IS VAGUS NERVE STIMULATION ASSOCIATED WITH SLEEP APNEA?

Vagus nerve stimulation (VNS), a therapy for refractory epilepsy, is associated with adverse changes in respiration during sleep, according to B. A. Malow, MD, of the University of Michigan Medical School, in Ann Arbor, and colleagues.

Vagus nerve stimulation has been associated with respiratory symptoms such as dyspnea and voice alteration in humans; in animal studies, it has caused respiratory arrest, noted Dr. Malow and colleagues, whose pilot study of the effect of VNS on four patients with medically refractory epilepsy is in the November 28 Neurology.

"All patients showed consistent sleep-related decreases in airflow and effort coinciding with VNS activation, although most events did not meet laboratory criteria for apneas or hypopneas," said Dr. Malow. She noted that respiratory changes were clinically significant for the one patient with preexisting obstructive sleep apnea (OSA) and that, to such patients, VNS should be administered with care. "Lowering VNS stimulus frequency or prolonging off-time may prevent exacerbation of OSA," concluded the authors.

Breathing patterns during sleep may be altered through either central or peripheral mechanisms, suggested the authors. Peripheral stimulation of vagal afferents may alter neuromuscular transmission to the upper airway muscles of the pharynx and larynx to restrict the upper airway. Also, central stimulation may restrict upper airway musculature and alter frequency of breathing, tidal volume, and minute ventilation. The authors also noted that VNS increases REM sleep, which is "a vulnerable state for sleep disordered breathing."

Sleep apnea may affect up to one third of patients with medically refractory epilepsy, said Dr. Malow and colleagues. Such patients may benefit if treatment of sleep apnea reduces sleep fragmentation or arousals from sleep, suggested the authors. Care should be taken through minimizing stimulus frequency and minimizing stimulation activations to reduce sleep apnea. If moderate to severe apnea persists, "it may be advisable to treat sleep apnea with continuous positive airway pressure, oral appliances, surgery, positional therapy, or weight loss," said the authors.

Suggested Reading
Malow BA, Edwards J, Marzec M, et al. Effects of vagus nerve stimulation on respiration during sleep: a pilot study. Neurology.2000;55:1450-1454.

FETAL CELL GRAFTS OFFER PROMISE TO HUNTINGTON'S DISEASE PATIENTS

Transplantation of fetal tissue has produced motor and cognitive improvements in three patients with Huntington's disease, according to a pilot study in the December 9 Lancet.

Five patients with mild to moderate Huntington's disease were selected to undergo intrastriatal transplantation of human fetal tissue. At the beginning of the study, the patients had shown clinical symptoms (eg, chorea and other symptoms such as sweating, dystonia, falls, tiredness, and slowness of thinking and acting) for two to seven years. Fetal neuroblasts were grafted in the patients' right striatum and then, after a year, in the patients' left striatum. The results of neurologic, physiologic, and psychiatric assessments were compared with those for a control group of 22 untreated patients at similar stages of the disease.

Motor and cognitive functions, as well as the ability to perform daily activities, either were maintained or improved in three of five patients who underwent the fetal cell transplantation. The positive changes concerned general function, bradykinesia and chorea, and attention and executive functions, the researchers said. Patient 1 improved on the Mattis Dementia Rating Scale, Trail-Making Test A, verbal fluency, and articulatory rate. Patient 2 improved in the symbol digit codes and Trail-Making Test A and B. Patient 3 gained in the Mini Mental State Examination but declined in the Mattis Dementia Rating Scale and Trail-Making Test A.

At the final assessment, the three patients could perform activities such as cycling, mowing the lawn, and taking their children to school. "Relatives indicated that patients were intellectually much more 'present,' [were] physically much fitter, and got weary less quickly," the researchers said.

Accordingly, the three patients showed increased metabolic activity in various subnuclei of the striatum on final positron emission tomography (PET) and magnetic resonance imaging (MRI) assessments. Decreased metabolic activity in the striatum was seen in the other two patients, they pointed out. Taken together, this indicated that the survival of the grafts accounted for the clinical improvements, they said.

It is difficult to assess clinical improvement since the symptoms among patients with Huntington's disease are "diverse and evolve over time in a heterogeneous manner," the researchers acknowledged. They are currently planning a multicenter trial that will include a greater number of patients. The protocol will be in accordance to the Core Assessment Program for Intracerebral Transplantation in Huntington Disease (CAPIT-HD), a program that aims to establish the conditions under which each treated patient can be used as his or her own control.

According to a commentary written by Olle Lindvall and Anders Björklund, professors from the Wallenberg Neuroscience Center, Lund University, Sweden, this study provides the "first evidence that intrastriatal grafts of tissue taken from the human fetal striatum can survive and induce measurable functional improvement in patients with Huntington's disease."

Although these findings are promising, the clinical usefulness of cell-replacement therapy for Huntington's disease remains unclear. "Whether the striatal transplants can survive and function long enough to prevent further clinical deterioration remains to be seen," they said. Reconstruction of the striatal circuitry alone may be insufficient, they said, because of extensive and progressive degeneration associated with the disease course. They agreed that further trials are needed before fetal cell grafts can be considered a viable option in the treatment of Huntington's disease.

Suggested Reading
1. Bachoud-Lévi A-C, Rémy P, Nguyen J-P, et al. Motor and cognitive improvements in patients with Huntington's disease after neural transplantation. Lancet. 2000;356: 1975-1979.
2. Lindvall O, Björklund A. First step towards cell therapy for Huntington's disease. Lancet.2000;356:1945-1946.

ARE SPOUSES OF PATIENTS WITH MULTIPLE SCLEROSIS ALSO AT RISK?

A recent study found no evidence to support the theory that multiple sclerosis may be caused by a transmissible or infective agent. G.C. Ebers, MD, of the University of Oxford, UK, and colleagues reported their findings in the December Annals of Neurology.

Ebers and colleagues used data collected as part of the Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (a population-based study of more than 15,504 patients with multiple sclerosis) to evaluate the incidence of multiple sclerosis in spouses of people with multiple sclerosis; a higher incidence in this population could imply that multiple sclerosis is associated with an infectious agent transmitted in adulthood. The study also evaluated the incidence of multiple sclerosis in the children of conjugal couples with multiple sclerosis; a higher incidence in this population could suggest the genetic transmission of multiple sclerosis, explained the authors.

Of the 13,550 spouses (currently married, divorced, widowed, separated, or common-law) of study probands, only 23 had multiple sclerosis. This crude conjugal rate (0.17%) was not significantly different than the lifetime prevalence rate of the general population (0.2%), said Dr. Ebers and colleagues. "We therefore believe that there is no increased risk to spouses of MS patients," said Dr. Ebers. This conclusion is supported by conjugal data from the United Kingdom, according to the authors.

The study also identified 26 conjugal pairs in which both members had multiple sclerosis. Six of the 49 offspring of these pairs had clinically definite multiple sclerosis, so their crude risk of multiple sclerosis was 12.2%. The crude risk of multiple sclerosis among individuals who had only one parent with multiple sclerosis was 0.7%. Both of these rates are higher than the lifetime risk of multiple sclerosis in the general population (0.2%). Although these data indicate a genetic component to the incidence of multiple sclerosis, the concordance rate in children of two parents with multiple sclerosis is not 100%. "If alleles producing MS susceptibility were largely recessive and identical by state, we would expect the risk for offspring of conjugal matings to rise substantially, as offspring should be all homozygous at such loci," said Dr. Ebers and colleagues. Therefore, not only genetic factors but also environmental factors could be involved, they said. Environmental factors that are thought to increase the risk of multiple sclerosis include chemicals, microbes, and radiation.

"The data fit with the paradigm of MS being a disease of both genes and environment; but the environmental factors are not operating at the microenvironmental level, but at a broader, population level," concluded Dr. Ebers.

Suggested Reading
Ebers GC, Yee IML, Sadovnick AD, Duquette P. Conjugal multiple sclerosis: population-based prevalence and recurrence risks in offspring. Canadian Collaborative Study Group. Ann Neurol.2000;48:927-931.

STRATIFIED VERSUS STEP CARE FOR ACUTE MIGRAINE

The findings of a controlled study of step care strategies for acute migraine treatment, by Richard Lipton, MD, and colleagues, are wholly consistent with the recommendations of the United States Headache Consortium (USHC), said David B. Matchar, MD, and colleagues in an editorial in the November 22 JAMA.

Step care for acute migraine is the initial treatment of migraine with the least expensive therapies, followed by more expensive, migraine-specific therapies when the initial treatment proves ineffective. In 1999, the USHC recommended the earlier use of migraine-specific therapies. The decision was based on "general humanistic principles that favor minimizing patient morbidity" rather than on controlled trials, because no such trials had yet been done, said Dr. Matchar and colleagues.

Dr. Lipton and colleagues studied a cohort of 835 adult migraine patients with a Migraine Disability Assessment Scale (MIDAS) grade of II, III, or IV. For their next six migraine attacks, the patients were randomized to receive step care across attacks (n = 271), a step care within attacks (n = 285), or stratified care (n = 279).

In step care across attacks, migraines were initially treated with aspirin (800 to 1000 mg) and metoclopramide (10 mg); if two of the first three attacks were not controlled with this treatment, zolmitriptan (2.5 mg) was used for the remaining three attacks. In step care within attacks, patients received aspirin (800 to 1000 mg) and metoclopramide (10 mg) for all attacks; patients who did not respond within two hours were then given zolmitriptan (2.5 mg). In stratified care, patients who had a MIDAS grade of II were treated with aspirin (800 to 1000 mg) and metoclopramide (10 mg) and patients with a MIDAS grade of III or IV were treated with zolmitriptan (2.5 mg).

The stratified care group showed a greater headache response (52.7%) at two hours across six attacks than did either the step care across attacks group (40.6%) or the step care within attacks group (36.4%) showed. The stratified care group also reported less disability time than the other two groups reported. Although there was a higher incidence of adverse events in the stratified care group, most events were mild to moderate, said Dr. Lipton and colleagues. "The next step," concluded Dr. Matchar and associates, "is to translate this evidence into practice."

Suggested Reading
1. Lipton RB, Stewart WF, Stone AM, et al. Stratified care vs step care strategies for migraine: the Disability in Strategies of Care (DISC) study: a randomized trial. JAMA.2000;284:2599-2605.
2. Matchar DB, McCrory DC, Gray RN. Toward evidence-based management of migraine. JAMA.2000;284:2640-2641.

INSULIN PRECURSOR LINKED WITH INCREASED STROKE RISK

High proinsulin levels may act as a sensitive marker for cardiovascular disease and stroke, particularly in women, suggested a study published in the December Stroke. Stroke risk was quadrupled among women in the highest tertile for proinsulin levels (›8.3 pmol/L), compared with women in the lowest tertile (‹5.1 pmol/L), the researchers reported. For men, stroke risk was doubled in the highest proinsulin tertile (›7.7 pmol/L) compared with the lowest tertile (‹5.3 pmol/L).

This study included 94 nondiabetic subjects with first-ever stroke and 178 matched controls, all from northern Sweden. Because proinsulin may be more strongly associated than insulin to dyslipidemia, hypertension, impaired glucose tolerance, and intima-media wall thickness, the researchers examined the relationship of stroke risk with levels of proinsulin, insulin, glucose, and cholesterol, as well as smoking, blood pressure, and body mass index. They used a two-site enzyme-linked immunosorbent assay (ELISA) that measures true insulin separately from proinsulin and split proinsulin.

Proinsulin levels, in addition to systolic and diastolic blood pressure, were significantly higher in the stroke patients than in controls. Logistic regression analysis showed that for every 1-pmol/L elevation in proinsulin level, the risk of first-ever stroke increased by 16% among women; the relationship was weaker (and not statistically significant) among men. Similar calculations with insulin found only a marginally significant risk increase for stroke.

Proinsulin remained a risk factor for stroke after the researchers controlled for traditional cardiovascular risk factors of total cholesterol, smoking, systolic blood pressure, and body mass index. However, its significance disappeared when diastolic blood pressure replaced systolic blood pressure in the analysis. Synergy was found between proinsulin and systolic blood pressure, the researchers said.

"It is not easy to compare the impact of different cardiovascular risk factors in the etiology of a first-ever stroke," the researchers acknowledged. Proinsulin has been shown to directly influence plasminogen activator inhibitor type 1 activity; however, they suggested that proinsulin may simply act as an indirect marker of metabolic disturbance involving the pancreatic beta cells. More study is needed to determine the mechanism by which proinsulin contributes to the development of stroke, the researchers concluded.

NR