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PET examinations using L-18F-DOPA were performed on 14 patients with Parkinsonism-plus syndromes (PPLUS). A rate constant Ki was calculated by a graphical method using an arterial input function. Sequential PET images were obtained and no specific activity was measured both in cortical and cerebellar background regions. These results were compared with those in 20 normal controls and tested for intra- and interobserver variability. All patients with PPLUS showed reduced Ki values with a mean of 0.154 (ml/striatum/min), whereas controls exhibited Ki values with a mean of 0.690 (ml/striatum/min) using cortical background regions. The correlation coefficient was calculated to be r = 0.973 for the intraobserver variability and r = 0.879 for the interobserver variability in controls, and r = 0.989 or = 0.973 in PPLUS, resp. There was no significant difference in the Ki values for cortical and cerebellar background regions (p = 0.1). PET examinations using L-18F-DOPA can reliably assess the extent of nigrostriatal degeneration in vivo. Since this radiotracer binds irreversibly within the striatum PET examinations allow the quantification of a disturbed dopaminergic function which is observer-independent.

Parkinson's disease evolves slowly, and there is current interest in exploring the earliest stages of the disorder, because of new approaches to studying pathogenesis and developing potential neuroprotective treatment. Recognizing early Parkinson's disease is not easy. The certainty of diagnosis increases as the disease advances. To address the problem of identifying Parkinson's disease in its initial phases of clinical expression, we propose the following designated levels of confidence for the diagnosis: (1) clinically possible, (2) clinically probable, and (3) clinically definite. Laboratory support for the diagnosis may be applied to each category. Criteria are provided as a framework underpinning this classification.

Artificial dopamine agonists are widely employed for the treatment of idiopathic parkinsonism. Pleuropulmonary disease has previously been reported to occur with the use of bromocriptine and mesulergine. We report similar adverse effects induced by the newer agonists lisuride and cabergoline. All these agents are tetracyclic ergot derivatives. This suggests a causal link between ergot-derived dopamine agonists and pleuropulmonary disease.

Numerous examples exist where neurotoxins have been shown to induce selective death of certain groups of nerve cells. While the peripheral nerves are particularly vulnerable, neurotoxins are also capable of generating models of the major degenerative disorders of the central nervous system: dementia of Alzheimer's type, Parkinsonism, and amyotrophic lateral sclerosis. Important organic toxins, in this context, include certain pyridines, amines, aminoacids, nitriles, hexacarbons, and sulphides. Inorganic toxins include free radicals and certain metals. Toxins may also be classified according to their origin--exogenous or endogenous. This review will not consider neurological damage that can result from exposure to alcohol, or neurological adverse reactions to medications.

Cynomolgus and rhesus monkeys have been studied via PET with [18F]-L-6 fluorodopa tracer. Striatal fluorodopa uptake rate constants have been derived by graphical analysis of transaxial slice images centered on the striata. The differences between pairs of values of the rate constant, obtained from two scans on the same monkey separated by two weeks or more, exhibited a relative standard deviation of 34.4%. If the two scans were conducted one immediately after the other, with the position of the monkey undisturbed, the standard deviation was reduced to 14.0%. The utility of this technique was demonstrated by comparing the effects on the scans of halothane and pentobarbital anesthesia and by the administration of NSD 1015, a peripheral and central inhibitor of L-aromatic amino-acid decarboxylase, between back-to-back scans. With NSD 1015, the fluorodopa uptake constant was reduced by an average of 76.0%.

We performed sequential positron emission tomography scans with 6-[18F]fluoro-L-dopa in 9 patients with idiopathic parkinsonism and 7 age-matched normal control subjects to compare changes in the nigrostriatal dopaminergic pathway over time. The mean interval between the scans was 3.3 years for the group with idiopathic parkinsonism and 3.9 years for the control subjects. The scans were analyzed by calculating the ratio of striatal to background radioactivity. Both groups showed statistically significant reductions of striatal uptake over the interval. The rate of decrease was almost identical in each group (p = 0.6). We infer that the usual rate of loss of integrity of the dopaminergic nigrostriatal pathway in patients with idiopathic parkinsonism is slow and the rate of change between the two groups was comparable.

Positron emission tomography with 6-[18F]fluoro-L-dopa (6-FD) provides in vivo information on the function of nigrostriatal dopaminergic neurons. We used 6-FD and positron emission tomography to investigate the integrity of the nigrostriatal system in seven patients with progressive supranuclear palsy. All patients had axial hypertonia, vertical gaze palsy, and parkinsonian features. Dementia, pyramidal signs, and ataxia were seen in varying proportions. We analyzed the scans with a graphic method to calculate a steady-state 6-FD uptake rate constant for the whole striatum. Results were compared with those obtained in seven age-matched controls. As a group, the patients with progressive supranuclear palsy had reduced 6-FD uptake constants. The 6-FD uptake constant correlated inversely with the duration of the disease. Normal positron emission tographic findings in one patient with the shortest duration of symptoms suggests that in early progressive supranuclear palsy, parkinsonism may relate to dysfunction distal to the dopaminergic neurons.

In animal models of parkinsonism, the ability to lose a substantial proportion of dopaminergic neurons without behavioral deficits does not derive from other systems taking over function of the dopaminergic pathway. The surviving nigrostriatal projection increases both the rate of synthesis and the release of dopamine, as compensatory adjustments. This capacity allows at least a fivefold rise in dopamine delivery per neuron, and this enhancement is potentiated further by receptor up-regulation. Decreased reuptake, due to loss of nerve endings, may also lead to augmented occupancy of dopamine receptors, and so constitute yet another compensatory mechanism. In humans, positron emission tomography has revealed subclinical impairment of the dopaminergic nigrostriatal pathway in subjects at risk for parkinsonism caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and Lytico-Bodig (the amyotrophic lateral sclerosis-parkinsonism dementia complex of Guam). However, the separation of patients with clinically overt idiopathic parkinsonism from controls is less marked in vivo (by positron emission tomography) than in postmortem analysis (by neurochemical assay). This disparity may be attributable to the reduction in the number of nigrostriatal nerve endings, leading, in vivo, to a relative increase of extracellular dopamine because active reuptake into the nerve endings is an important mechanism for removing dopamine from the synaptic cleft. In contrast, in a postmortem setting, dopamine that is not sequestered in the storage vesicles of nerve endings is readily available for biochemical degradation during the interval between death and brain analysis. Finally, it is also possible that differences may derive, in part, from dissimilar kinetic systems for handling exogenous and endogenous levodopa.

Movement disorders, including Parkinsonism, are prominent features of neurological Wilson's disease (WD). This suggests there may be dysfunction of the nigrostriatal dopaminergic pathway. To explore this possibility, five patients were studied using positron emission tomography (PET) with 18F-6-fluorodopa (6FD), and magnetic resonance imaging (MRI). We calculated striatal 6FD uptake rate constants by a graphical method and compared the results with those of 18 normal subjects. It was found that four patients with symptoms all had abnormally low 6FD uptake, and the one asymptomatic patient had normal uptake. PET evidence for nigrostriatal dopaminergic dysfunction was present even after many years of penicillamine treatment. It is concluded that the nigrostriatal dopaminergic pathway is involved in neurological WD.

Characteristic regional patterns of decreased cerebral glucose metabolism (rCMRG) have been described in a variety of neurodegenerative conditions associated with dementia. The present study was undertaken to determine whether the metabolic pattern in Parkinson's disease is altered by the presence of impaired cognitive function. Glucose metabolism was measured with positron emission tomography in 6 patients with Parkinson's disease and dementia (PDD), 8 patients with Parkinson's disease and normal cognition (PD), and 6 patients with Alzheimer's disease (AD). All AD patients subsequently had the diagnosis proven neuropathologically at autopsy. Correlation coefficients of the metabolic rates across 32 regions of interest were calculated between each pair of patients. Q-component analysis of the correlation matrix showed that the AD and PD groups formed two distinct clusters and that the PDD group had a metabolic pattern which was similar to that of the AD group. Comparison of standardized rCMRG values showed that the PDD group differed from the PD group in having significantly lower relative rCMRG in the left perirolandic and bilateral angular gyrus regions. There were no significant differences between the PDD and AD groups. These results suggest a similar pattern of cortical dysfunction in both Alzheimer's disease and in Parkinson's disease/dementia.

We studied the effect of botulinum-A toxin on spasticity of the leg adductors in 9 patients who were either chair-bound or bed-bound with chronic stable multiple sclerosis. We injected botulinum toxin (400 mouse units) or placebo into the adductor muscles in a randomized, crossover, double-blind design. Two physicians, who were unaware of the treatment order, used an objective rating scale and independently assessed the patients; interobserver correlation was excellent (r = 0.93-0.81). We found that botulinum toxin produced a significant reduction in spasticity (p = 0.009) and a significant improvement in the ease of nursing care (p = 0.009). There were no adverse effects during this short-term trial. This is the first demonstration of the beneficial effect of botulinum toxin on focal spastic muscle contractions.

Two patients with neuroacanthocytosis are described. One presented with parkinsonism and the other resembled diurnal dystonia of the Segawa type. Both patients responded well to dopaminomimetic therapy. A PET scan with fluorodopa revealed a nigrostriatal deficit in the first patient.

We studied the nigrostriatal dopaminergic pathway in 3 patients with Shy-Drager syndrome, by using positron emission tomography and [18F]6-fluoro-1-dopa to determine whether their parkinsonism correlated with impaired functional integrity of the presynaptic nigrostriatal pathway. One patient had short duration of disease, mild parkinsonism, and a normal positron emission tomographic scan, suggesting pathological changes functionally distal to the nigrostriatal pathway. Two patients with longer duration of disease had more severe parkinsonism and reduced [18F]6-fluoro-1-dopa uptake, suggesting impaired nigrostriatal dopaminergic function with progression of Shy-Drager syndrome.

In a double-blind placebo-controlled study, we evaluated the effects of clozapine (75 to 250 mg/day, mean 170.8) on dopaminomimetic psychosis and parkinsonian disability. Clozapine prevented deterioration of psychosis during the increase of dopaminomimetics in the 3 patients who completed the study. Worsening of parkinsonism occurred in 3 of the 6 patients. In the dosage used, clozapine's usefulness was limited by its propensity to produce sedation, confusion, and increased parkinsonism.

We studied 6 parkinsonian patients 6 weeks after unilateral adrenal-to-caudate implants. We withheld medications the night before each of 2 study days and gave the patients a single test dose of either a combination of levodopa and carbidopa, or levodopa alone in double-blind random order. We administered the modified Columbia scale, objective measurements of rigidity and movement velocity, and the pegboard test at regular intervals after the single test dose. The results revealed that the improvements in performance recorded by the Columbia scale and the pegboard test were significantly less on the side contralateral to the operation when patients received carbidopa, whereas there was no significant difference in performance between the 2 observations on the ipsilateral side. Carbidopa apparently crossed the disrupted blood-brain barrier and lowered the efficacy of levodopa.

Cynomolgus monkeys received intracarotid injections of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to produce a chronic unilateral model of parkinsonism. Extensive dopamine (DA) depletion was observed in the caudate nucleus and putamen on the side ipsilateral to the injection and this was associated with contralateral tremor, rigidity, and bradykinesia. A dose of 1.25 mg of MPTP caused ipsilateral DA loss of 99.4% in the caudate nucleus, 99.8% in the putamen, and 74.2% in the nucleus accumbens. A dose of 2.5 mg caused ipsilateral DA depletion of 99.3% in the caudate nucleus, 99.5% in putamen, and 90.1% in the nucleus accumbens. The unilateral aspect of the lesion was dose sensitive, with the 2.5-mg dose causing bilateral asymmetric DA depletion. Tissue concentrations of serotonin were not affected by the toxin. These findings confirm that intracarotid injection of MPTP may produce a useful primate model of hemiparkinsonism that can be associated with selective unilateral DA depletion when the appropriate dose of toxin is used.

Positron emission tomographic (PET) data on local cerebral metabolic rates for glucose (LCMR) are reported for 32 regions of interest (ROI)s in cross-sectional studies on 57 patients with clinically diagnosed Alzheimer's disease (AD) and 20 neurologically normal controls, and in serial studies on 13 of the AD cases, including a familial, young-onset case where the diagnosis has been confirmed at autopsy. Extensive psychological testing was done on all the AD cases. Almost all cortical regions showed a significant decline in LCMR with age in the control subjects. There were the expected cortical metabolic deficits in AD and the serial studies showed a general increase in such deficits over time in 12 of the 13 cases. The regions showing the greatest declines with time in serial studies are the same as those showing the most severe deficiencies in cross-sectional studies. The young-onset case did not show a greater rate of metabolic decline than many of the older cases studied. Results on individual psychological tests tended to correlate with metabolic rates in multiple, rather than single, cortical regions, suggesting intact neuronal networks are required for good performance. The correlations with cortical metabolic activity found were of a sign indicating that the higher the metabolic rates and the better the left:right asymmetry index, the better was the performance.

The cause of neurodegenerative disease is considered. For Alzheimer's disease, Parkinson's disease, and motoneuron disease, accumulating evidence over the last 3 years indicates that (a) the usual etiological mechanisms involve a subclinical lesion which kills some neurons and reduces the life expectation of their surviving neighbors, and (b) there may be more than one cause for each of the idiopathic syndromes now termed AD, PD, and MND.

A 25-year-old man developed classical hydrophobic rabies 3 months after being bitten on the face. We present his involuntary movements on videotape and discuss the clinical and epidemiological features of rabies. Though rabies is seen in tropical countries commonly and in North America occasionally, recording of the clinical features is rare.

Treatment of refractory PD with autologous adrenal medullary implants utilizing two-stage surgery warrants further investigation. This transplantation technique is associated with prolonged transplant area BBB disruption which may require a change in medical treatment strategies including the withdrawal of peripheral dopa decarboxylase inhibitors and possible intravenous or intraventricular dopamine therapy. Of 5 patients receiving adrenal medullary transplants, 3 have demonstrated varying degrees of clinical improvement which has persisted for the duration of the study. The positive correlation between clinical outcome and caudate function (i.e., 6-fluorodopa PET scans) suggests a positive influence of the transplantation procedure on the diseased striatum. Whether or not the grafted tissue remains viable for an extended period is currently being investigated utilizing 6-FDG-PET studies. Because of the presence of persistent BBB disruption, we surmise that at least viability of implanted fenestrated adrenal medullary capillaries exists. We conclude that this prolonged leakage is the result of the implanted tissue rather than the cavitation procedure as prolonged BBB disruption was not witnessed in a control group of patients with post-traumatic cerebral contusions or in Parkinson's patients subjected to thalamotomies. Whether two-stage surgery results in increased graft viability, and host neuronal sprouting, leading to prolonged clinical improvement and slowing the progression of PD awaits continued longitudinal (greater than 24 months) studies.

Of all the movement disorders, Huntington's disease has been most consistently associated with dementia, while it is only over the last decade that intellectual cognitive decline have been recognized as common features of Parkinson's disease. It is now known that the pathology in these two conditions reflects differential involvement of the striatum. The Huntington lesion is primarily in the caudate, while the Parkinson lesion preferentially affects the putamen. Both conditions have more diffuse pathology, and dementia may also occur in a wide range of other extrapyramidal diseases, such as progressive supranuclear palsy, the parkinsonism-dementia complex of Guam, and certain spinocerebellar degenerations. Clinicopathological correlations will be reviewed in these disorders of primarily subcortical pathology, and comparisons will be made with Alzheimer's disease, a disorder of predominantly cortical pathology.

1. Five-carbon-atom organic acids (C-5 acids) have been administered intravenously to rabbits with ventriculocisternal perfusion and continuous electroencephalographic recording (EEG). The concentration of the acids in the cerebrospinal fluid (CSF) perfusate have been compared with changes in integrated low-frequency activity in the EEG. 2. The C-5 acids investigated were those accumulating in inborn errors of metabolism, i.e. isovaleric acid, beta-methylcrotonic acid, tiglic acid and alpha-keto- and alpha-hydroxy-isovaleric acid. There activity was compared with that of valeric acid. 3. Valeric acid and isovaleric acid produced coma and pronounced increase in slow-wave electrical activity and these changes paralleled the increase in concentration of the acids in the CSF perfusate. 4. The concentration of beta-methylcrotonic acid and tiglic acid in the CSF perfusate reached values comparable with valeric acid and isovaleric acid but showed less encephalopathic activity. An interaction between beta-methylcrotonic acid and isovaleric acid was observed. 5. Although the concentrations of alpha-ketoisovaleric acid and alpha-hydroxyisovaleric acid rose to the lesser extent in the CSF perfusate, changes in rousability of the animal and in the EEG recording were demonstrated. 6. It is concluded that all the C-5 acids tested have encephalopathic activity although this is lessened by the presence of either a double bond or an oxygenated functional group.

Twenty-four parkinsonian patients compared pergolide and bromocriptine therapy in a randomized double-blind, two-period crossover study. Both drugs were adjusted to an optimal balance between benefits and side effects. The mean daily dose and dose range for pergolide and bromocriptine were 3.3 mg (0.7 to 7.2) and 42.7 mg (5.8 to 87.5), respectively. Adjunctive medications, which for most patients included levodopa (plus carbidopa), were not altered during the study. A similar spectrum of clinical effects was found with both drugs and with lisuride, which was used to treat 13 of the patients in a previous study. Despite neurochemical differences in the antiparkinsonian ergots, their clinical utility is quite similar. We draw attention to hepatotoxicity and pleural reactions that may occur rarely with these drugs.

In cynomolgus monkeys, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces irreversible clinical, chemical, and pathological alterations that are similar to those found in Parkinson's disease. Unilateral carotid injections of this toxin produce ipsilateral nigrostriatal dopamine depletion while sparing the contralateral dopaminergic pathways. In order to study the damage to the nigrostriatal dopamine system in asymptomatic animals after unilateral MPTP administration, positron emission tomography (PET) scans were performed with [18F]fluoro-L-dopa (6-FD). This study demonstrates that clinically asymptomatic MPTP lesions may be assessed in vivo using 6-FD and PET.

We argue against the dominant status assigned to conventional microscopy in the categorization of disorders such as Alzheimer's disease, Parkinson's disease and ALS. As an example we criticize the emphasis that has been placed on correlating the presence of Lewy bodies with the diagnosis of Parkinson's disease. In essence, we submit that Parkinson's disease can exist without Lewy bodies, and Lewy bodies can exist without Parkinson's disease. Nevertheless, we consider that the newer techniques available to histology have led to an important concept that constitutes a shared feature for Alzheimer's disease. Parkinson's disease and ALS; they are all characterized by the deposition of cytoskeletal debris in tissue, so they may perhaps be collectively termed the "Cytoskeletal Disorders".

Rapid voluntary eye movements in bradykinetic parkinsonian patients and normal subjects were recorded when the movement was executed with visual feedback (closed-loop mode) and in darkness without visual feedback (open-loop mode). The patients had a tendency to generate abnormal saccades consisting of multiple small steps (multiple step saccade), both in the closed-loop and open-loop mode. They were, however, also capable of generating large amplitude saccades. The amplitude-velocity relation of both the small step saccades and the large saccades was normal. The presence of multiple step saccades in the open loop mode suggests that the patients used internal rather than external (visual) feedback to compare the actual eye position with the desired (programmed) eye position and the program for rapid movement is normal but its execution is defective. Horizontal eye movements were also recorded when the head was stationary with a target moving sinusoidally, and when the target was stationary with the head rotated sinusoidally. In both cases the amplitude of the eye movement relative to the head was about 50 degrees. The patients were observed to generate irregular, saccadic eye movements in pursuit of a slowly moving target when the head was stationary, but their eyes could follow a stationary target smoothly when their eyes could follow a stationary target smoothly when their head was moved sinusoidally. These findings suggest that the neuronal circuitry in the paramedian pontine reticular formation, responsible for the final integration of different types of eye movements, is physiologically normal in Parkinsonism.

Both reaction time and movement time tend to be prolonged in Parkinson's disease, but they are often impaired independently of each other. Prolongation of RT is relatively slight, while MT undergoes more substantial and consistent disturbance. Choice RT and kinaesthetic RT do not have any advantage over simple visual RT as measurements of neurological deficit in parkinsonism, since they are all impaired to the same extent. MT is more useful than RT as an objective indicator of therapeutic efficacy, but further studies of RT (with tests requiring programming of displacement, velocity, and accuracy) may provide insights into the nature of the central motor disorder in Parkinson's disease.

Eight out of 12 unselected patients with Shy-Drager syndrome were found to have severe bilateral paresis of vocal cord abduction by fibre-optic laryngoscopy. This commonly presented as increased snoring followed by episodes of inspiratory and expiratory stridor and sometimes by sleep apnoea. Respiratory failure eventually developed in four cases and was reversed by tracheostomy. In another patient tracheostomy relieved severe attacks of sleep apnoea. This complication was not necessarily associated with advanced disease, and it should be considered in all patients with Shy-Drager syndrome as appropriate treatment can lead to a useful extension of life.

A pigmentary retinopathy resembling that sometimes seen in posterior ophthalmomyiasis interna was found in 26 (53.1%) of 49 Chamorro patients from Guam who have Lytico-Bodig (also known as amyotrophic lateral sclerosis-Parkinsonism-dementia complex of Guam). In nine cases, the retinopathy was bilateral. Similar changes were found in 6 (16.2%) of 37 clinically normal individuals from southern villages on Guam that have a high incidence of Lytico-Bodig, and in 1 (3.1%) of 32 individuals from Saipan, an island north of Guam that has a low incidence of the disease. These results indicate the possibility of an association-between Lytico-Bodig and a retinopathy on Guam that may be parasitic in origin. Occurrence of a similar association in other debilitating diseases on Guam and frequency of occurrence of retinopathy in Guamanians with Lytico-Bodig after leaving Guam have yet to be determined.

Continuous intravenous infusion of levodopa was used for eight days to manage a parkinsonian patient with "on-off" fluctuations who underwent abdominoperineal resection for carcinoma of the rectum. Reasonable control of parkinsonism was obtained initially with small doses of levodopa, but more than 4 g daily were eventually required. No adverse effects on cardiac rhythm, blood pressure, or gastrointestinal function occurred. Frequent adjustment of levodopa dosage was necessary in view of continuing "on-off" fluctuations. Severe akinesia, which can cause dysphagia, respiratory complications, and venous stasis in the legs, can benefit from this method of management after major abdominal surgery in a patient with advanced parkinsonism.

The dopamine depletion that is characteristic of Parkinson's disease has been hypothesized to result from the combination of environmentally induced subclinical damage to the substantia nigra and the age-related loss of additional nigral neurons. Essential to this hypothesis is the existence of deteriorating function in the nigrostriatal pathway with advancing age. The present study was undertaken with [18F]6-fluoro-L-dopa and positron emission tomography to determine in vivo the effects of age on the nigrostriatal pathway in a series of 10 asymptomatic subjects (age range, 22-80 years; mean, 49.8 years). A graphical approach was used in the analysis of multiple-time tracer-uptake data to establish the presence of a compartment with unidirectional uptake and to calculate the rate constant, K, for uptake of [18F]6-fluoro-L-dopa from blood to striatum during steady-state, an index of the functional integrity of nigrostriatal nerve endings. There was a significant linear relationship between K and age (r = 0.80, p less than 0.005) with a decrease of 53.3% over the age range studied. These results demonstrate the application of a unidirectional transfer model to the analysis of [18F]6-fluoro-L-dopa and positron emission tomography data and provide in vivo confirmation of an age-related impairment of nigrostriatal function.

The early clinical diagnosis of parkinsonism has been reviewed, together with consideration of investigations that may be helpful in certain cases. The controversial issues of management in early Parkinson's disease have been addressed, and some newer concepts of early diagnosis and management have been discussed, deriving from the study of a population of patients exposed to MPTP.

The measurement of movement time provides a satisfactory objective measure of hypokinesia in parkinsonism. It is relatively constant in normal subjects, and it is often greatly prolonged in parkinsonism and correlates with clinical disability. The reaction time is only of limited value, because of small difference from normal values and wide individual variations.

The single and multiple oral dose plasma kinetics of lisuride were followed by a recently developed radioimmunoassay method in 11 patients with Parkinson's disease. A very wide range of plasma drug concentrations resulted from a single dose of 300 micrograms, as reflected in large interindividual differences in peak concentration (0.27 to 3.30 ng/ml) and AUC after the initial dose (43.1 to 617 ng X min/ml). Absorption was rapid, with a mean time to peak of 39 min. Only 0.05% of the dose was excreted unchanged in urine in 24 hr. There was a 110% increase in apparent oral clearance after 2 to 4 wk of treatment.

We have treated 102 Parkinson patients with bromocriptine for up to 6 years; most of these posed problems of management when referred to us. Forty-two continue to take bromocriptine, at a mean dose of 49 mg daily (range 10-160), in combination with some 50% of their previous optimal dose of levodopa (with or without a decarboxylase inhibitor). We consider the main indications for bromocriptine are severe dyskinesia, early morning dystonia, and "wearing off" reactions. Contraindications include hallucinations, delusions, substantial confusion, acute myocardial infarction, active peptic ulceration, and active pleuropulmonary disease.

Two recent sporadic cases of progressive Parkinsonism after encephalitis are described. Both patients had two oligoclonal protein bands in their CSF. These bands were not present in patients with idiopathic Parkinson's disease and might, therefore, be useful for diagnostic purposes, particularly when the history of encephalitis is uncertain.

92 patients with parkinsonism have been treated with bromocriptine for up to 30 months. 48 continue to receive bromocriptine with benefit; of these, 35 take bromocriptine (mean dose 53 mg daily) in combination with levodopa and 13 take bromocriptine (mean dose 45 mg daily) without levodopa. In those who were originally on levodopa, addition of bromocriptine allowed a mean 41% reduction in the dose of levodopa; the largest group of patients to benefit from bromocriptine entered the study because of excessive dyskinesia or "on-off" phenomena induced by levodopa. In 40 patients bromocriptine was stopped because of adverse reactions, absence of therapeutic response, or non-compliance with the protocol. The main problems were psychiatric disturbance (8 patients) and erythromelalgia (7 patients); these effects tended to occur late (mean 6 months and 10 months, respectively) and with high dosage (mean 66 mg and 115 mg daily). Other frequent adverse effects were dizziness and nausea; these began considerably earlier (at 2 months and 1 month) and with much lower dosage (31 mg and 12 mg daily). 4 patients died, for reasons apparently unrelated to therapy.

The quantitative assessment of clinical deficits in Parkinson's disease has become more difficult due to such factors as the introduction of therapy that induces involuntary movements, the recognition of marked fluctuations in response to treatment, and an increasing of memory disturbance in patients. An attempt to take these problems into account using a brief and simple scale of evaluation is presented.

Over the last two decades there have been spectacular advances in understanding and treating Parkinson's disease, but there remain major areas of uncertainty and ignorance. The nigrostriatal pathway has features resembling the peripheral sympathetic system, rather than conventional central projections of sensory and motor nuclei. Like sympathetic activity, nigrostriatal function is diffuse, tonic, and more accessible to analysis by measuring biochemical rather than electrical changes. These findings are difficult to interpret in the context of the established importance of the basal ganglia in programming movement. The role of the depletion of dopamine in Parkinsonism is also unclear; we do not even know whether the impact of the deficit is more significant in the basal ganglia, or the substantia nigra. Confusion over the actions of dopamine underlies the obscurity of the mechanisms by which levodopa produces both wanted and unwanted effects. Finally, the nature of Parkinson's disease is still an enigma: we have not identified its cause, and we do not know what influences its progress.

We found abnormal supranuclear ocular or lid motility in all of 37 patients with Lytico-Bodig (amyotrophic lateral sclerosis/parkinsonism-dementia complex). Twenty-one patients had pursuit paresis, 18 abnormal vestibulo-ocular reflex (VOR) cancellation, 15 abnormal convergence, 13 abnormal optokinetic nystagmus (OKN), 12 conjugate gaze limitation, nine nystagmus, nine saccadic paresis, and six abnormal fixation. Lid abnormalities included glabellar hyperreflexia in 21, involuntary levator inhibition in three, and blepharospasm in two. Earlier reports have indicated infrequent ocular disturbances in Lytico-Bodig, but we now find supranuclear eye and lid deficits are universal and sometimes very prominent.