Variability in Parkinson's disease; clinical aspects, causes and treatment.

As we have earlier shown, sudden extreme changes in disease severity are a characteristic feature of Parkinson's disease. These variations take two main forms, those natural to the disease and those occurring as a result of treatment. Treatment-related response variations can sometimes be attributed to the known pharmacokinetic properties of anti-parkinsonian drugs and, in particular, levodopa. These responses are time-dependent. In contrast, other types of response variation may be unpredictable in time, and are at present rarely amenable to treatment. Identification of the cause of variation is necessary for the management of parkinsonism, and particularly for the successful use of deprenyl.

Clonidine in Parkinson disease.

Several theoretical considerations suggest that potentiation of central norepinephrine mechanisms may improve motor performance in patients with Parkinson disease receiving concurrent treatment with levodopa. Clonidine hydrochloride, an antihypertensive drug believed to directly stimulate brain norepinephrine receptors, was administered to a group of patients with relatively mild Parkinson disease and coexisting essential hypertension and to three patients with Parkinson disease manifesting the "on-off" response to levodopa. Although a significant antihypertensive effect was achieved, a change in parkinsonian disability could not be demonstrated.

Control of on/off phenomenon by continuous intravenous infusion of levodopa.

In 10 parkinsonian patients with severe, chaotic clinical response fluctuations, oral levodopa treatment was replaced by continuous intravenous infusion of levodopa (with orally administered benserazide). Four patients were also given levodopa infusions in addition to their usual oral treatment. All patients remained continuously mobile and ambulant during the infusions. Side effects were minimal, except in two patients with diphasic dyskinesias whose abnormal movements were consistently suppressed by a further increase in the rate of levodopa administration, only to return after an interval. If a soluble nonacidic dopamine replacement drug can be developed for continuous subcutaneous infusion, "brittle" parkinsonians may be chronically controlled by portable, minipump technology.

Proton spectroscopy in the narcoleptic syndrome. Is there evidence of a brainstem lesion?

There is controversy regarding the relationship of structural or biochemical brainstem lesions to "idiopathic" narcolepsy. Most cases of the narcoleptic syndrome are considered to be idiopathic because no structural lesion is detectable, although some cases of secondary narcolepsy are known to be associated with no structural brainstem lesions. Using proton spectroscopy, we determined levels of ventral pontine metabolite pools in 12 normal subjects and 12 subjects with idiopathic narcolepsy. REM sleep is generated in ventral pontine areas. Proton spectroscopy was used to study levels of N-acetyl aspartate (NAA) as a marker of cell mass, creatine and phosphocreatine (Cr + PCr), and choline (Cho). The intensity of the peaks, as determined by the area under the peak (AUP), was measured. The AUP correlates with the quantity of chemical present. In this study, the ratios of NAA to Cr + PCr were similar in normal subjects and in narcoleptic subjects with idiopathic narcolepsy. No differences in measured metabolic ratio were observed in subjects who slept during the scan procedure compared with those who remained awake. Subjects with "symptomatic" narcolepsy accompanied by an obvious structural brain lesion were not studied. Proton spectroscopy of the brain initiates a new kind of neurochemistry, allowing the noninvasive study of metabolic pools in the living human brain without the use of any kind of tracer or radioactive molecule. In this study, there was no evidence of cell loss in the ventral pontine areas of subjects with the narcoleptic syndrome.

Adverse effects of antiparkinsonian drugs.

In the last decade neurohormone replacement therapy with levodopa has revolutionised the treatment of Parkinson's disease. At the same time the use of amantadine and dopamine-like ergot drugs has developed, although there is still a place for anticholinergic drugs, not in use for a century. These advances have resulted in the availability of many different drugs to treat Parkinsonism with different pharmacological actions. It is now usually possible to control disability, at least in the initial stages of disease, although sometimes at the expense of frequent and disabling side effects. In most cases these result from the widespread distribution of cholinergic and dopaminergic systems inside and outside the brain and the non-selective action of therapeutic agents on these different systems. Despite the recent division of dopamine receptors into D1 and D2 classes, no selective dopamine-like antiparkinsonian drugs are known. The practical treatment of Parkinsonism depends on accurate knowledge of the side effects as well as therapeutic effects of many different drugs, and requires titration of individually determined dosages in different patients to achieve the optimum response. This is usually determined by dose-limiting side effects as well as by improvement. The possibility that the eventual development of response fluctuation and failure may result from the sustained use of large doses of dopamine-like drugs must be considered, and it is probably wise at present to give low rather than high doses of the agents. No presently available treatment appears to influence the natural progression of Parkinsonism.

Bromocriptine in the treatment of parkinsonism.

Bromocriptine alters the motor behaviour of animals and improves the motor defect of parkinsonism. Changes in movement are accompanied by biochemical changes in the central nervous system, consistent with the idea that bromocriptine has a dopamine agonist action in the basal ganglia and also in the mesolimbic system and hypothalamus. The overall anti-parkinsonian effect of bromocriptine is similar to that of l-dopa alone or with benserazide (a decarboxylase inhibitor) when optimum doses are used, although individual patients may respond better to 1 drug than to the other.

Selegiline in narcolepsy.

We examined the effect of the specific monoamine oxidase-B (MAO-B) inhibitor selegiline (deprenyl, Eldepryl), 20-30 mg p.o. daily, in 21 subjects with the narcoleptic syndrome for 4 weeks. Selegiline was compared to no treatment (7 subjects) or conventional central stimulant drugs, including dexamphetamine or mazindol (14 subjects). Severity and frequency of narcolepsy, accessory symptoms, and effects of selegiline on mood were measured. Selegiline, as well as causing MAO-B inhibition, is interconverted to amphetamine. Urinary amphetamine and methamphetamine excretion were determined in 18 subjects after 4 weeks on selegiline and the results were compared with amphetamine excretion in subjects on dexamphetamine. The effect of selegiline, 20-30 mg p.o., on alertness and mood was similar to that of dexamphetamine in the same dosage, with comparable sympathomimetic side effects. Selegiline, 20 mg p.o., caused a subjective increase in alertness for 4-8 h. Mean urinary amphetamine excretion on dexamphetamine, 15-70 mg daily (mean 29 mg) at pH 5.6-6.6, was 5,184 micrograms/24 h, and on selegiline, 20-30 mg daily (mean 22.5), was 4,127 micrograms/24 h. We conclude that selegiline, 20-30 mg daily, requires further evaluation in narcolepsy.

Immune factors in narcolepsy.

Most but not all subjects with the narcoleptic syndrome have the human leukocyte antigen (HLA) DR2 (and DQ1). The narcolepsy-DR2 association is the highest disease-HLA linkage known, and occurs in nonfamilial as well as familial cases of the narcoleptic syndrome. In other forms of daytime drowsiness, there is no relationship with a specific HLA, although some subjects considered to have "essential" hypersomnolence probably have the narcoleptic syndrome. The cause of the narcoleptic syndrome remains unknown, although in a few instances the condition follows infection. There is no evidence for a circulating sleep factor in the blood or in the cerebrospinal fluid of narcoleptic subjects, and no unequivocal marker of cellular immunity has yet been found. However, a few subjects with the narcoleptic syndrome have oligoclonal bands or raised immunoglobulin concentration in the cerebrospinal fluid. It is highly likely that the narcoleptic syndrome is an immune-mediated disorder, occurring in a genetically susceptible (DR2/DQ1-positive) subject.

Continuous subcutaneous lisuride infusions in Parkinson's disease.

Thirteen patients with idiopathic Parkinson's disease and "on-off" fluctuations on oral levodopa plus dopa decarboxylase inhibitor (DDI) were treated with continuous (24 hour) subcutaneous lisuride infusions together with a reduced dose of levodopa (plus DDI). An improvement in motor performance was seen in 10 patients, with a mean increase in percentage of waking time spent "on" of 32 per cent (range 13-59 percent). However, adverse effects were common, especially psychiatric effects, leading to treatment withdrawal in 11 of 13 subjects after a mean of 40 days' treatment. Continuous lisuride infusion together with a small dose of levodopa (plus DDI) are effective treatment for "on-off" fluctuations in Parkinson's disease, but the frequency of adverse effects limits the number of patients who can be treated successfully with this technique.

Comparison of levodopa with carbidopa, and levodopa with domperidone in Parkinson's disease.

In a comparison of the effects of domperidone and carbidopa during levodopa treatment, 20 patients with idiopathic Parkinson's disease were treated with fixed dose regimens of either levodopa 500 mg-domperidone 20 mg or levodopa 100 mg-carbidopa 25 mg; each for 8 weeks. Clinical response, incidence of side effects, and plasma levodopa concentration resulting from each treatment were compared. Overall, in the dosages used, Parkinson's disease was less well controlled with levodopa-domperidone than with levodopa-carbidopa. In eight subjects there was a severe deterioration 2 to 7 days after changing from a fixed dose of levodopa-carbidopa to levodopa-domperidone. In nine subjects who completed the trial, the clinical response, occurrence of dyskinesias and of nausea and vomiting, were similar with both treatments, although peak plasma levodopa concentration and levodopa bioavailability were greater on levodopa-domperidone than on levodopa-carbidopa.

A double-blind trial of clonazepam in benign essential tremor.

Clonazepam has been reported to be of some value in the treatment of benign essential tremor in open trials. The efficacy of clonazepam was evaluated in a double-blind placebo-controlled study using up to 4 mg/day. By a variety of objective measures, clonazepam was not found to be an effective form of therapy.

Use of apomorphine in parkinsonian patients with neuropsychiatric complications to oral treatment.

Neuropsychiatric side effects often complicate anti-Parkinsonian therapy and pose a significant problem in the optimal management of idiopathic Parkinson's disease. Several publications report a relative lack of neuropsychiatric side effects in Parkinsonian patients treated with subcutaneous apomorphine. To investigate this further, we have used subcutaneous apomorphine to treat 12 non-demented IPD patients with previous oral drug-related neuropsychiatric problems. Treatment with apomorphine allowed alteration of anti-Parkinsonian medication and led to the abolition or reduction of neuropsychiatric complications in all patients. The mechanism remains unclear but may be due, in part, to a reduction in oral medication or a psychotropic action of apomorphine, possibly due to the piperidine moiety in its structure, or both.

Functional echoplanar brain imaging correlates of amphetamine administration to normal subjects and subjects with the narcoleptic syndrome.

Two subjects with narcoleptic syndrome and three healthy volunteers underwent functional magnetic resonance imaging during the simultaneous presentation of periodic auditory and visual stimuli both before and after administration of amphetamine. The effect of amphetamine in control subjects was a small reduction in the extent of sensory-induced activation. In the narcoleptic subjects, amphetamine led to an increase in the extent of induced activation within primary and association sensory cortex.

A late haemorrhagic complication in an arteriovenous malformation cured with radiosurgery. Case report.

Radiosurgery is a recognized safe form of treating and usually curing arteriovenous malformations (AVMs). Complications related to radiosurgery, especially late sequelae, are rare. Such sequelae may be secondary to incomplete treatment of the original lesion such as haemorrhage, or secondary to the radiation damage to the tissue, or both. Sometimes treatment may induce new lesions. We report a patient who had an AVM cured with radiosurgery, but developed hemisensory loss acutely and had changes on MRI in keeping with a haematoma. We discuss the possible differential diagnosis that should be considered.