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Rats were treated for 12 months with L-dopa (191.4-210.4 mg/kg/day) plus carbidopa (23.9-26.2 mg/kg/day), or carbidopa (24.4-26.3 mg/kg/day) alone. Four days after drug withdrawal, animals received an acute challenge with either L-dopa (50 mg/kg p.o.) alone or following acute carbidopa (25 mg/kg i.p.) pretreatment, and the uptake and metabolism of L-dopa in muscle was studied. Following the acute bolus challenge, plasma levels of L-dopa peaked between 0.5 and 3 h after L-dopa alone and between 1.5 and 2 h after L-dopa plus carbidopa. Peak levels in muscle were observed between 1.5 and 4 h after L-dopa administration, and this accumulation was enhanced by the acute pretreatment with carbidopa. Chronic administration of L-dopa plus carbidopa or carbidopa alone for 12 months had no effect on the accumulation of L-dopa into muscle following the acute challenge with L-dopa alone or after carbidopa pretreatment. 3-O-Methyldopa, dopamine, DOPAC, and HVA levels were elevated in both plasma and muscle following acute oral challenge with L-dopa or L-dopa plus carbidopa. Levels of these metabolites were unaffected by chronic administration of L-dopa plus carbidopa or carbidopa alone. In conclusion, chronic administration of L-dopa plus carbidopa did not alter the accumulation of L-dopa into muscle following an acute oral challenge with the drug, with or without carbidopa pretreatment.

Conventionally, the standard test for detection of antibodies against botulinum toxin (BT-A) has been the mouse lethality assay (MLA). Because this test has a number of disadvantages, a novel mouse protection assay (MPA) was recently introduced. We sought to compare the results of both tests. Forty-three samples from 38 patients with cervical dystonia and complete or partial subjective BT-A therapy failure underwent simultaneous MPA and MLA testing. Twenty-seven samples showed concordant results in both tests. Eleven of them were MPA- and MLA-positive and 16 MPA- and MLA-negative, resulting in a significant association of the dichotomous test results (Fisher exact test, p

Paroxysmal dystonic choreoathetosis (PDC) is an unusual hyperkinetic movement disorder characterized by attacks of chorea, dystonia, and ballism with onset in childhood. We report a large British family with dominantly inherited PDC linked to chromosome 2q and describe the clinical features in 20 affected family members. Attacks were precipitated by a variety of factors, including caffeine, alcohol, or emotion, and could be relieved by short periods of sleep in most subjects. The clinical features in the family are compared with those of 11 other PDC families in the literature and a core phenotype for PDC suggested. CSF monoamine metabolites measured at baseline and during an attack in one subject were found to increase during the attack. Magnetic resonance spectroscopy of brain and basal ganglia performed both during and between attacks was normal. Positron emission tomography using the D2 receptor ligand, 11C-raclopride, showed no abnormalities.

The existence of "benign hereditary chorea" (BHC), a rare disorder of childhood-onset familial chorea without other neurologic features or progression, has increasingly been questioned, because many patients with this disorder were subsequently diagnosed with different conditions. We therefore analyzed all published reports of families with BHC and contacted their authors to obtain follow-up information. In addition, we reviewed all patients in whom at least one of the authors had at some stage considered a possible diagnosis of BHC. Of 42 families reported to have BHC in the literature, we obtained follow-up information on ii families, three of which had been seen by us. An additional seven new, unreported families and four sporadic cases, in which this diagnosis was suspected by at least one of us at one point, were reviewed and videotaped. On reviewing the videotapes of the II families in the Literature, the diagnosis of BHC was changed in nine. In the remaining two families, atypical features suggesting different diagnoses were present in the original reports. In none of our own previously unreported patients (seven familial and four sporadic) was BHC diagnosed unequivocally by all evaluators after review of their video recordings. In three of these families and all four sporadic patients the diagnosis was changed; in one family multifocal myoclonus could, not be differentiated from chorea by any author, and in the remaining three families no consensus between the raters was found. Apart from the II families in whom we obtained follow-up information, analysis of the remaining 31 reports on families with BHC also revealed atypical features in the majority. We conclude that BHC is not a diagnosis, but a syndrome that requires further investigation. Whether there is a distinct entity "BHC" with a single gene abnormality remains to be proven.

In a preliminary report we demonstrated an association between the slow acetylator genotype of N-acetyltransferase 2 (NAT2) and familial cases of Parkinson's disease (FPD). Using a considerably more precise NAT2 typing method, which detects all mutant NAT2 alleles with a frequency of >1% in the white population, we have now retyped all the original patients and control subjects to investigate the reliability of our initial findings. The slow acetylator genotype remained considerably more common among FPD (73%) than normal control subjects (NPC, 43%) or the disease (Huntington's disease [HD]) control group (52%) with an odds ratio (OR) of 3.58 (95% confidence interval (CI): 1.96-6.56; p = 0.00003) for FPD versus NPC and an OR of 2.50 (95% CI: 1.37-4.56, p = 0.003) for FPD versus HD. Furthermore, the wild-type allele 4 conferred a protective effect with an OR of 0.39 (95% CI: 0.23-0.64; p = 0.0025) for FPD versus NPC and an OR of 0.50 (95% CI: 0.30-0.85, p = 0.01) for FPD versus HD. The results of this study support an association between the NAT2 slow acetylator genotype and FPD in our population.

It is generally recognized that focal dystonia of the limbs or cervical region and blepharospasm sometimes follow, and in these cases may be caused or triggered by, peripheral injury. However, the association between peripheral injury and lower cranial dystonia is rare. We report eight cases who developed cranial dystonia within hours to months following a dental procedure. One group of five cases, all women, developed atypical dystonia associated with painful paresthesias at the site of dystonia. Two of these five cases had fixed jaw-deviating dystonia, whereas the remaining three had additional tremor and spread of their dystonia to involve the tongue in all three, and the lips and neck in two cases. These five patients are reminiscent of cases of limb causalgia-dystonia syndrome, which occurs after minor peripheral trauma and can spread. The remaining three cases developed more typical cranial dystonia following the dental procedure. There was no family history of dystonia or prior use of neuroleptics in any of the patients. The close association in time and location of the procedure and onset of symptoms suggests that the onset of the dystonia may have been caused by the dental intervention, but whether there is a causal relationship between the dental intervention and the development of the dyskinesias requires further epidemiologic studies.

Most positron emission tomography (PET) studies of regional cerebral function in idiopathic torsion dystonia (ITD) have failed to show abnormalities, but there have been few studies of the changes in regional cerebral blood flow (rCBF) that occur during movement in dystonia. Using PET, we have studied six patients with familial generalized ITD both at rest and while moving a joystick with the right hand. The patterns of CBF change obtained were compared with those in six age-matched control subjects. In the dystonia group, free selection of movement was associated with relative increases in rCBF above that observed in control subjects in the left premotor area, the supplementary motor area (SMA), the anterior cingulate cortex, and the left dorsolateral prefrontal area. Subcortical increases were observed within the cerebellum and the putamen. There was a relative decrease in flow through the contralateral primary sensorimotor cortex. These findings contrast with those reported in patients with Parkinson's disease undertaking the same task in which the activity in the SMA and putamen was decreased. We suggest that arm dystonia in ITD is associated with overactivity of the premotor areas, including the SMA, and that this results from release of the thalamus from the normal inhibitory influence of the globus pallidus internal segment. Other abnormalities of basal ganglia control of brain stem centers may be involved in axial dystonia.

We report eight new sporadic cases of paroxysmal dystonia induced by prolonged or sustained exercise and review an additional seven previously reported cases. The attacks in our patients lasted from a few minutes to up to 2 h, and patient age at onset ranged from 2 to 30 years. Four of the eight patients had hemidystonic attacks, both legs were involved in two other cases, and the remaining two patients had involvement of the right foot only. We propose that such cases should be classified as paroxysmal exercise-induced dystonia.

Oral administration of levodopa (L-dopa) (2.5–25.0 mg/kg) plus carbidopa (12.5 mg/kg p.o.) to MPTP-treated common marmosets produced a dose-related increase in locomotor activity and a corresponding decrease in motor disability. Pretreatment with the peripheral COMT inhibitor entacapone (12.5 mg/kg p.o.) enhanced the intensity and duration of the increase in locomotor activity and the reversal of motor disability produced by a threshold dose of L-dopa (2.5 mg/kg p.o.) plus carbidopa. By contrast, entacapone pretreatment did not potentiate the increased locomotor activity or reversal of motor disability produced by a near-maximal dose of L-dopa (12.5 mg/kg p.o.) plus carbidopa. The effects of entacapone (5.0–25.0 mg/kg p.o.) were dose related, with doses of >12.5 mg/kg tending to produce less potentiation of L-dopa's effects compared to lower doses. Pretreatment with entacapone (12.5 mg/kg p.o.) without carbidopa caused a short-lasting enhancement of L-dopa's (12.5 mg/kg p.o.) action, whereas pretreatment with carbidopa (12.5 mg/kg p.o.) alone had a more dramatic effect. However, pretreatment with both carbidopa and entacapone produced the greatest overall motor response. In conclusion, entacapone enhances the motor response produced by a low threshold dose of L-dopa plus carbidopa. However, optimization of both the dose of L-dopa and entacapone appears necessary to obtain the maximal therapeutic response.

Estimates of points of entering and exiting from upright posture were obtained from 25 seated, restrained patients with idiopathic spasmodic torticollis (ST) and matched normal subjects exposed to cycles of 1.5 degrees/s tilts in a flight simulator. Estimates were obtained for displacements in roll and pitch about upright and for yaw tilts about a rostrocaudal, "barbecue," axis with the subjects supinated. For both pitch and roll, normal subjects estimated entering upright when they were still approximately 1 degree from machine upright and perceived themselves to be upright through a mean arc of 6 degrees. In barbecue tilt, entering upright was estimated at 0.2 degree for an arc of 6 degrees. Patients estimated entering upright at 2.8 degrees in roll and 3 degrees in pitch but estimated exiting upright at the same tilt as normal subjects; that is, they were less specific in detecting verticality. Patients were normal in barbecue tilt. No relationship between tilt estimates and head deviation was found. There were no differences between normal subjects when tested with their head in normal posture and with an assumed tilt of 20 degrees. Normal subjects probably based their estimates on combined vestibular-somatosensory signals, whereas torticollis patients appeared to derive more from a vestibular signal. However, patients referred the vestibular signals to the trunk long axis when asked to indicate the whole-body vertical. The findings suggest disruption of the normal combined vestibuloproprioceptive mechanism for detecting body uprightness in ST.

Multiple system atrophy (MSA) is a clinico-pathological entity distinct from idiopathic Parkinson's disease (PD) that is responsible for 5-10% of cases of parkinsonism. Degeneration of nigral neurones is a feature of both diseases. A specific deficiency of mitochondrial complex I activity has been found in PD substantia nigra. We have analysed mitochondrial function in substantia nigra and platelets from MSA patients to identify any respiratory chain defect in this disorder and to determine its tissue specificity. As our MSA patients had been on L-DOPA, we also sought to establish whether this treatment could cause the complex I defect as seen in PD. We found no significant difference in respiratory chain activity corrected for mitochondrial mass between control and MSA patients in either of the tissues studied. These results provide a biochemical dimension to the differences between MSA and idiopathic PD. In addition, the fact that L-DOPA failed to induce a complex I defect in MSA substantia nigra suggests that this treatment is unlikely to cause the complex I deficiency in PD, without additional factors that may operate in PD.

The clinical and neurophysiologic features of 14 patients with chronic posthypoxic myoclonus are presented. Patients were first seen a mean of 2.5 years (range, 2 to 105 months) after the hypoxic event and followed up for 3.7 years (range, 7 to 84 months) thereafter. All patients had had a cardiorespiratory arrest, most caused by an acute asthmatic attack (11 cases). All patients had multifocal action myoclonus. Eleven patients had additional stimulus-sensitive myoclonus. There was late improvement in the myoclonic syndrome and the level of disability in all but one patient. Three patients were eventually able to discontinue antimyoclonic medication, and five patients were able to walk unaided. Cognitive deficits were found in seven patients and were usually mild. Other neurologic deficits were rare. Electrophysiologic investigation confirmed cortical action myoclonus in every case, although this could be combined with cortical reflex myoclonus, an exaggerated startle response, or brainstem reticular reflex myoclonus. We conclude that posthypoxic myoclonus typically consists of multifocal cortical action myoclonus that improves with time. It is only rarely associated with severe additional neurologic deficit.

We have developed a rodent model of striatonigral degeneration, one of the core pathologies underlying the disease multiple system atrophy (MSA). 6-Hydroxydopamine (6-OHDA) was administered into the left medial forebrain bundle of male Wistar rats, followed 3-4 weeks later by intrastriatal injection of quinolinic acid into the ipsilateral striatum. The 6-OHDA lesion resulted in ipsilateral rotation to (+)-amphetamine and contralateral rotation to apomorphine. Following the subsequent striatal lesion, amphetamine-induced ipsilateral rotation persisted, but apomorphine-induced contralateral rotation was reduced or abolished. Subsequently, the lesioned striatum was implanted with fetal CNS allografts consisting of cell suspensions derived from striatal primordium alone or combined with cografts of ventral mesencephalon. Cografted rats showed a reduction or reversal of amphetamine-induced rotation. This was not observed in animals receiving striatal grafts alone. Apomorphine-induced contralateral rotation was restored after striatal grafts alone, but only partially in animals receiving sham or cografts. Tyrosine hydroxylase (TH) and dopamine- and cyclic adenosine 3':5'-monophosphate-regulated phosphoprotein (DARPP 32) immunocytochemistry showed mesencephalic and striatal graft survival in most animals. However, dopaminergic outgrowth was restricted to the graft deposit. The latter was surrounded by a markedly gliotic glial fibrillary acidic protein-positive capsule continuous with corpus callosum. Dopaminergic reinnervation of denervated and lesioned adult striatum itself was absent, suggesting that rotational recovery was due to diffuse dopamine release. The study shows that combined unilateral lesioning of rodent medial forebrain bundle and striatum results in a characteristic drug-induced rotational response that can be partly restored by mesencephalic/striatal cografts.

We report the results of treatment of 16 patients (14 women, two men; 18-81 years old) with nonoccupational limb and trunk dystonia with botulinum toxin A (BTX; Dysport). A total of 18 clinical problems were identified. Outcomes were assessed in terms of pain relief and improvement in posture and function by the combined observations of the patient and physician. Patients' satisfaction with treatment was high--the benefit in 15 of 18 problems was rated as good to excellent. Reduction in pain was achieved in nine of 10 painful problems, with total relief in four cases. Some normalisation of posture was obtained in 17 of 18; it was complete in three cases. Functional improvement was less common (10 of 18). Excessive weakness was the most common side effect, affecting five patients, but it was disabling in only two. We conclude that BTX can provide substantial benefit with minimal side effects in the majority of patients with these conditions, particularly with pain relief and postural improvements.

Dyskinesias occur in the majority of patients with Parkinson's disease chronically treated with L-DOPA and also occur in several nonhuman primate species after 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) and L-DOPA treatment. The common marmoset (Callithrix jacchus) shows parkinsonian motor deficits after MPTP administration, and we now report dyskinesias occurring in this species during chronic L-DOPA exposure. Marmosets rendered chronically parkinsonian after MPTP administration were treated orally with L-DOPA plus carbidopa for 3 weeks. After several days the animals began to display chorea, choreoathetosis, and dystonia. The severity of dyskinesias varied between the animals, with the most severely parkinsonian animals displaying the most dyskinetic movements. Each animal showed an idiosyncratic pattern of dyskinesias, which was highly reproducible. These L-DOPA-primed animals also received other D2 D1, and mixed D1/D2 agonist drugs. Quinpirole, bromocriptine, pergolide, apomorphine, and A-77636 all produce dyskinesias that were identical in character to those seen after L-DOPA administration, but the D1 agonist A-77636 gradually abolished dyskinesias while preserving its antiparkinsonian activity. The MPTP-treated marmoset provides a useful model in which to study dyskinesias in Parkinson's disease and to examine new therapeutic strategies aimed at alleviating this common side effect of chronic dopamine replacement therapy.

Voluntary movements, such as the self-paced finger extension task used in the present experiments, are preceded by a slowly rising negative electroencephalographic potential [the movement-related cortical potential (MRCP)]. The early NS1 component of the potential was no different in patients with primary dystonia affecting the arm (n = 6) compared with matched controls. In contrast, the peak amplitude of the MRCP was smaller in the patients, despite the fact that the movements made by the two groups were very similar; it was of equal size over both left and right hemispheres, rather than being larger on the side contralateral to the movement. These results are similar to those observed by others in patients with symptomatic dystonia secondary to lesions of the basal ganglia or their output pathways and may reflect abnormal basal ganglia input to motor areas of cortex before the onset of a self-paced movement.

We developed a teaching tape of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS) to provide investigators with a visual document of three raters' interpretations of the scoring system for each item except rigidity. The rate of agreement for the selected samples was always significant, with Kendall's coefficient of concordance W ranging between 0.97 and 0.62. We also provided full UPDRS ratings on sample patients that may be used for training and for multicenter studies to assure uniformity of rating. The study identified several items of the UPDRS motor examination for which written instructions were vague, including speech, action tremor, finger taps, rapid alternating movements, and postural stability. Future versions of the scale should address these problems and correct ambiguities. This project offers the first attempt to provide a visual analog for the UPDRS.

The cerebral activity preceding voluntary, self-paced ankle dorsiflexion movements while seated was compared with that before a stepping movement of the same foot while standing in four patients with isolated gait ignition failure. Results within the patients group were variable, but all exhibited some increase in the Bereitschaftspotential (BP) amplitude when stepping as compared with sitting, similar to that seen in normal subjects. This differs from previous results in patients with Parkinson's disease in which stepping was not accompanied by a normal increase in BP amplitude. This difference suggests that the mechanisms responsible for the start hesitation that is common to both Parkinson's disease and gait ignition failure may differ in the two conditions.

Reports of 62 cases with a movement disorder associated with a focal lesion in the thalamus and/or subthalamic region were analyzed. Thirty-three cases had a lesion confined to the thalamus. Sixteen cases had a thalamic lesion extending into the subthalamic region and/or midbrain. Thirteen cases had a lesion in the subthalamic region or a subthalamic lesion extending into the midbrain. Nineteen cases with dystonia, 18 with asterixis, 17 with ballism-chorea, three with paroxysmal dystonia, and five with clonic or myorhythmic movements have been described. No case with isolated tremor has been described. In 53 cases with unilateral thalamic or subthalamic lesions, all but one with bilateral blepharospasm (associated with right posterior thalamic, pontomesencephalic, and bilateral cerebellar lesions) had dyskinesias in the limbs contralateral to the lesion. The other nine cases had bilateral paramedian thalamic lesions; seven developed bilateral dyskinesias, and the remaining two had unilateral dyskinesias. Regarding the 19 patients with dystonia, the two with bilateral blepharospasm had thalamic and upper brainstem lesions, and one with hemidystonia and torticollis had a subthalamic lesion. The other 16 patients all had a unilateral thalamic lesion with contralateral dystonia (10 hemidystonia, five focal dystonia affecting a hand and/or and one segmental dystonia involving face, arm, and hand). The exact location of the thalamic lesion was mentioned in 10 cases; the posterior or posterolateral thalamus was involved in six and the paramedian thalamus in four. These areas are more posterior or medial to the ventrolateral and ventroanterior thalamic nuclei, which receive pallido-thalamic and nigro-thalamic afferents. Two cases developed dystonia immediately after thalamotomy, and one case developed it 4 days after head trauma. The others initially had a hemiplegia and developed dystonia 1-9 months after the acute insult. Fifteen of the 17 patients with chorea had a unilateral lesion in the subthalamic nucleus or subthalamic region (eight due to infarcts, one to hemorrhage, five to mass lesions, and one to multiple sclerosis). All had contralateral hemichorea or hemiballism. One other case had bilateral chorea of the hands and tongue due to paramedian thalamic infarction. Another case with generalized chorea and thalamic atrophy was complicated by stereotaxic surgery. Thirteen of the 18 cases with asterixis had lesions confined to the thalamus. Eight were associated with thalamotomy, and five others had a stroke (four infarction and one hemorrhage) affecting the contralateral thalamus.(ABSTRACT TRUNCATED AT 400 WORDS)

The clinical presentation, symptoms, and signs in 20 new patients with the painful legs and moving toes syndrome are presented. Painful legs and moving toes may develop in the setting of spinal cord and cauda equina trauma, lumbar root lesions, injuries to bony or soft tissues of the feet, and peripheral neuropathy. In 4 of the 20 cases in the present study, no definite cause was found. Pain preceded the onset of toe movements in 18 cases, but in 2 the reverse sequence occurred. The pain had many of the characteristics of causalgia, but none of the patients exhibited the full picture of reflex sympathetic dystrophy, and peripheral trauma was the trigger in only 5 cases. Several patients reported that the occurrence of toe movements was closely related to the pain, although abolition of pain with lumbar sympathetic blocks was not necessarily associated with disappearance of the movements. Several features suggest a central origin for the movements. Symptoms may begin on one side and become bilateral; movements may be momentarily suppressed by voluntary action or exacerbated by changing posture; and electromyography reveals complex patterns of rhythmic activity with normal recruitment of motor units involving several myotomes. Three other patients with similar moving toes but no pain are also described. The occurrence of similar movements in the absence of pain raises the possibility that these cases represent examples at one end of a spectrum of disorders, with pain alone (causalgia) at the other end and the syndrome of painful legs and moving toes in between.(ABSTRACT TRUNCATED AT 250 WORDS)

Fourteen patients with focal or segmental involuntary movements affecting the ears, back, shoulder girdle, and upper extremity, as well as the abdomen and pelvic girdle, are presented. The unusual locations and appearance of these dyskinesias distinguishes them from recognized movement disorder syndromes. It is argued that the slow, sinuous, and semirhythmic character of the movements and the variable long-duration bursts of motor unit activity responsible for them most closely fit into the spectrum of dystonia. A history of pain in the affected region and/or peripheral trauma in some cases also suggests that peripheral factors may play a role in their pathogenesis.

The prognosis for patients who survive carbon monoxide (CO) poisoning is uncertain, particularly in those who develop persistent neurological complications after recovery from the initial coma. Thirty-one patients with the sequelae of CO poisoning, followed for a year, are described. Eight had a progressive course, and 23 had a delayed relapse after an initial recovery period of approximately 20 days (range, 1-36 days). Those with a progressive course developed a persistent akinetic-mute state, and four of the eight died. Those with the delayed relapsing course either developed a parkinsonian state with behavioral and cognitive impairment but could walk (nine cases), or progressed further to an akinetic-mute state, and were bed-bound (14 cases); the deterioration to either condition occurred rapidly over a few days to a week. Fourteen of the patients with the delayed relapses (61%) subsequently improved, but three (13%) died. Those with a progressive course without initial recovery were younger (mean age, 37.0 years) than those with a delayed relapsing course (55.2 years; p < 0.01). The mean duration of their initial coma (9.8 days) was longer than that in delayed relapsing cases (2.0 days; p < 0.01). The mean initial CO hemoglobin level was not different in the two groups. Brain computed tomography (CT) scans were obtained at the onset of sequelae in both groups. Ten patients had a normal CT scan, 13 had white matter low-density lesions, and four had globus pallidus low-density lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

In six patients with Parkinson's disease exhibiting severe "on-off" phenomena, a 200-mg intravenous bolus of either L-DOPA or of its methyl ester were equally effective in reversing motor deficits, although the duration of action of the methyl ester was shorter. There were no marked differences in pharmacokinetic parameters for L-DOPA plasma levels after administration of L-DOPA and the methyl ester. In three patients, optimal infusion rates for the maintenance of mobility were established for L-DOPA and L-DOPA methyl ester. Both drugs were able to maintain patients "on" throughout a 12-h infusion period. However, on average the optimal infusion rate of L-DOPA methyl ester was 2.7 times greater than that for L-DOPA. There was no marked difference in the plasma levels of L-DOPA achieved, but 3-O-methyl DOPA levels increased more after infusion of L-DOPA methyl ester than after infusion of L-DOPA itself. The half-life of elimination and volume of distribution of L-DOPA formed from the methyl ester were markedly increased compared with values obtained after either an intravenous bolus of methyl ester or after an intravenous infusion of L-DOPA itself. An intravenous bolus of L-DOPA methyl ester produces an equivalent magnitude of clinical response to the same dose of L-DOPA. However, higher optimal infusion rates of methyl ester than L-DOPA are required to produce continuous effect. The pharmacokinetic handling of L-DOPA methyl ester given by intravenous infusion may differ from that of L-DOPA when given by the same route.

The sex ratio, age at onset, and ictal features of nine patients with nocturnal paroxysmal dystonia were compared with those of eight patients with daytime frontal lobe seizures and eight patients with nocturnal motor attacks of known epileptic origin. All patients underwent video electroencephalography telemetry. There were no clinical features that would allow distinction between the groups and no single phenomenon was uniquely seen in nocturnal paroxysmal dystonia. This study provides no evidence that nocturnal paroxysmal dystonia is a separate diagnostic entity.

A mosaic pattern of striatal pathology is described in a male who developed severe generalised dystonia from the age of 10 years, and died at the age of 18 years. There was no family history of dystonia, and extensive investigations during his life failed to identify a cause for the dystonia. The caudate nucleus and putamen showed a network of cell loss and gliosis surrounding islands of preserved striatum. Dorsal parts showed confluent gliosis, and ventral parts were spared. The pattern suggested a correlation with patch-matrix organisation, but there was no correlation with the distribution of calbindin immunoreactive cells, which are present in the matrix of the classical striosome-matrix organisation. The pathological findings were unlike those in status marmoratus, perinatal hypoxia-ischaemia, Huntington's disease, and neuroacanthocytosis, but similar to those reported in a 44-year-old man with predominantly cranial dystonia.

Dyskinesias associated with dopaminergic treatment in idiopathic Parkinson's disease (PD) can be indistinguishable from those arising spontaneously in other conditions involving degeneration of, or damage to, the basal ganglia. However, those due to levodopa treatment of PD disappear on cessation of therapy. We report a patient with a clinical diagnosis of PD who, on levodopa treatment, developed hemiballism and chorea that were originally thought to be drug induced. However, the dyskinesias persisted despite stopping levodopa. Postmortem analysis showed a multisystem degeneration.

A patient with postanoxic encephalopathy, with both action- and stimulus-sensitive reflex myoclonus, is described. The action myoclonus was multifocal and cortical in origin. In contrast, reflex myoclonus elicited by somaesthetic and auditory stimulation was generalised. The earliest reflex electromyograph activity was recorded in the sternocleidomastoid; myoclonic activity then spread up the brainstem and down the spinal cord, suggesting that this reflex myoclonus had its origin in the caudal brainstem. Stimulus sensitivity was greatest in the limbs. The bulbospinal motor pathways involved in the generalised reflex myoclonus were rapidly conducting, and this characteristic distinguishes this form of brainstem reflex myoclonus from that described in hyperekplexia.

The reduced form of nicotinamide adenine dinucleotide coenzyme Q reductase (complex I) activity has recently been shown to be deficient in the substantia nigra of patients dying with Parkinson's disease. This biochemical defect is identical to that produced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which also produces parkinsonism in humans. Complex I comprises 25 polypeptides, seven of which are encoded by mitochondrial DNA. Restriction fragment analysis of substantia nigra DNA from six patients with Parkinson's disease did not show any major deletion. In two cases, there were different novel polymorphisms that were not observed in control brain (n = 6) or blood (n = 34) samples.

Tyrosine hydroxylase (TH) is a theoretical candidate gene determining susceptibility to Parkinson's disease (PD), and an association between one allele of a polymorphism at the TH locus and sporadic PD has been reported. We investigated TH polymorphism in 44 patients with sporadic PD, 48 patients with familial PD and 89 of their unaffected relatives, and 50 control subjects. No evidence of allelic association was detected in either familial or sporadic PD, and linkage analysis excluded the TH locus, or a closely linked gene, as a major determinant of familial PD.

Administration of MPTP (1-4 mg/kg ip daily for 5-7 days) to common marmosets induced persistent parkinsonian motor deficits. The subcutaneous administration of (+)-PHNO [(+)-4-propyl-9-hydroxynaphthoxazine; 1-4 micrograms/kg] caused a dose-dependent reversal of the akinesia and incoordination of movement. Similarly, oral administration of (+)-PHNO (5-20 micrograms/kg) caused an equivalent reversal of the motor abnormalities. No dyskinetic phenomena were induced by (+)-PHNO on oral or subcutaneous administration. Oral or subcutaneous administration of (+)-PHNO to normal control marmosets also increased the usual repetoire of motor behaviour, but this was not as marked as in MPTP-treated animals. (+)-PHNO is a potent dopamine agonist drug of potential use in the treatment of Parkinson's disease.

The corticomotoneurone pathways were examined in 21 patients with movement disorders, using the technique of percutaneous electrical stimulation of the motor cortex. Conduction in these pathways was assessed by measuring the latency to onset of electromyographic activity in the muscles of the upper limb after cortical stimulation. In all patients [five with primary (idiopathic) torsion dystonia and two with secondary (symptomatic) hemidystonia, seven with Huntington's disease, four with essential tremor, and three with Parkinson's disease] central motor conduction was normal. This and other evidence suggests that the origin of the disorder of movement in these conditions lies in the delivery of abnormal motor commands to a normal corticomotoneuronal system.

It has been suggested that patients with Parkinson's disease have a basic deficit in shifting "set." Previous authors have used this hypothesis as an explanation for deficits on a range of cognitive tasks. An experiment was conducted to investigate this phenomenon. A reaction time paradigm was used in which the subject had to make left-right decisions under two stimulus conditions. Both patients and controls showed a facilitation in performance with repetition within each block of trials, followed by a deterioration in performance when the stimulus type switched. Furthermore, the shapes of the reaction-time functions were equivalent in both groups, suggesting that the patients had no deficit in either switching or establishing set in this task. In contrast, they were impaired on the Wisconsin Card Sorting Test. This dissociation suggests that patients with Parkinson's disease do not have a generalized deficit in switching set. It is suggested that patients with Parkinson's disease are impaired on tasks where they have to rely upon internal control for the regulation of behaviour, but are relatively unimpaired on tasks where external cues are available.

Loss of the ability to move is the most characteristic and fundamental motor deficit in Parkinson’s disease. Parkinsonian patients exhibit akinesia (inability to initiate movement), hypokinesia (reduced movement), and bradykinesia (slowness of the movement itself). (All these phenomena will be subsumed under the title akinesia.) Rigid muscles may contribute to akinesia, but they are not the cause. This is evident from the effects of both stereotactic surgery and treatment with levodopa. Stereotactic thalamotomy is an effective means of abolishing contralateral rigidity (and tremor), but does not relieve akinesia, which progresses to cause increasing disability. Levodopa therapy, on the other hand, dramatically relieves akinesia, even in those who have undergone previous stereotactic surgery. The akinesia of Parkinson’s disease represents a major negative symptom and, as such, probably gives the best clue as to what goes wrong with basal ganglia function in that condition (1,2). However, analysis of the pathophysiology of akinesia has proved difficult. One is dealing with higher-order motor function in all its complexity. Normal Movement Two approaches have been employed to investigate events in the brain before the initiation of movement in Parkinson’s disease; (a) the study of reaction times, and (b) the investigation of the Bereitschaftspotential.

Thermal injury (30-s immersion in water at 62 degrees C) of one hind limb of rats caused a gradual withdrawal of the limb from use, such that after 1 week 50% of the animals walked on three legs. At 24 h following thermal lesion and at a time when the lesioned paw was still used for walking there was a reduction in met- and leu-enkephalin content in the periaqueductal grey (PAG) and bilateral reduction in leu-enkephalin content of the globus pallidus, but no change in enkephalin levels in caudate-putamen. One week following the lesion, animals exhibiting complete withdrawal of the injured limb, showed bilateral reduction of met- and leu-enkephalin content of PAG. Both met- and leu-enkephalin content in caudate-putamen. In each case the change was more marked in basal ganglia areas contralateral to the lesion. In animals lesioned 1 week previously and which did not use the injured limb, there was no change in the monoamine (or metabolite) content of caudate-putamen or in the spontaneous or potassium-evoked release of 3H-dopamine from strial slices. Thermal injury did not cause any general change in pain sensitivity and the time of change in pain threshold in the injured limb did not parallel the withdrawal of the affected limb from walking. The results suggest that after a thermal limb lesion, delayed changes in basal ganglia enkephalin content may be important in withdrawing the injured limb from the normal pattern of locomotion. Basal ganglia enkephalins may be involved in a physiological rest mechanism, which allows healing of the affected part.

The effect of stimulation of cerebral dopamine D-1 receptors by CY 208-243 on motor disability was tested in MPTP-treated parkinsonian marmosets and patients with Parkinson's disease. CY 208-243 (0.5-1.25 mg/kg s.c.) produced a dose-related reversal of akinesia and rigidity in the marmosets, lasting some 2 h. Single morning doses of CY 208-243 (5-40 mg) were compared with the usual morning dose of levodopa in eight patients with Parkinson's disease on long-term levodopa therapy who had developed motor fluctuations from immobility with akinesia and rigidity (off) to mobility often with dyskinesias (on). CY 208-243 alone was capable of switching such patients from off to on; five of the eight patients responded to the highest dose (40 mg), sometimes with dyskinesias. The response to CY 208-243 was comparable to that produced by levodopa in these cases. Drugs designed to stimulate both dopamine D1 and D2 receptors in the brain may improve the therapy of Parkinson's disease.