High prevalence of malignant melanoma in Israeli patients with Parkinson's disease.

The risk of melanoma is higher in patients with Parkinson's disease (PD) than in the general population. Whether the association is disease related or treatment related is unclear. The objective of this study was to assess melanoma prevalence in PD patients in Israel using active dermatologic screening. Consecutive patients with idiopathic PD were recruited by 12 Israeli centers. A movement disorder specialist assessed the severity of PD and obtained a medical, neurological, and medication history. Subsequently, a dermatologist assessed melanoma risk factors, recorded a dermatologic history, proactively performed a whole-body skin examination, and biopsied suspicious skin lesions. Of the enrolled patients (n = 1,395, mean age 69.5 ± 10.6 years, mean PD duration 7.3 ± 6.0 years), 95.3% were treated with dopaminergic agents. Biopsies revealed 8 patients with melanoma in situ and 1 with invasive malignant melanoma; 14 patients reported a melanoma prior to enrollment. The observed 5-year limited duration prevalence of melanoma in PD patients was 4.4 times greater (95% CI 2.6-7.6) than expected from melanoma prevalence in an age- and sex-matched cohort from the Israel National Cancer Registry. The increase was accounted for by an elevated prevalence of melanoma in situ [relative risk 12.5 (95% CI 6.7-23.2)]. Occurrence of melanoma did not correlate with levodopa therapy or time of onset of PD. Melanoma prevalence in PD patients was higher than expected in the general Israeli population. This was not related to levodopa treatment. PD patients should be actively screened for melanoma on a routine basis.

Progression of dysautonomia in multiple system atrophy: a prospective study of self-perceived impairment.

To assess severity and progression of self-perceived dysautonomia and their impact on health-related quality of life (Hr-QoL) in multiple system atrophy (MSA), twenty-seven patients were recruited by the European MSA Study Group (EMSA-SG). At baseline, all patients completed the Composite Autonomic Symptom Scale (COMPASS) and the 36 item Short Form Health Survey (SF-36), and they were assessed using the 3-point global disease severity scale (SS-3) and the Unified MSA Rating Scale (UMSARS). After 6 months follow-up, the self completed COMPASS Change Scale (CCS), the SF-36, SS-3, and UMSARS were obtained. MSA patients showed marked self-perceived dysautonomia at baseline visit and pronounced worsening of dysautonomia severity on the CCS at follow-up. Severity and progression of dysautonomia did not correlate with age, disease duration, motor impairment and overall disease severity at baseline. There were no significant differences between genders and motor subtypes. Baseline COMPASS scores were, however, inversely correlated with SF-36 scores. Progression of self-perceived dysautonomia did not correlate with global disease progression. Hr-QoL scores were stable during follow-up. This is the first study to investigate self-perceived dysautonomia severity in MSA and its evolution over time. Our data suggest that dysautonomia should be recognized as a key target for therapeutic intervention in MSA.

Effect of medical cannabis on thermal quantitative measurements of pain in patients with Parkinson's disease.

BACKGROUND: Cannabis can alleviate pain of various etiologies. This study assessed the effect of cannabis on motor symptoms and pain parameters in patients with Parkinson's disease (PD). METHODS: Twenty patients with PD who were licensed to use cannabis underwent evaluation before and 30 min after cannabis consumption and again after long-term use. Motor function was assessed with the Unified PD Rating scale (UPDRS) by two raters, one blinded. Pain was assessed with the Pain Rating Index (PRI) and Visual Analogue Scale (VAS) of the short-form McGill Pain Questionnaire. Thermal quantitative sensory testing (QST) was performed in 18 patients. The two consecutive QST measurements were validated in 12 cannabis-naïve patients with PD. RESULTS: There was a significant decrease from baseline to 30 min after cannabis consumption in mean motor UPDRS score (38.1 ± 18 to 30.4 ± 15.6, p < 0.0001), total PRI (27 ± 13.5 to 9.7 ± 11, p = 0.001), and VAS score (6.4 ± 2.8 to 3.6 ± 3.1, p = 0.0005). Mean cold pain threshold decreased significantly in the more affected limb, but only after exclusion of two patients who consumed cannabis by vaporizer rather than smoking (19.5 ± 5.2 to 15.6 ± 8.7 °C, p = 0.02). After long-term (median 14 weeks) exposure, mean heat pain threshold decreased significantly in the more affected limb in all treated patients (43.6 ± 3.5 to 40.9 ± 3.3 °C, p = 0.05) and in cannabis smokers (43.7 ± 3.6 to 40.3 ± 2.5 °C, p = 0.008). CONCLUSIONS: Cannabis improved motor scores and pain symptoms in PD patients, together with a dissociate effect on heat and cold pain thresholds. Peripheral and central pathways are probably modulated by cannabis. SIGNIFICANCE: Quantitative sensory test results are significantly altered following cannabis consumption in patients with PD. Cannabis probably acts on pain in PD via peripheral and central pathways.

Developmental cell death in dopaminergic neurons of the substantia nigra of mice.

Dopaminergic neurons in the substantia nigra pars compacta (SNpc) undergo natural cell death during development in rats. Controversy exists as to the occurrence of this phenomenon in SNpc dopaminergic neurons in the developing mouse. Herein, by using an array of morphologic techniques, we show that many SNpc neurons fulfill the criteria for apoptosis and that the number of apoptotic neurons in the SNpc vary in a time-dependent manner from postnatal day 2 to 32. These dying neurons also show evidence of DNA fragmentation, of activated caspase-3, and of cleavage of beta-actin. Some, but not all of the SNpc apoptotic neurons still express their phenotypic marker tyrosine hydroxylase, confirming their dopaminergic nature. Consistent with the importance of target-derived trophic support in modulating developmental cell death, we demonstrate that destruction of intrinsic striatal neurons by a local injection of quinolinic acid (QA) dramatically enhances the magnitude of SNpc apoptosis and results in a lower number of adult SNpc dopaminergic neurons. Strengthening the apoptotic nature of the observed SNpc developmental cell death, we demonstrate that overexpression of the anti-apoptotic protein Bcl-2 attenuates both natural and QA-induced SNpc apoptosis. The present study provides compelling evidence that developmental neuronal death with a morphology of apoptosis does occur in the SNpc of mice and that this process plays a critical role in regulating the adult number of dopaminergic neurons in the SNpc.

Management of response fluctuations: practical guidelines.

More than 50% of patients with Parkinson's disease (PD) develop response fluctuations following prolonged treatment with levodopa. Some are due to central pharmacodynamic mechanisms such as reduced striatal synthesis and storage of dopamine from exogenous levodopa and subsensitization of post synaptic dopaminergic receptors. Other fluctuations, especially the "delayed on" (increased time latencies from dose intake to turning "on") and "no on" (complete failure of levodopa dose to induce an "on" response) are caused by peripheral pharmacokinetic mechanisms. Patients with PD, especially those with response fluctuations, have gastric atony. The reduced motility of the stomach, combined with the poor solubility of levodopa, is the cause for the delayed and incomplete absorption of levodopa. The best strategy to overcome central pharmacodynamic mechanisms and to increase daily "on" hours can be achieved by using dopamine agonists, controlled release preparations, MAO-B and COMT inhibitors. Therapeutic strategies that improve levodopa absorption are needed to overcome response fluctuations that are caused by peripheral mechanisms. This can be achieved by crushing levodopa and drinking it as a suspension. Administration of crushed levodopa or levodopa/carbidopa/ascorbic acid solutions orally or through gastroduodenal or gastrojejunostomy tubes may also be helpful. Prokinetic drugs, such as prepulsid, improve absorption of levodopa by enhancing gastric motility. Bypassing the stomach by subcutaneous dopamine agonists (apomorphine and lisuride pumps) or by the novel prodrug of levodopa, i.e., levodopa ethylester, may produce dramatic rescue from incapacitating "off" states.

Fatigue in multiple sclerosis compared with chronic fatigue syndrome: A quantitative assessment.

Fatigue, a common complaint among patients with multiple sclerosis (MS), is poorly characterized. We developed a computerized method that quantitatively measures fatigue, and defined a fatigue index (FI), which is the ratio between the integral of muscle strength decay over time and maximal voluntary contraction. Thirty patients (mean age, 37.4 +/- 10.3 years) were examined - 20 patients with pyramidal tract involvement and 10 patients with involvement of other neurological systems. We evaluated 10 patients during relapse and 3 months afterwards, and compared their results with those of four patients with chronic fatigue syndrome (CFS) and 13 age-matched health subjects. The FI was significantly higher in the MS patients as compared with the CFS patients and normal controls: 34.2 +/- 6.4% versus 27.5 +/- 1.0% and 23.6 +/- 6.8%, p < 0.05. Within the MS group, the FI correlated with the presence of pyramidal signs- 43.5% compared with 33% in patients without pyramidal signs, p < 0.01. In MS patients, fatigue worsened during a relapse affecting the pyramidal tract, but not during a relapse in other systems. These results demonstrate that fatigue can be quantitatively measured in MS patients, and that pyramidal dysfunction leads to increased fatigability.

Gastric emptying in Parkinson's disease: patients with and without response fluctuations.

Delayed gastric emptying may be an important pharmacokinetic mechanism underlying some of the response fluctuations that develop after long-term levodopa therapy. We performed a radionuclide gastric emptying study using a standard Tc-99m colloid-labeled solid meal in 30 patients with Parkinson's disease (PD), 15 fluctuators with "delayed-on" and "no-on" phenomena, and 15 nonfluctuators. Fasting patients were given the standard meal, and gastric emptying was monitored with a gamma camera positioned over the stomach, recording data for 1 hour. PD patients had prolonged gastric emptying measured after 60 minutes compared with the normal control subjects (70.7 +/- 16% versus < 60%). Gastric retention measured after 1 hour was increased in patients with fluctuations compared with patients without fluctuations (77.4 +/- 15.5% versus 64.0 +/- 14.3%; p < 0.05). Half-time emptying was significantly delayed in patients with, as compared with those without, response fluctuations (221 +/- 202 minutes versus 85 +/- 31 minutes; p < 0.05). This demonstrates that delayed gastric emptying is common in PD patients and is more marked in those with response fluctuations. The stomach is an important target organ in PD, affected either by the basic PD pathology, chronic drug administration, or both.

Aphasia in multiple sclerosis: clinical and radiologic correlations.

Aphasia is not commonly reported in multiple sclerosis (MS). We report on two clinically definite MS patients, with a remitting-relapsing course, who presented with acute onset of aphasia. MRI demonstrated giant plaques in the left frontal region in one and in the left centrum semiovale in the other. These lesions were not evident in MRI performed several months previously, and may account for the aphasia. In both patients, language functions markedly improved within several weeks. In one patient, follow-up MRI 3 months later revealed a moderate reduction in the size of the plaque.

Enhanced fatigue during motor performance in patients with Parkinson's disease.

OBJECTIVE: To measure fatigue quantitatively during continuous motor performance in patients with PD. BACKGROUND: Enhanced fatigue on performance of motor tasks is a very frequent and disabling complaint of PD patients, and is poorly characterized and understood. Recent evidence suggests a role for mitochondrial dysfunction in the pathogenesis of PD. Reduced exercise capacity is one of the hallmarks of systemic mitochondrial impairment. METHODS: The authors used an automated system to measure muscle fatigue during a continuous (30-second), maximal, isometric forearm flexion in 17 PD patients and 10 age-matched control subjects. A fatigue index (FI) was then calculated. Peak force (PF) was measured as an internal standard of the examination. Measurements were performed before and 2 hours after an oral dose of levodopa/carbidopa (125 mg/12.5 mg). RESULTS: In PD patients there was a 50% increase in FI. The increased FI was often asymmetric and more pronounced on the side more affected by the disease. FI was significantly responsive to, and improved after, an oral dose of levodopa. The rate of improvement in FI induced by levodopa correlated with disease severity, as measured by the Unified Parkinson's Disease Rating Scale. No significant alterations in PF were observed. CONCLUSIONS: Enhanced muscle fatigue should be recognized as an integral part of the spectrum of motor impairment of PD. However, our data argue for its association with a central dopamine deficiency rather than with a muscle mitochondrial abnormality.

Familial infantile bilateral striatal necrosis: clinical features and response to biotin treatment.

BACKGROUND: Infantile bilateral striatal necrosis (IBSN) encompasses several syndromes of bilateral symmetric, spongy degeneration of the caudate nucleus, putamen, and globus pallidus. The familial form of IBSN is rare, and inheritance is either autosomal recessive or maternal. METHOD: The authors describe an Israeli Bedouin kindred in which 15 children born to consanguineous parents were affected with familial IBSN. They evaluated the clinical and radiologic evolution of the disease in 11 patients and the cerebral pathologic findings in one patient. Three of the children were treated with oral biotin 100 mg/day. RESULTS: Inheritance was apparently autosomal recessive. The untreated children had a similar clinical picture including developmental arrest beginning at the age of 7 to 15 months, choreoathetosis, and dysphagia. Pendular nystagmus appeared at a late stage. MRI, performed at various stages of the disease, showed severe basal ganglia atrophy. Postmortem study in one patient showed severe atrophy of the lenticular nuclei with gliosis and loss of neurons. Biotin, 100 mg/day, administered to the proband over a period of 15 months, may have slowed progression. In two other children treatment was initiated earlier and appeared to arrest or improve disease. CONCLUSIONS: Familial infantile bilateral striatal necrosis was inherited as an autosomal recessive trait. Clinical features included developmental arrest, dysphagia, and choreoathetosis. Imaging and pathology showed atrophy and degeneration of the basal ganglia. Oral biotin may have benefited three children.

Detection and measurement of an endogenous clonidine-displacing substance in human cerebrospinal fluid.

Clonidine-displacing substance (CDS) is a novel endogenous ligand for clonidine receptors previously detected in bovine brain and human serum. We examined for the first time whether CDS can be detected and measured in human cerebrospinal fluid (CSF). Using the [3H]clonidine displacement assay, we found that CDS could be identified and quantified in each of the CSF samples obtained from 81 patients with various neurological disorders. Mean level of CDS in CSF was 4.66 units/ml. Exceedingly high levels were observed in the CSF of patients with neoplastic meningitis (mean, 36.75 units/ml) and stroke (mean, 19.5 units/ml) (P < 0.0001). No correlation was found between CDS levels in CSF and age, gender, CSF protein or number of cells. CDS levels in CSF were higher than those in the serum (P < 0.01). We conclude that CDS is present and can be measured in human CSF. High CDS levels in CSF from patients with leptomeningeal metastases may serve as a tumor marker for malignant infiltration of the meninges. Additional studies in stroke patients will determine whether this endogenous ligand plays a role in the pathogenesis of cerebral ischemia.

New therapies for Parkinson's disease.

In the last decade there has been a surge of new therapeutic strategies for the treatment of Parkinson's disease along with a change of concepts about how the disease should be treated. The gold standard remains levodopa preparations, which have a rapid and dramatic symptomatic effect by replenishing the reduced dopamine levels in caudate and putamen nuclei. However, keeping in mind the complications that may emerge following long-term treatment, its initiation should possibly be delayed to the more advanced stages of the illness, especially in younger patients, in favour of dopamine agonists monotherapy. The adverse reactions that become prominent and disabling in late stages of the disease, i. e., dyskinesias, response fluctuations, and psychiatric side effects, can currently be managed by novel pharmacological as well as surgical strategies. Future therapies will focus on transplantation of dopaminergic embryonic tissue, gene therapy, and neuroprotective treatments.

Diagnosis of "non-organic" limb paresis by a novel objective motor assessment: the quantitative Hoover's test.

The differentiation of "non-organic" limb weakness from genuine paralysis is sometimes difficult in neurological practice. To address this problem, we developed a computerized quantitative method, based on the Hoover's test principle, that determines the extent of involuntary limb activation when contralateral movement is performed. Measurements of hip or arm extension isometric force are performed during direct maximal voluntary effort and during contralateral hip flexion. Maximal involuntary/voluntary force ratio (IVVR) is calculated. IVVR of the lower limbs in ten healthy subjects was 0.614, 0.044 (mean, SEM). Similar results were obtained from seven patients with genuine weakness and in the non-affected limbs of nine patients with "non-organic" mono- or hemiparesis. In contrast, IVVR in the affected limbs in the "non-organic" group was markedly increased (2.48, 0.61; P < 0.001). The same pattern was elicited in the upper limbs (2.27, 0.46 vs 0.406, 0.06; P < 0,001). We conclude that Hoover's sign in "nonorganic" paralysis is a preservation or increase of a normal synkinetic phenomenon. Quantitative measurement of the IVVR can serve as a useful ancillary test in diagnosing non-organic weakness in either lower or upper limbs.

Current management of motor fluctuations in patients with advanced Parkinson's disease treated chronically with levodopa.

Motor fluctuations after long-term administration of levodopa may be due to central pharmacodynamic mechanisms such as reduced striatal synthesis and storage of dopamine from exogenous levodopa and subsensitization of postsynaptic dopaminergic receptors. Peripheral pharmacokinetic mechanisms may be equally important, particularly in motor fluctuations of the "delayed on" (increased time latencies from dose intake to start-up of clinical benefit) and "no-on" (complete failure of a levodopa dose to exert an "on" response) types. Levodopa itself has a very poor solubility. In addition, there is delayed gastric emptying in many advanced patients. Therefore, an oral dose of levodopa may remain in the stomach for long periods of time before it passes into the duodenum where there is immediate absorption. Consequently, in order to overcome response fluctuations caused by impaired pharmacokinetic mechanisms and to improve its absorption, we recommend that levodopa be taken in multiple small doses, on an empty stomach, preferably crushed and mixed with a lot of liquid. Protein intake should be minimized. Prokinetic drugs such as prepulsid (Cisaprid) could be used to facilitate gastric motility and levodopa transit time. Administration of crushed levodopa through nasoduodenal or gastrojejunostomy tubes may be helpful in certain circumstances. Bypassing the stomach with subcutaneous injections of apomorphine may provide dramatic rescue from difficult "off" situations. Oral and s.c. administration of novel, extremely soluble prodrugs of levodopa, e.g., levodopa ethylester, may offer a new approach to overcome difficulties in levodopa absorption. Addition of dopamine agonists, MAO-B inhibitors, COMT inhibitors and controlled release levodopa preparations may be helpful in prolonging the duration of efficacy of each single levodopa dose. Levodopa, administered orally, usually combined with peripheral dopa decarboxylase inhibitors, continues to be the most widely-used and most effective pharmacological treatment for Parkinson's disease (Melamed, 1987). Undoubtedly, the outstanding therapeutic success of levodopa represents a dramatic and revolutionary breakthrough in medicine, in general, and in neurology, in particular. Although, since the introduction of levodopa, there have been many additional pharmacological and even surgical anti-parkinsonian strategies, it still stands out as a mandatory axis of treatment in the majority of patients (Steigler and Quinn, 1992). Indeed, levodopa therapy improves, sometimes markedly, the motor signs and symptoms of the illness, the functional capacity and quality of life and perhaps also life expectancy of the afflicted patients. It is therefore unfortunate that after an initial problem-free period of successful, smooth and stable clinical benefit from levodopa that lasts about two to five years, the responsiveness of many patients worsens with the emergence of a variety of complications (Marsden et al., 1982; Hardie et al., 1984). These adverse reactions include dyskinesias and dystonias, psychotic problems and, particularly, the troublesome motor fluctuations (Marsden and Parkes, 1977; Marsden, 1994). The latter phenomenon may be particularly complex, limiting and disabling. It is believed that most patients on long-term levodopa therapy will, sooner or later, develop response fluctuations of varying types and severity (Riley and Lang, 1993). Because of the serious impact of these phenomena on the quality of life and function of the patients, many efforts are now being undertaken to identify the responsible mechanisms and to devise preventive and therapeutic measures.

Effect of subcutaneous administration of levodopa ethyl ester, a soluble prodrug of levodopa, on dopamine metabolism in rodent striatum: implication for treatment of Parkinson's disease.

Levodopa ethyl ester (LDEE), a highly soluble prodrug of levodopa, was synthesized and administered to mice and rats subcutaneously or intraperitoneally. Striatal levels of levodopa, dopamine, and the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were determined using high-performance liquid chromatography with electrochemical detection and compared with those obtained after intraperitoneal injections of levodopa. LDEE injections produced significant and rapid elevations of striatal levodopa, dopamine, and DOPAC, which were similar to those achieved after levodopa administration, with similar dose-response curves. The elevations achieved by LDEE given s.c. were higher than those achieved after i.p. administration and lasted for longer periods. In addition, intraperitoneal administration of levodopa or LDEE to rats with unilateral 6-hydroxydopamine (6-OHDA) nigral lesions produced similar contraversive circling responses. We suggest that LDEE may be a beneficial antiparkinsonian agent. It has potential pharmacokinetic advantages that are superior to those of levodopa itself, and its subcutaneous administration may become an effective rescue strategy to overcome "off" situations in patients with Parkinson's disease and response fluctuations.

The pharmacokinetic profile of the "first ever" oral dose of levodopa in de novo patients with Parkinson's disease.

To understand the delay in the clinical benefit that commonly occurs after initiation of levodopa (L-Dopa) treatment, we examined the pharmacokinetic profile of L-Dopa after the first oral dose ever taken of L-Dopa/carbidopa in untreated patients with Parkinson's disease and followed these parameters after 1 month of treatment. This was performed in correlation with the clinical therapeutic effect. Plasma levels of L-Dopa were measured with use of high-performance liquid chromatography with electrochemical detection after administration of the "first ever" 125 mg L-Dopa/12.5 mg carbidopa tablet in 15 patients with de novo Parkinson's disease (mean age, 69 +/- 11 y, mean disease duration, 1.5 +/- 0.8 years). Blood samples were drawn before administration and thereafter at various intervals for a period of 4 hours. Repeated measurements after the same oral dose were performed after 1 month of continued therapy with L-Dopa/carbidopa 125/12.5 mg three times daily. Patients were clinically evaluated by unified Parkinson's disease rating scale motor scores. There was a modest clinical improvement after 1 month of continuous L-Dopa treatment (motor scores, 13.1 +/- 11.6 vs. 17.6 +/- 11.7; p < 0.01). Peak plasma L-Dopa levels and area under the curve did not differ significantly between the first-ever dose and after 1 month of continuous treatment (0.9 +/- 0.1 vs. 1.0 +/- 0.1 microg/mL and 66.0 +/- 30.9 vs. 86.2 +/- 34.9 microg/mL, respectively; p < 0.1. There was also no change in time to peak levels between measurements. Results indicate that the first-ever dose of oral L-Dopa is well absorbed and that pharmacokinetic mechanisms such as reduced absorption of L-Dopa probably do not play a major role in the initial delay in clinical response to oral L-Dopa/carbidopa in patients with Parkinson's disease. The latter phenomena may be linked to central pharmacodynamic mechanisms.

Short-term beneficial effect of deprenyl monotherapy in early Parkinson's disease: a quantitative assessment.

It was recently shown that early treatment with deprenyl in patients with Parkinson's disease can delay the need for initiation of levodopa therapy. It was therefore suggested that deprenyl may slow down disease progression. Alternatively, the observed stabilization of clinical disability may merely reflect drug-induced symptomatic benefit. We therefore examined a possible short-term beneficial effect of deprenyl (10 mg/day) as the first and only drug in 15 consecutive de novo patients. Bradykinesia was quantitatively assessed by computerized analysis of isometric force/time curves of biceps and triceps bilaterally and by calculation of simple reaction time (RT) and maximal muscle contraction rate (MMCR). We also measured maximal muscle force, evaluated clinical status by the Unified Parkinson's Disease Rating Scale (UPDRS) motor score, and recorded patients' subjective reports. All tests were carried out before and at 1 and 2 months of treatment. Only one patient reported a beneficial effect. No significant changes in the UPDRS or score or muscle force were observed. In contrast, MMCR and RT improved at 1 month by an average of 12.1 and 7.2%, respectively (p < 0.01, paired t test). This improvement persisted after 2 months of treatment. Study shows that deprenyl monotherapy exerts a short-term beneficial effect in de novo parkinsonian patients. This effect, however, appears to be small, subclinical, and probably cannot account for the observed delay in the need to start levodopa therapy.

Can nimodipine affect progression of motor neuron disease? A double-blind pilot study.

Recently, there has been some evidence suggesting that exposure to neuroexcitotoxic amino acids, culminating in excessive neuronal calcium influx, may cause nerve cell destruction in motor neuron disease (MND). We therefore hypothesized that central calcium channel blockade with nimodipine might slow-down progression of MND. Two patients with sporadic MND were treated in a double-blind placebo controlled cross-over study with oral nimodipine (120 mg/day) for 5 months. Disease progression was assessed by repeated computerized measurements of isometric force from 20 muscle groups, and calculation of global force score. Global force deterioration slopes during the 5-month periods of nimodipine or placebo therapy were highly linear and almost identical. Nimodipine therefore does not seem to be effective in changing the course of MND. The observed remarkable linearity of disease course also confirms that cross-over methodology and serial measurements of muscle force are constructive tools in the clinical evaluation of novel therapeutic strategies for this devastating disease.

Rasagiline mesylate, a new MAO-B inhibitor for the treatment of Parkinson's disease: a double-blind study as adjunctive therapy to levodopa.

Rasagiline mesylate (TVP-1012) is a potent, selective, non-reversible MAO-B inhibitor, without the tyramine-potentiating effect and with neuroprotective activities. The benefit of rasagiline as monotherapy in patients with early Parkinson's disease (PD) has already been reported. To evaluate the safety, tolerability, and clinical effect of rasagiline as adjunctive therapy to levodopa, a multicenter, double-blind, randomized, placebo-controlled, parallel-group study (0.5, 1, and 2 mg/d) was conducted for 12 weeks in 70 patients with PD (mean age, 57.4 y; mean disease duration, 5.7 y; 32 patients had motor fluctuations). A beneficial clinical effect was observed in fluctuating patients treated with rasagiline (all doses), expressed as a decrease in total Unified Parkinson's Disease Rating Scale (UPDRS) score (23.0% vs 8.5% in the placebo group). The treatment effect was still evident 6 weeks after drug discontinuation (in all doses). The safety and tolerability of rasagiline were good. Adverse events were no different than those of patients taking placebo. Almost complete platelet MAO-B inhibition was obtained at all rasagiline doses. This study has demonstrated that rasagiline (up to 2 mg/day) has a good safety profile and a beneficial clinical effect in fluctuating patients with PD when given as an add-on to chronic levodopa therapy.

Abnormal skin wrinkling in the less affected side in hemiparkinsonism-a possible test for sympathetic dysfunction in Parkinson's disease.

Some patients with Parkinson's disease (PD) suffer from autonomic dysfunction, even in the early stage of the disease. We examined the skin wrinkling response following immersion of the hands in warm water in 18 patients with hemiparkinsonism. This test evaluates the function of the sympathetic autonomic system. Mean age of the patients was 61 +/- 10 and mean disease duration 5.5 +/- 3.5 years. Both hands of each patient were immersed in warm water for 30 minutes and the number of skin ridges of the fingertip of each finger was counted. The results of each hand were compared to those of nine healthy controls. The mean number of the ridges of the less affected hand was significantly decreased as compared to the affected hand and controls (6.1 +/- 6.8 vs 13.1 +/- 6.8 and 15.3 +/- 8.5, respectively; P < 0.01). These results suggest that autonomic dysfunction is prevalent in the less affected side of patients with PD and can be simply tested by the skin response test.