STATIN THERAPY FOR MS?

Oral simvastatin might inhibit inflammatory components of multiple sclerosis (MS), according to a report in the May 15 Lancet. Timothy Vollmer, MD, of the Department of Neurology at Yale School of Medicine, New Haven, Connecticut, and colleagues conducted the first multicenter, open-label, single-arm study of simvastatin for the treatment of MS. They enrolled 30 patients (mean age, 44; 21 women) with clinically definite relapsing-remitting MS and no treatment with interferons or glatiramer in the previous three months or corticosteroids within 30 days of screening. Participants were monitored for three months. MRI scans of the brain were conducted on a monthly basis. Patients with at least one gadolinium-enhancing lesion detected during this phase received 80 mg of simvastatin per day for six months. MRIs were repeated at months 4, 5, and 6 of the study.

The investigators reported that the average mean number of gadolinium-enhancing lesions was reduced by 44% during treatment compared to pretreatment, and that gadolinium-enhancing lesion volume also fell by 41% after treatment. Pretreatment and treatment phase yearly relapse rates did not differ, and no relevant change between pretreatment and treatment expanded disability status scores was detected, they noted.

“These findings suggest that an 80-mg daily dose of oral simvastatin over a six-month period could inhibit the inflammatory components of MS that lead to neurologic disability,” Dr. Vollmer and colleagues wrote. They called for randomized controlled trials to establish the safety and efficacy of statins in the treatment of relapsing-remitting MS.

“These results provide hope, although they should be interpreted cautiously,” added Chris H. Polman, MD, and Joep Killestein, MD, in an accompanying editorial. Drs. Polman and Killestein, of VU Medical Centre Amsterdam in the Netherlands, raised several issues with Dr. Vollmer and colleagues’ work. “The number of patients and the design of the study do not allow for a definitive conclusion on the role of statins in MS,” they noted. Their main concern was one that Dr. Vollmer also acknowledged in his concluding remarks: “whether, without a placebo group, the reduction in disease activity as measured with MRI could be due to regression to the mean.” Drs. Polman and Killestein also remarked that “the presence of gadolinium-enhancing lesions might have selected for patients with active disease who would have subsequently had reduced disease activity” even without statin intervention.

Despite these and other reservations, they concluded that “Vollmer and colleagues’ study is a big step forward because it is the first to provide some evidence of an effect with a statin in MS.” Like the study investigators, they noted that additional data are required before a recommendation of statins for the treatment of MS can be made without reservations.

Polman CH, Killestein J. Statins for the treatment of MS: cautious hope. Lancet. 2004;363:1570.
Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004;363:1607-1608.

BONE MARROW CELLS MAY HELP REGENERATE BRAIN TISSUE

A study in the May 1 Lancet suggests that donor bone marrow cells can migrate to the brain and turn into neural cells and thus could be a useful source of cells to repair damaged tissues. Christopher R. Cogle, MD, of the University of Florida Shands Cancer Center in Gainesville, and colleagues examined the autopsy brain specimens from three sex-mismatched female bone marrow transplantation patients, a female control, and a male control. The investigators performed immunohistochemistry, fluorescence in-situ hybridization, and tissue analysis to look for multilineage, donor-derived neurogenesis.

The researchers found that hippocampal cells containing a Y chromosome were present up to six years posttransplant in all three patients. Transgender neurons accounted for 1% of all neurons, and there was no evidence of fusion events, because only one X chromosome was present, they noted. In addition, transgender astrocytes and microglia made up 1% to 2% of all glial cells.

“Postnatal human neuropoiesis happens, and human hemopoietic cells can transdifferentiate into neurons, astrocytes, and microglia in a long-term setting without fusing. Transplantable human hemopoietic cells could serve as a therapeutic source for long-term regenerative neuropoiesis.

“The transdifferentiating cell is probably of hemopoietic origin since no other primary cells from bone marrow have proved capable of substantial engraftment after transplantation,” the investigators continued. “Furthermore, this transdifferentiation seems to result in durable, long-term, multilineage engraftment since the patient who survived long-term after transplantation was the only one who had transgender neurons.”

Dr. Cogle and colleagues stated that their results have implications for both neurobiology and stem cell biology. “They suggest that a transplantable hemopoietic cell responds to instructive neurotrophic cues, crosses the blood-brain barrier, migrates into CNS parenchyma, and activates neural-specific genetic programming,” the researchers reported. “In other words, bone marrow can make brain. Future work should focus on identification of the developmental cues that promote transdifferentiation along the neural lineage. If these cues can be manipulated, bone marrow could be used as a therapeutic source of readily harvestable cells for regenerative neuropoiesis, with application to various neurodegenerative diseases and traumatic CNS insults,” the investigators concluded.

Cogle CR, Yachnis AT, Laywell ED, et al. Bone marrow transdifferentiation in brain after transplantation: a retrospective study. Lancet. 2004;363:1432-1437.

GENE LINKED TO AUTISM

Researchers at the Mount Sinai School of Medicine in New York City have identified a gene that increases susceptibility to autism among individuals in a broad population group. Nicolas Ramoz, PhD, and colleagues demonstrated a strong association of autism with single nucleotide polymorphisms within the SLC25A12 gene, although they cautioned that further study is needed to confirm this association and to decipher any potential etiologic role of mitochondrial aspartate/glutamate carrier in autism.

As reported in the April American Journal of Psychiatry, mutation screening of positional candidate genes was performed in two stages. The first stage involved identifying, in unrelated subjects showing linkage to 2q24-q33, genetic variants in exons and flanking sequence within candidate genes and comparing the frequency of the variants between autistic and unrelated nonautistic subjects. In the second stage, the two single nucleotide polymorphisms in SLC25A12 were further genotyped in 411 autistic families, and linkage and association tests were carried out in 197 informative families.

The researchers observed linkage and association between autistic disorder and the two single nucleotide polymorphisms, rs2056202 and rs2292813, found in SLC25A12. Using either a single affected subject per family, or all affected subjects, evidence for excess transmission was found by the Transmission Disequilibrium Test for rs2056202, rs2292813, and a two-locus G*G haplotype. Genotype relative risk could be estimated to be between 2.4 and 4.8 for persons homozygous at these loci, Dr. Ramoz’s team noted.

“Assuming that our results reflect true association of SLC25A12 with autism, the data indicate a genotype relative risk for a two-locus (G*G) haplotype of between 3 and 5,” the researchers reported. “This, while significant, must be taken in context of the observation that the susceptibility variants (or the variants in linkage disequilibrium with the true susceptibility variants) are common alleles. This is consistent with the idea that this locus plays a significant role in the epidemiology of the disorder but would not be immediately useful for genetic counseling until it can be considered together with additional loci.”

Ramoz N, Reichert JG, Smith CJ, et al. Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. Am J Psychiatry. 2004;161:662-669.

SICKLE CELL DISEASE LINKED TO SILENT STROKE

Children and adolescents who have sickle ß-thalassemia—a common variety of sickle cell disease—may appear neurologically normal, but many have suffered silent strokes or have circulatory system abnormalities that put them at risk for overt strokes, according to Greek researchers in a study published in the May 3 advanced online Annals of Neurology.

Sickle ß-thalassemia is the overlap of two distinct hereditary anemias—sickle cell disease and thalassemia. Many people with sickle ß-thalassemia are subject to the additive effects of different disruptions in the blood’s ability to carry oxygen to the organs of the body, explained study lead author Dimitrios I. Zafeiriou, MD, PhD. Stroke is a well-known consequence of sickle cell disease, but patients with sickle ß-thalassemia typically show no overt signs of stroke, nor do they show any mental deterioration that might point to undetected silent strokes, he added.

Dr. Zafeiriou and his colleagues at Aristotle University of Thessaloniki, Greece, performed extensive testing on a group of 21 children and young adults with sickle ß-thalassemia without overt stroke. The assessment included MRI, magnetic resonance angiography (MRA), and transcranial Doppler testing to assess blood flow to the brain, visual and median nerve somatosensory-evoked potential recordings, and the Wechsler Intelligence Scale to determine if the subjects had experienced deficits in cognitive ability.

Although the patients did not show significant deficits on the neuropsychological testing, more than a third (38%) showed MRI evidence of previous silent strokes in the parieto-occipital cortex, deep white matter, or basal ganglia, Dr. Zafeiriou and colleagues reported. Similarly, nearly a third of the patients tested—including many that had not had silent strokes—exhibited abnormal blood flow to the brain on MCA and/or transcranial Doppler testing. All but one of the children who had had silent infarctions had IQ scores greater than 85 on the Wechsler Intelligence Scale, the investigators noted, indicating that “cognitive function is not necessarily compromised” in children with sickle ß-thalassemia.

According to the authors, the implications of the study are clear. “All patients with sickle ß-thalassemia should be routinely screened with MRI and tests of brain blood flow in order to detect abnormalities not easily seen in clinical examination,” they said. “The next step will be to follow these patients in order to see if they will experience clinically overt stroke,” Dr. Zafeiriou added. The authors would also like to know if factors such as diet might increase or decrease the risk of strokes. “If certain criteria for abnormality—especially in transcranial Doppler—are established from larger studies, then protocols for therapeutic intervention in order to prevent nervous system damage could be initiated,” concluded Dr. Zafeiriou and colleagues.

Zafeiriou DI, Prengler M, Gombakis N, et al. Central nervous system abnormalities in asymptomatic young patients with sß-thalassemia. Ann Neurol. 2004. Epub ahead of print.

TRAINING CAREGIVERS OF STROKE PATIENTS PAYS DIVIDENDS

Training caregivers during stroke patients’ rehabilitation reduced costs and improved quality of life for both groups within one year, according to two reports in the May 8 BMJ. Both studies were based on a single, blind, randomized controlled trial of 300 stroke patients and their caregivers.

Lalit Kalra, PhD, of the Guy’s, King’s, and St. Thomas’s School of Medicine in London, and colleagues observed improvements in psychosocial outcomes in both caregivers and patients. “Caregiver training in basic nursing, moving, and handling and facilitation of activities of daily living is feasible during stroke rehabilitation,” the researchers reported.

In addition, “caregiver training significantly reduces caregiver burden, anxiety, and depression and improves quality of life and satisfaction with care among caregivers at three and 12 months,” they noted.

In the second report, Anita Patel, MSc, of the Centre for the Economics of Mental Health, Institute of Psychiatry in London, and colleagues also found that the overall quality of life in caregivers improved at one year. The investigators stated that costs of informal care are similar between trained and untrained caregivers, and therefore no shift in the burden of care from statutory services toward caregivers was becoming apparent. The researchers also found that caregiver training was associated with smaller losses of quality of life among caregivers; this effect was apparent soon after the patient’s stroke.

“Despite caregivers being recognized as one of the building blocks of community care, little is known about how caregivers can be assisted effectively,” Ms. Patel and her colleagues reported. “Improving the skills of consenting informal caregivers during inpatient rehabilitation reduces stroke care costs and improves their quality of life without increasing the burden of care to families or transferring costs to the community.”

In an accompanying editorial, Graeme J. Hankey, MD, from the Royal Perth Hospital in Australia, commented, “The implications of these results, if they can be generalized widely, are that the (inpatient and outpatient) rehabilitation and care of disabled stroke survivors should be broadened to include the proposed caregiver in the multidisciplinary rehabilitation team, involving them actively in setting goals, rehabilitation, care, and planning discharge and ensuring they are as adequately trained, supported, and followed as the patient.”

NR

Hankey GJ. Informal care giving for disabled stroke survivors. BMJ. 2004;328:1085-1086.
Kalra L, Evans A, Perez I, et al. Training care givers of stroke patients: randomised controlled trial. BMJ. 2004;328:1099-1101.
Patel A, Knapp M, Evans A, et al. Training care givers of stroke patients: economic evaluation. BMJ. 2004;328:1102-1104.

Return to table of contents