LONG-TERM BENEFIT OF UNILATERAL PALLIDOTOMY?

Significant improvements in off-period contralateral signs of parkinsonism were sustained for up to five and a half years following unilateral pallidotomy in advanced Parkinson's disease patients, according to University of Toronto researchers reporting in the June 8 New England Journal of Medicine. Although there was a sustained improvement in on-period contralateral dyskinesia, improvement was not sustained in other on-period signs of parkinsonism.

Previously published studies have reported the efficacy of pallidotomy. However, the majority of these assessments are based on data gathered during the first year following pallidotomy, noted the authors. In the University of Toronto study, the mean follow-up was 52 months (range, 41 to 64).

The long-term follow-up study included a cohort of 40 patients who underwent unilateral posteroventral medical pallidotomy between 1993 and 1996. The outcomes of 20 patients were not evaluated because they underwent a subsequent surgical procedure, died, developed dementia or another debilitating illness, lived too far away, or were lost to follow-up. The remaining 20 patients were periodically examined both while they were taking medication (on-period) and after overnight withdrawal (off-period).

Evaluations were conducted according to the modified protocol of the Core Assessment Program for Intracerebral Transplantations, which includes parts of the Unified Parkinson's Disease Rating Scale (UPDRS) and the assessment of dyskinesia. A single person assessed the patients at baseline and during follow-up. At six months, 20 patients were evaluated; at one year, 10 were evaluated; and at two years, 17 were evaluated. The primary efficacy measure was the combined activities of daily living and motor function scores. Secondary outcome measures included the off-period scores on the UPDRS for contralateral bradykinesia, tremor, and rigidity and the on-period score for contralateral dyskinesia.

Follow-up data indicated that the mean overall UPDRS scores improved after pallidotomy. However, the scores, which at six months had improved 37.4%, deteriorated to an improvement of 18% at final evaluation. An analysis of secondary outcome measures showed a sustained, significant improvement of tremor (65.4%), rigidity (43.2%), and contralateral on-period dyskinesia (70.6%) between baseline and last evaluation. The initial improvement of bradykinesia deteriorated over time.

An analysis of the data was conducted to identify long-term predictors of outcome. Age, the duration of the disease, and the overall off-period UPDRS score at baseline were not significantly correlated with long-term outcome of surgery. Percent improvement in the UPDRS score at six months was significantly correlated with the percent improvement at final evaluation. As well, there was a slight correlation between the degree of off-period asymmetry before surgery and overall long-term improvement—a higher degree of dysfunction was linked to a greater long-term benefit from surgery.

The deterioration in off-period UPDRS scores may reflect a loss of benefit from surgery or a progression of disease; the deterioration in on-period UPDRS scores may reflect a loss of responsiveness to levodopa, suggested the authors.

Fine J, Duff J, Chen R, et al. Long-term follow-up of unilateral pallidotomy in advanced Parkinson's disease. N Engl J Med. 2000;342:1708-1714.

THERAPY-INDUCED CORTICAL PLASTICITY FOLLOWING STROKE

Cortical reorganization was associated with improved movement in a cohort undergoing constraint-induced movement therapy after stroke, according to a report in the June Stroke. During constraint-induced therapy, the limb of which the patient has the most use is bound for 90% of waking hours while the patient undergoes long and intense training sessions in the use of the affected limb. The purpose of this study was not to assess the efficacy of constraint-induced movement therapy as a physiotherapeutic technique but to assess therapy-induced cortical plasticity following stroke, noted the authors.

To assess plasticity, the researchers used focal transcranial magnetic stimulation (TMS). Unlike functional magnetic resonance imaging or positron emission tomography, TMS is performance-independent and, thus, more suited to longitudinal studies, the researchers wrote. Several times before and after the constraint-induced movement therapy, the patients underwent TMS mapping and motor evaluation to establish baseline function and short- and long-term effects on plasticity.

The thirteen patients (10 men; mean age, 59.7) had had hemiparesis for a mean of 4.9 years. They were able to extend the wrist at least at a 20º angle and the fingers at a 10º angle and to walk while the less-affected arm was bound. Candidates excluded from the study were those who had serious uncontrolled medical conditions, global aphasia or cognitive impairment, or any metal object in their head; were pregnant; had epilepsy; or had a cardiac pacemaker.

Before treatment, the patients had a mean score of 2.2 as measured by the motor activity log, which tracked arm use through 20 activities of daily living. For 12 days, they underwent six hours of constraint-induced movement therapy. One day after treatment, the scores improved to 3.7. (A score of 2 indicates slight use; 3, half as much as before the stroke; and 4, three quarters as much as before the stroke, explained the authors.)

Transcranial magnetic stimulation mapping showed the correlation of behavior and cerebral plasticity. The authors mapped the cortical output area of the abductor pollicis brevis muscles. One day before treatment there were 40% fewer active positrons in the infarcted hemisphere than in the noninfarcted hemisphere. However, by the first day after treatment, there were 37.5% more active positrons in the infarcted hemisphere than in the noninfarcted hemisphere. The authors noted that TMS data four weeks after treatment showed an even more evident normalization of hemispheric response.

The smaller cortical output of the abductor pollicis brevis muscle on the infarcted side may be due either to the stroke itself or to the decreased use of the hand after the stroke, suggested the authors. The mechanism of cortical reorganization may reflect an increased excitability of neurons, an increase in excitable neuronal tissue, or both. As well, it could reflect a reduction in the activity of inhibitory neurons or an enhancement of the synaptic strength of existing synaptic connections, the authors suggested.

Liepert J, Bauder H, Miltner WHR, et al. Treatment-induced cortical reorganization after stroke in humans. Stroke. 2000;31:1210-1216.

HOW EFFECTIVE ARE THERAPIES FOR PAINFUL HIV-ASSOCIATED NEUROPATHY

Two studies in the June Neurology assessed therapeutic efficacy for HIV-associated peripheral neuropathy. As it is one of the most common pain syndromes to present in individuals with HIV, every neurologist has seen or will see patients with painful HIV-associated peripheral neuropathy, according to Joseph R. Berger, MD, and Avindra Nath, MD, in an accompanying editorial.

In one study, researchers at the Karolinska Institute, Stockholm, evaluated the response of the thermal and nociceptive systems to highly active antiretroviral therapy (HAART). The 49 patients who participated in the study were treated with several combinations of therapies. Response was assessed before therapy and at one, four, and eight months after the initiation of the therapy. Thermal testing (perception of cold, warmth, and heat) was performed on the dorsum of the right foot, to which a probe delivered warm and cold stimuli.

The researchers evaluated the participants' response to antiretroviral therapy by determining HIV-1 RNA plasma levels. A patient whose viral load declined by at least 1.0 log¹⁰ copies/mL was classified as a responder (76%) and the others as nonresponders (24%). The two groups did not differ in demographic characteristics such as age, gender, route of HIV-1 transmission, clinical disease classification, HIV-1 RNA, or CD4+ levels. After eight months of treatment, the responders' median HIV-1 RNA levels decreased from 4.55 log¹⁰ copies/mL to less than the detection limit of the assay. In the nonresponders, however, there was a trend towards increasing levels. The mean CD4+ levels increased in the responders but did not change in the nonresponders after eight weeks of treatment.

An improvement in the cold, warmth, and heat perception thresholds was seen in the responder group after eight months of therapy. The patients whose warmth and cold perception thresholds normalized had higher pretreatment CD4+ levels. "This suggests a shorter duration of neurologic deficit, and may argue in favor of both early antiretroviral treatment when signs of HIV-1—related neurologic dysfunction appear, and a more detailed maintaining of the neurologic status to detect subclinical involvement of peripheral nerves," according to the authors.

They concluded that while the improved function in the thermal and nociceptive somatosensory systems does not necessarily predict improvements in other parts of the somatosensory system, it is "not unlikely that the observed improvement to some extent could also be related to improved function of central somatosensory pathways."

In the second study, researchers from the Mount Sinai Medical Center, New York, the University of California at San Francisco, and the Johns Hopkins University, Baltimore, collaborated to study the analgesic efficacy of lamotrigine in the treatment of painful HIV-associated distal sensory polyneuropathy. During the placebo-controlled study, lamotrigine was initiated at 25 mg per day and titrated over seven weeks to 300 mg per day. The primary outcome measure was change in pain; and the secondary outcome measures included change in neurologic examination, use of concomitant analgesic medications, and global pain relief.

Of the 42 patients enrolled in the study, 20 received lamotrigine and 22 received placebo. In all, 13 members dropped out of the lamotrigine cohort due to rash, gastrointestinal infection, or loss to follow-up. The five rashes were mild or moderate morbilliform rashes, which cleared up with discontinuation of the therapy. The remaining nine members of the lamotrigine cohort achieved significantly lower pain scores at 14 weeks than the placebo group. The authors noted that lamotrigine showed efficacy only in those patients who had not been exposed to neurotoxic antiretrovirals within eight weeks of the study. Despite the high dropout rate and the small size of the study cohort, the authors concluded that lamotrigine shows promise in the treatment of painful HIV neuropathy.

In the accompanying editorial, Drs. Berger and Nath of the University of Kentucky at Lexington note that the pathogenesis of HIV-associated peripheral neuropathy remains uncertain but includes HIV, autoimmune processes, toxicity from antiretroviral agents or other therapies, nutritional factors, and co-infections. The Karolinska Institute study indicated, with the improvement in thermal sensitivity after the administration of HAART and the decline in viral load, evidence of the role of HIV infection in the pathogenesis of this peripheral neuropathy, they said. The study also demonstrated that it may be important to monitor viral load in the administration of neuromodulatory therapies and that sensitivity to cold and heat should be monitored. The lamotrigine study showed that antiretroviral therapies may be neurotoxic, although their suppression of HIV infection may improve neuropathy. As the studies varied in design and end points, their results cannot be directly compared, added Drs. Berger and Nath.

Berger JR, Nath A. Remedies for HIV-associated peripheral neuropathy. Neurology. 2000;54:2037-2038.
Martin C, Solders G, Sönnerborg A, Hansson P. Antiretroviral therapy may improve sensory function in HIV-infected patients: a pilot study. Neurology. 2000;54:2120-2127.
Simpson DM, Olney R, McArthur JC, et al. A placebo-controlled trial of lamotrigine for painful HIV-associated neuropathy. Neurology. 2000;54:2115-2119.

HETEROGENITY OF MS LESIONS—IMPLICATIONS FOR DIAGNOSIS AND THERAPY

Heterogeneity in multiple sclerosis lesions was recorded in a multicenter study. This heterogeneity has fundamental implications for the diagnosis and therapy of the disease, according to the authors in the June Annals of Neurology.

The collaborative study included researchers from the Mayo Clinic, Rochester, Minnesota, the Institute of Neuropathology at the University of Göttingen, Germany, and the Brain Research Institute at the University of Vienna, Austria. The researchers evaluated material from 51 biopsies and 32 autopsies of patients diagnosed with active multiple sclerosis. The 32 (22 female) patients who were autopsied were a mean age 39.7. They had a total of 325 lesions, 173 of which were active. The 51 patients (29 female; mean age, 38.3) who underwent biopsy had a total of 71 lesions, 62 of which were active.

Although the lesions met stringent criteria for demyelinating activity, there was a marked heterogeneity in their immunopathologic appearance. The authors described four different demyelination patterns based on myelin protein loss, the location and extension of the plaques, the patterns of oligodendrocyte distribution, and the immunopathological evidence of complement activation. Patterns I and II showed active demyelination associated with T-lymphocyte- and macrophage-dominated inflammation. While pattern I was distinguished by deposition of immunoglobulins at sites of active demyelination, pattern II was distinguished by C9neo antigen at such sites. Patterns III and IV were suggestive of oligodendrocytic dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity, according to the authors.

No evidence for intraindividual heterogeneity was found. As the study was not longitudinal in design, the researchers were unable to determine if the lesion patterns remained constant during the course of the disease. The data did, however, indicate that the mechanisms and targets of the disease differ among the four subgroups. Thus, they concluded, therapy may need to be tailored to the needs of the subgroups.

The homogeneity of lesions within each patient was an important finding of the study, noted Samuel K. Ludwin, MD, in an accompanying editorial. He is Professor of Neuropathology in the Department of Pathology at Queen's University, Kingston, Ontario. However, he added, each biopsy or autopsy yields "a single snapshot in time" and does not reveal the evolution of a lesion. The acute cases may not represent the earliest phase of the disease, he said. Thus, stages thought to be early may actually be secondary reactions to the initiating process.

The difference between patterns I/II and III/IV may represent degrees of severity of the same insult, suggested Dr. Ludwin. He noted that ischemia causes either apoptosis or necrosis and that lysolecithin causes either oligodendrocyte preservation or destruction. He concluded that this study presents the authors with an excellent opportunity to follow up initial biopsies and assess possible changes in intraindividual lesion pattern homogeneity and to determine if all cases become typical multiple sclerosis cases or if, in fact, they develop into different diseases.

Lucchinetti C, Brück W, Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000;47:707-717.
Ludwin SK. Understanding multiple sclerosis: lessons from pathology. Ann Neurol. 2000;4:691-693.

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