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.

Psychosis: impact on the patient and family.

Psychosis represents a milestone in the progression of PD, often severely taxing caregivers and frequently warranting nursing-home placement. This step is often necessary because caregivers cannot tolerate, among other stressors, their loved ones' sexual aberrations and irrational accusations (which can be caused by paranoid ideation). Other salient features of parkinsonian psychosis comprise vivid nightmares, which often herald its onset; hallucinations, which are principally visual and stereotypical in content; agitation; aggression; delirium; and confusion that exceeds the typical erosion in mentation. Hallucinosis and paranoid ideation may in turn precipitate weight loss; food may be deemed inedible because of imagined contaminants, for instance, either worm infestations or a delusional fear of poisoning by the caregiver. Parkinsonian psychosis exhibits an age predilection; correlates with the duration of disease and levodopa therapy; and may be associated with increases in the dosage of this agent or other drugs given, either as monotherapy or with levodopa. Levodopa or dopamine agonist toxicity can lead to psychosis because of dopaminergic hypersensitivity. Unfortunately, attempts to diminish this untoward effect (eg, reducing the levodopa dosage, introducing neuroleptics) may curb the psychosis but also erode control of parkinsonian features. To avert this "dopamine dilemma," we have tested a selective serotonin antagonist (ondansetron), which essentially attenuated visual hallucinosis, improved delusional ideation and confusion, and was well tolerated. Other agents that can be tried for parkinsonian psychosis include the atypical neuroleptics olanzapine and clozapine.

Early-occurrence of manual motor blocks in Parkinson's disease: a quantitative assessment.

OBJECTIVES: Quantitative analysis of internally-cued, repetitive motor performance in patients with Parkinson's disease (PD). MATERIAL AND METHODS: Computerized quantitative measurements of the frequency, duration and temporal profile of manual motor blocks (MMBs) during performance of a manual tapping task, in 39 patients with PD, as compared to 17 age-matched healthy controls. RESULTS: Performance of PD patients was markedly abnormal both quantitatively and qualitatively, as reflected by an increase (7.0% vs. 4.6%) in MMBs, and by their occurrence from onset of movement. The phenomenon was already observed in the early stages of the disease, and was also correlated with the occurrence of freezing of gait. A standard levodopa-carbidopa (125-12.5 mg) dose only partially affected this phenomenon. CONCLUSIONS: Augmented motor blocks in internally-cued performance should be recognized as a frequent, distinct and generalized feature of PD. Whereas the gait disorder is regarded as characteristic of the advanced stage of PD, our findings suggest that the basic defect in internal rhythm formation can be detected by sensitive measurement tools from the early stages of the disease. In addition, the methodology developed in this study to quantitatively measure manual motor blocks may be a useful tool for future development of therapeutic regimens for this debilitating aspect of motor dysfunction in PD.

[Apomorphine for treatment of "off-periods" in Parkinson's disease].

After 3-5 years of continuous use of 1-dopa preparations for Parkinson's disease, 25%-50% of patients develop side-effects such as the "on-off" phenomenon and involuntary movements that markedly impair function. One cause of these manifestations is evidently a disturbance in the absorption of 1-dopa. We attempted to avoid this problem by using subcutaneous injections. Apomorphine is a rapid-acting dopamine agonist which causes a return from "off" to "on" within minutes. We present the results of a trial of subcutaneous injections of apomorphine in 22 Parkinsonian patients (12 males, 10 females) with severe motor fluctuations. During 5 days prior to the apomorphine all received Motilium (domperidone, 60 mg/d) to prevent nausea and vomiting. All were hospitalized initially to determine optimal dosage and to teach them the technique of self-injection. 2 to 4 mg of apomorphine were injected 1 to 3 times daily for 2 to 12 months. In 17 patients (80%) "off" periods were reduced without significant side-effects. Apomorphine seems to be effective, tolerable treatment for shortening 1-dopa induced "off" periods.

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.

Parkinson Psychosis Rating Scale: a practical instrument for grading psychosis in Parkinson's disease.

The Parkinson Psychosis Rating Scale (PPRS) was designed to assess the severity of specific symptoms of levodopa-induced psychosis in patients with Parkinson's disease. The scale is administered by the clinician and consists of six items, each rated from 1 (no symptoms) to 4 (extreme symptoms); total score ranges from 6-24 points. To test its reliability, validity, and stability, the authors administered the PPRS to 29 patients with parkinsonian psychosis before and after a 6-week course of treatment with the 5HT3 antagonist ondansetron. Each patient and their caregivers were interviewed by three raters. Results were compared with two other available psychotic symptom scales and one cognitive scale given to the same patients. It was found that the interrater reliability for the total PPRS scores and for each of the individual items was high (Spearman's rho = 0.80-0.99). A significant reduction in PPRS scores was obtained after ondansetron administration, concomitant with a decrease in the Global Functional Impairment score, which was assessed by the family. The changes in PPRS scores occurred irrespective of cognitive dysfunction, as measured by the Minimental State Examination. It appears that the PPRS is a relevant, reliable, valid, and easily-administered instrument for measuring the severity of parkinsonian psychosis. Further studies are needed to evaluate its utility in other organic psychoses and in the assessment of additional pharmacologic treatments for levodopa-induced psychosis.

Acute stroke after coronary angiography associated with protruding mobile thoracic aortic atheromas.

We describe two patients who developed acute embolic stroke immediately after coronary catheterization for unstable angina. Transesophageal echocardiography (TEE) and spiral CT of the chest revealed protruding floating atheromas within the aortic arch. These cases of stroke immediately after coronary catheterization suggest that protruding floating atheromas of the thoracic aorta place patients at risk for stroke. TEE or CT might predict a risk of stroke in such patients.

Multiple symmetric lipomatosis presenting with polyneuropathy.

We describe an unusual case of multiple symmetric lipomatosis (MSL) that presented with severe polyneuropathy, and review the literature. To the best of our knowledge, this is the first description of polyneuropathy as the presenting sign of MSL and the first report of this syndrome in Israel. MSL has to be included in the differential diagnosis of unexplained polyneuropathy.

Psychosis in advanced Parkinson's disease: treatment with ondansetron, a 5-HT3 receptor antagonist.

Psychosis, linked to chronic levodopa and other antiparkinsonian drug treatments, is a common and incapacitating complication of advanced Parkinson's disease (PD). The psychosis may be due, in part, to overstimulation of central serotonergic (5-HT) receptors. We treated 16 PD patients who had psychosis of 6 to 60 months' duration with the 5-HT3 receptor antagonist ondansetron (12 to 24 mg daily) in an open-label, short-term (4 to 8 weeks) trial. There was marked to moderate improvement (p < 0.01) in measures of visual hallucinations, paranoid delusions, confusion, and the associated global functional impairment in all but one of the patients, and there was moderate improvement in the Brief Psychiatric Rating Scale and the Nurse's Observation Scale for Inpatient Evaluation; the Mini-Mental State Examination scores remained unaltered. Ondansetron did not cause any worsening in basic PD symptoms or levodopa efficacy and was well tolerated with no major side effects. Our study suggests that pharmacologic blockade of central 5-HT receptors may become a strategy to attenuate PD psychosis without inducing motor deterioration or suppression of antiparkinsonian action of levodopa, and it lends support to the hypothesis that serotonergic mechanisms are pathogenetically important in the emergence of psychosis in PD.

Synovial copper deposition as a possible explanation of arthropathy in Wilson's disease.

A patient with longstanding Wilson's disease and arthritis is presented. Synovial biopsy disclosed thickening of the membrane, intimal histiocytes, and lymphocyte infiltration without pigmentation. X-ray energy spectroscopy demonstrated copper and iron in high concentrations. These findings may contribute to our understanding of the development of the arthropathy in patients with Wilson's disease.

Acute central nervous system complications after pulse steroid therapy in patients with systemic lupus erythematosus.

We describe 2 patients with systemic lupus erythematosus (SLE) who developed an acute psychosis and a cerebrovascular accident after pulse methylprednisolone therapy. A literature review revealed 8 additional patients with SLE with acute central nervous system complications after pulse therapy.

[The diagnostic value of CT and MRI studies in brain-stem tumors].

The combination of lower cranial nerve palsy and contralateral motor impairment, presenting subacutely and following a progressive course in a child or young adult, suggests the possibility of brain-stem tumor. However, if the CT scan is normal, the diagnosis of multiple sclerosis or a vasculitis is frequently considered. Since CT scans may miss lower brain-stem tumors, MRI is recommended as the definitive diagnostic test in such cases.

Transient regional and migratory osteoporosis. A possible neural mechanism.

Transient osteoporosis of the hip is a rapidly developing painful osteoporosis of benign nature and as yet unexplained pathophysiology. We add 5 new cases of transient osteoporosis, 4 of which are regional and 1 migratory, to 70 cases abstracted from the literature. Our review of the literature confirmed that there are two major subgroups of transient osteoporosis: regional and migratory. Two of our cases exhibited abnormal neurological findings. A possible neural mechanism related to regional osteoporosis should be further explored by a meticulous neurological and electrophysiological workup of such patients.

Schizophreniform episode following measles infection.

A case of schizophreniform episode following measles infection in a 27-year-old woman is presented. The possibility that the clinical picture is a first description in the literature of an association between a schizophreniform episode and possible measles-induced allergic encephalitis is discussed. Other possible connections between measles infection and schizophreniform episode are also mentioned.

Pre-eclampsia, "HELLP" syndrome and postictal cortical blindness.

The unusual case of a woman with pre-eclampsia and "HELLP" syndrome associated with postictal transient cortical blindness is described. Immediate delivery should be performed in order to achieve good maternal and neonatal outcome.