MS-RELATED DISABILITY WORSENS OVER 10 YEARS

Survival was reduced and 30% of patients with multiple sclerosis (MS) progressed to needing a cane or wheelchair or worse over the course of a 10-year follow-up, according to a report in the January 13 Neurology. Investigators from the Mayo Clinic in Rochester, Minnesota, studied the change in disability over 10 years (1991–2001) as measured on the Expanded Disability Status Scale (EDSS) for 162 patients with MS constituting the 1991 Olmsted County, Minnesota, MS prevalence cohort. Mean change in EDSS disability, change in disability leading to a milestone such as needing a cane or wheelchair, and group change in disability over the course of the follow-up were measured.

Of the 162 patients, 24 were dead at 10-year follow-up. Medical records (with neurologic examination within one year prior to death) were available for 23 of these cases and provided the data for the analysis. Of the 138 patients who were still living, 113 were interviewed and examined; 19 had a telephone follow-up. The investigators reported that 24 patients were receiving immunomodulatory therapies for MS and that EDSS was 6 or greater at the start of therapy in these patients. There was no significant change in EDSS between start of treatment and 2001 or end of treatment, they noted.

Overall, the entire cohort worsened by an average of 1 EDSS point over 10 years, the researchers said. Of patients with EDSS scores less than 3 in 1991, 83% did not require walking aids in 2001. However, 51% of patients with EDSS scores 3 through 5 in 1991 required a cane to ambulate in 2001 and 51.3% of patients with EDSS scores of 6 or 7 in 1991 had progressed to wheelchair-confinement or worse in 2001.

Men tended to worsen more than women, as did patients who were older at the time of diagnosis, the investigators noted. Motor pathway deficit, gait difficulty, sphincter dysfunction at disease onset, and longer duration of MS (greater than 25 years) were all significantly associated with greater worsening of EDSS scores at 10-year follow-up. However, the number of attacks in the first year did not significantly impact disability progression at follow-up in the relapsing-remitting and secondary progressive group.

Death was directly attributable to medical complications of MS in 61% of the patients, and 10-year survival was decreased compared with the Minnesota white population for both men and women, the investigators said.

Pittock SJ, Mayr WT, McClelland RL, et al. Change in MS-related disability in a population-based cohort: a 10-year follow-up study. Neurology. 2004;62:51-59.

LOSS OF GLUTAMATE SYNTHETASE IN MESIAL TEMPORAL LOBE EPILEPSY

A deficiency in glutamine synthetase in astrocytes is a possible molecular basis for extracellular glutamate accumulation and seizure generation in mesial temporal lobe epilepsy, according to a report in the January 3 Lancet. Investigators from the Departments of Neurosurgery and Pathology at Yale University School of Medicine in New Haven, Connecticut, analyzed the hippocampi of 29 patients with intractable temporal lobe epilepsy, 14 of whom were classified as having mesial temporal lobe epilepsy. Immunohistochemistry, Western blot, and functional enzyme assays were used to assess the distribution, quantity, and activity of glutamine synthetase. A deficiency in glutamine synthetase might be responsible for the high extracellular concentrations of glutamate that are indicted as a likely trigger of epileptic seizures, the researchers noted.

The investigators found that in Western blots, the expression of glutamine synthetase in the hippocampus was 40% lower in patients with mesial temporal lobe epilepsy than in non-mesial temporal lobe epilepsy samples. Enzyme activity was lower by 38% in patients with mesial temporal lobe epilepsy as compared to those without mesial temporal lobe epilepsy. The loss of glutamine synthetase “was particularly pronounced in areas of the mesial temporal lobe epilepsy hippocampus with astroglial proliferation, even though astrocytes normally have high content of the enzyme,” they noted. Finally, quantitative immunoblotting showed no significant change in the amount of excitatory amino acid transporter 2, the predominant glial glutamate transporter in the hippocampus.

Further studies are needed, the investigators said, but their findings “suggest that glutamate accumulation and epileptic seizures could be coupled to a highly localized enzyme defect.” According to their results, the main cause of glutamate aggregation in the hippocampus is decreased enzymatic catabolism rather than altered transport. Though the investigators did not define the cause of the decreased catabolism, they asserted that, based on their work, “manipulations of glutamine synthetase activity might constitute a novel principle for curtailing seizures in patients with mesial temporal lobe epilepsy.”

Eid T, Thomas MJ, Spencer DD, et al. Loss of glutamate synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Lancet. 2004;363:28-37.

METAL CHELATION THERAPY MAY HELP IN TREATING ALZHEIMER’S DISEASE

A treatment strategy using a metal-protein–attenuating compound has slowed the progression of cognitive decline in a group of patients with moderately severe Alzheimer’s disease. Researchers at the University of Melbourne and the University College London developed a clinical intervention using clioquinol, which inhibits zinc and copper ions from binding to ß-amyloid, thereby promoting ß-amyloid dissolution and diminishing its toxic properties.

As detailed in the December 15 edition of the Archives of Neurology, 36 patients were randomized for the study. Craig W. Ritchie and colleagues found that the effect of treatment was significant in the more severely affected group, due to a substantial worsening of scores in those taking placebo compared with minimal deterioration for the clioquinol group. In addition, plasma ß-amyloid42 levels declined in the clioquinol group and increased in the placebo group. Plasma zinc levels increased in the clioquinol-treated group, and the drug was well tolerated.

“The findings support a proof of concept in humans that a drug targeting metal–ß-amyloid interactions can have a significant effect on ß-amyloid metabolism and, through this, a beneficial modification on the progression of Alzheimer’s disease,” Dr. Ritchie’s team stated. “The clinical benefit of clioquinol in this study population was only seen in the more severely affected subjects.”

The researchers stated that the safety profile and biochemical efficacy of clioquinol in these patients were “sufficiently encouraging to allow for future trials to take this investigation of a novel therapeutic intervention (clioquinol itself or a pharmacologically improved backup) targeting ß-amyloid to the next phase. This class of metal-protein–attenuating compounds may also be considered for related conditions such as Parkinson disease, in which alpha-synuclein and iron could interact in a manner analogous to ß-amyloid and zinc and copper ions.”

In an accompanying editorial, Roger N. Rosenberg, of the University of Texas Southwestern Medical Center in Dallas, stated, “Zinc-copper chelation offers promise as a new therapeutic strategy. Clearly, it is an innovative therapeutic approach to Alzheimer’s disease and merits a closer and more comprehensive assessment in larger clinical trials.”

Ritchie CW, Bush AI, Mackinnon A, et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Aß amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol. 2003;60:1685-1691.
Rosenberg RN. Metal chelation therapy for Alzheimer disease. Arch Neurol. 2003;60:1678-1679.

SUNNY SIDE UP—SOLAR RADIATION MAY BE PROTECTIVE AGAINST MS

Solar radiation may influence the processes that underlie the development of multiple sclerosis (MS), according to a study in the January Journal of Epidemiology and Community Health. Researchers from Oxford University in the United Kingdom analyzed data from hospital records and death certificates to assess the prevalence of skin cancer—a proxy for prolonged exposure to solar radiation—in the former English health service region of Oxford. Records spanning over 30 years (from 1963 up to 1999) of persons with MS and other autoimmune or neurological diseases were included in the study, which was designed to test the hypothesis that persons with MS would have a lower than average risk of skin cancer if indeed solar radiation protected against MS.

The results showed that rates of cancer in general were not especially low among the 5,004 persons with MS (243 patients with cancer) as compared to an age- and sex-matched control cohort of 430,000 patients with other immune-related or neurologic disease, the investigators reported. If anything, they were slightly higher than would be expected (rate ratio, 1.15), they noted. However, there were only 10 cases of skin cancer reported in the MS cohort, yielding a rate ratio of 0.49—significantly lower than that of the reference population. This deficit was greater for skin cancers other than melanoma (rate ratio, 0.38 and 0.91, respectively).

“As far as we know, ours is the first study to provide evidence about MS and a marker of solar radiation at an individual patient level as distinct from a population level,” the researchers said. “Our cohort study adds to the ecological and occupational evidence from previous studies that solar radiation influences the processes that underlie the development of MS.” This may occur via a suppression of the immune system response, “perhaps mediated via changes to vitamin D3 or melatonin production,” they postulated.

Goldacre MJ, Seagroatt V, Yeates D, Acheson ED. Skin cancer in people with multiple sclerosis: a record linkage study. J Epidemiol Community Health. 2004;58:142-144.

STATE OF DISUNION—NEUROPROTECTION IN PARKINSON’S DISEASE

A review of clinical trials aimed at detecting neuroprotection in Parkinson’s disease addressed the controversies surrounding the interpretation of these studies and surveyed the state of the field in Parkinson’s disease research. The review, authored by Anthony H. V. Schapira, DSc, MD, of the Department of Clinical Neurosciences, Royal Free and University College Medical School, and the Institute of Neurology, Queen Square, London, and C. Warren Olanow, MD, of the Department of Neurology at Mount Sinai School of Medicine in New York, was published in the January 21 JAMA.

“Neuroprotective treatment is essential in order to limit the disability experienced by millions of patients with Parkinson’s disease,” the investigators said. “The development of a disease-modifying or neuroprotective agent for Parkinson’s disease would be greatly facilitated by understanding the mechanism responsible for neuronal degeneration.” The etiology of neurodegeneration in Parkinson’s disease is likely multifactorial, they noted, with the current thinking favoring “a complex interplay between different genetic and environmental factors.”

The clinical neuroprotection trials reviewed by Drs. Schapira and Olanow ran the gamut from antioxidants to coenzyme Q10 to the more recent neuroimaging trials of dopamine agonists. They concluded that while laboratory studies have provided numerous candidate neuroprotective drugs, “the clinical end points that have been used to date are readily confounded by any symptomatic effect of the study intervention and thus do not provide an unequivocal measure of disease progression that can be used to determine if a drug has a neuroprotective effect.”

In a more lengthy consideration of the neuroimaging trials, they noted that two recent trials of pramipexole and ropinirole—CALM-PD-CIT and REAL-PET—reported that patients randomized to receive these dopamine agonists had a reduced rate of decline compared with levodopa. They noted, however, that the cause of this reduction—putatively a protective effect of dopamine agonists but possibly a toxic effect of levodopa—was not able to be determined from the studies, as neither included a placebo control.

With critical review of the available data on neuroprotective drugs for Parkinson’s disease yielding “conflicting and inconclusive” results, Drs. Schapira and Olanow opined that “the fairest position at this time is that there is insufficient information to draw the conclusion that the results of the pramipexole and ropinirole trials have been caused by spurious pharmacologic effects, but neither can one say with certainty that the agonists are protective or that levodopa is toxic.” Though there is no clear answer regarding neuroprotection for patients with early Parkinson’s disease, the investigators remained optimistic that such a treatment will eventually come to light. “The combination of in vitro and in vivo laboratory evidence demonstrating a neuroprotective effect of dopamine agonists, together with the results of the [neuroimaging] studies, make a compelling story that should stimulate further research,” they said.

NR

Schapira AHV, Olanow CW. Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA. 2004;291:358-364.

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