders and recommendations for treatment and prophylaxis. The investigators found that a higher proportion of pediatric (about 41%) than adult (about 28%) neurologists screen for AED-induced bone disease. This difference might reflect greater experience in the treatment of epilepsy, because pediatric neurologists treat more patients with seizures and more often subspecialize in epileptology.

Of physicians who detected bone disease through diagnostic testing, 40% of pediatric and 37% of adult neurologists prescribed calcium or vitamin D, and about half (54% of pediatric and 57% of adult neurologists) referred patients to specialists. Few (9% of pediatric and 7% of adult neurologists) prescribed prophylactic calcium or vitamin D for patients taking AEDs. Adult neurologists commonly prescribed phenytoin, and pediatric neurologists tended to avoid administration of this drug. The researchers suggested that this may be related more to apprehension about adverse cosmetic effects in children with long-term use of phenytoin than to concern about skeletal effects.

“Because there are no official recommendations for calcium and vitamin D therapy in AED-treated individuals, it would be prudent for now to follow recommendations issued by the Institute of Medicine for daily calcium and vitamin D intake in the general population,” according to the researchers. They further advised that “a well-controlled prospective study is needed to determine the precise effects of AEDs on bone, the benefits of screening, and the effects of prophylaxis with calcium and vitamin D.”

In an accompanying editorial, Howard J. Heller, MD, and Khashayar Sakhaee, MD, said that the study by Valmadrid and colleagues “emphasizes the need to educate clinicians about the skeletal impact of anticonvulsant therapy. Specific monitoring and treatment guidelines should be developed and tested in clinical trials.”

Suggested Reading
1. Valmadrid C, Voorhees C, Litt B, Schneyer CR. Practice patterns of neurologists regarding bone and mineral effects of antiepileptic drug therapy. Arch Neurol. 2001;58:1369-1374.
2. Heller HJ, Sakhaee K. Anticonvulsant-induced bone disease: a plea for monitoring and treatment. Arch Neurol. 2001;58:1352-1353.

BLOOD-PRESSURE LOWERING REGIMEN REDUCES STROKE RISK

Blood pressure, a known determinant of stroke risk in individuals with cerebrovascular disease, may provide the means of preventing such insults. So concluded the perindopril protection against recurrent stroke study (PROGRESS), a four-year examination of the effects of lowering blood pressure in hypertensive and normotensive patients with a history of stroke or transient ischemic attack. Study results appeared in the September 29 Lancet.

A cohort of 6,105 individuals (mean age, 64) from 172 centers in Asia, Australasia, and Europe were randomly assigned to receive active treatment or placebo. Active treatment consisted of the angiotensin-converting-enzyme inhibitor perindopril (4 mg daily) either alone or in conjunction with the diuretic indapamide. Of the 3,051 participants assigned active treatment, 1,281 received single-drug therapy and 1,770 received the combination. The 3,054 placebo controls were divided into single (1,280 individuals) or double (1,774 individuals) placebo and matched to the corresponding active treatment group.

Participants were followed for four years through regularly scheduled clinical visits. The only qualification for participation was a history of stroke. The primary outcome was occurrence of fatal or non-fatal stroke. After adjustment for variables, statistical analysis revealed a reduction in blood pressure on an average of 9/4 mm Hg among those in the active treatment group, and a reduction in relative risk of stroke of 28% (307 versus 420 incidents) as compared to those in the placebo group. There were similar reductions in the risk of stroke for both hypertensive and non-hypertensive subgroups.

However, the combination active treatment was largely responsible for the positive results, reducing blood pressure by 12/5 mm Hg and stroke risk by 43%, as compared with the 5/3 mm Hg and 5% respective reductions garnered by perindopril when taken without indapamide. This finding led researchers in the PROGRESS group to suggest that “treatment with these two agents should be considered routinely for patients with a history of stroke or ischemic attack, irrespective of their blood pressure.”

In an accompanying commentary, Jan A. Staessen, MD, and Jiguang Wang, MD, of the University of Leuven, Belgium, questioned the ease with which the PROGRESS findings might be implemented as guidelines for clinical practice. According to Drs. Staessen and Wang, shortcomings in the PROGRESS study include a threshold of systolic hypertension “20 mm Hg higher than the definition of normotension in recent consensus documents”; a failure to define the level to which blood pressure should be lowered; and an inability to extrapolate the findings to patients with occlusive or stenotic disease, whose “risk of infarct is substantially raised.”

Additionally, PROGRESS reported a negligible impact on stroke reduction for perindopril alone. Because of the often prohibitive cost of such drugs, this finding led Drs. Staessen and Wang to advise that their efficacy as compared to diuretics be better evaluated before they are adopted as “agents for the secondary prevention of stroke.”

Suggested Reading
1. Staessen JA, Wang J. Blood-pressure lowering for the secondary prevention of stroke. Lancet. 2001;358:1026-1027.

ESTROGEN MAY PROVIDE PROTECTION AGAINST PARKINSON'S DISEASE

Indications that estrogen may indeed play a role in the etiology of Parkinson’s disease gained strength with the publication of a study conducted at the Mayo Clinic. The hormone was targeted because of previously recorded observations of a higher incidence of Parkinson’s disease in men than in women at all ages, as well as its possible influence on other neurodegenerative disorders such as Alzheimer’s disease. Researchers hypothesized that “there is an increased risk of Parkinson’s disease in conditions causing an early reduction in endogenous estrogen.”

In an exploratory, case-control study, Walter Rocca, MD, and colleagues in the Department of Neurology at Mayo Clinic in Rochester, Minnesota, compared medical records and phone interviews for a cohort of 144 resident women in Olmstead County, Minnesota. Seventy-two women with at least two of the four cardinal signs of parkinsonism (rest tremor, bradykinesia, rigidity, and impaired postural reflexes), responsiveness to levodopa, and no other cause for the symptoms were age-matched against 72 randomly selected controls who were healthy in terms of the parkinsonism criteria.

Statistical analysis of the data compiled from the cohort revealed that hysterectomy without bilateral oophorectomy was more common in patients with Parkinson’s disease (18%) than in controls (7%). Unilateral oophorectomy and contralateral partial removal of the remaining ovary were also more frequent in case subjects. Age at menopause was younger in cases (median, 49) than in controls (median, 50) and the frequency of estrogen use for at least six months after menopause was higher in control subjects (14%) than in cases (8%). However, none of the findings for age at menopause or postmenopausal estrogen use were statistically significant.

Dr. Rocca and colleagues observed that their findings were the first to link Parkinson’s disease and hysterectomy and are at the least highly suggestive of a “real and causal” association between estrogen and Parkinson’s disease. Though aware of the statistical limitations imposed on their results because of the small study population, the researchers feel the potential etiological relationship between hormones and Parkinson’s disease merits further attention. “The hypothesis needs to be confirmed in a larger study,” said Dr. Demetrius Maraganore, one of the authors, “to better determine the possibilities of estrogen replacement therapy in postmenopausal women with Parkinson’s disease, and also to learn whether translational applications to men with or at an increased risk of Parkinson’s disease might exist.”

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