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Biomedical subjects

C D Marsden

Publications and source records attributed to C D Marsden.

At least 163 records · Page 9Linked to original sources
PubMed1996

Glutamate decarboxylase-67 messenger RNA expression in normal human basal ganglia and in Parkinson's disease.

Expression of glutamate decarboxylase-67 messenger RNA was examined in the basal ganglia of normal controls and of cases of Parkinson's disease using in situ hybridization histochemistry in human post mortem material. In controls glutamate decarboxylase-67 messenger RNA expression was detected in all large neurons in both segments of the globus pallidus and in three neuronal subpopulations in the striatum as well as in substantia nigra reticulata neurons and in a small sub-population of subthalamic neurons. In Parkinson's disease, there was a statistically significant decrease of 50.7% in glutamate decarboxylase-67 messenger RNA expression per neuron in the lateral segment of the globus pallidus (controls: mean 72.8 microns2 +/- S.E.M. 8.7 of silver grain/neuron, n = 12; Parkinson's disease: mean 35.9 microns2 +/- S.E.M. 9.7 of silver grain/neuron, n = 9, P = 0.01, Student's t-test). In the medial segment of the globus pallidus, there was a small, but non-significant decrease of glutamate decarboxylase-67 messenger RNA expression in Parkinson's disease (controls: mean 100.6 microns2 +/- S.E.M. 7.2 of silver grain/neuron, n = 11; Parkinson's disease: mean 84.8 microns2 +/- S.E.M. 13.0 of silver grain/neuron, n = 7, P = 0.1, Student's t-test). No significant differences in glutamate decarboxylase-67 messenger RNA were detected in striatal neuronal sub-populations between Parkinson's disease cases and controls. These results are the first direct evidence in humans that there is increased inhibitory drive to the lateral segment of the globus pallidus in Parkinson's disease, as suggested by data from animal models. We therefore provide theoretical support for current experimental neurosurgical approaches to Parkinson's disease.

Aged↗
PubMed1996

Abnormalities of the balance between inhibition and excitation in the motor cortex of patients with cortical myoclonus.

Patients with cortical myoclonus may have purely focal or multifocal jerks, or they may have additional bilateral or generalized jerks, suggesting the spread of excitatory myoclonic activity between the cerebral hemispheres and across the sensorimotor cortex. The factors contributing to this spread of activity were investigated in 10 patients with multifocal cortical myoclonus and eight patients with multifocal and bilateral or generalized cortical myoclonus. The two groups were termed 'non- spreaders' and 'spreaders' respectively. Eight of the patients were also epileptic. Motor thresholds to single transcranial magnetic shocks at rest were higher in 'non- spreaders' (median 88%, range 45-100% of stimulator output) than either 'spreaders' (50%, range 26-90%, P=0.023) or health controls (38%, range 28-53%, P<0.001). This pathological elevation in motor threshold was not simply an effect of treatment with antiepileptic drugs. Paired transcranial magnetic stimuli were used to investigate ipsilateral cortico-cortical and transcallosal inhibition, There was less (MANOVA, P<0.05) ipsilateral inhibition at interstimulus intervals (ISIs) of 1-6 ms in 'spreaders' (mean 107+/-SEM 23% of control) compared with 'non- spreaders' (75+/-15%) or healthy subjects (59+/-10%). There was also less (P<0.05) transcallosal inhibition across inhibitory timings (10, 12 and 14 ms) in the 'spreaders' (98+/-6% of control) compared with the 'non-spreaders' (64+/-8%) or healthy subjects (59+/-6%). There was no relationship between ipsilateral cortico-cortical and transcallosal inhibition and the presence or absence of epilepsy, although non-epileptic patients did have higher motor thresholds (median 85%, range 32-100% of stimulator output) than either epileptic patients (50%, range 26-90%, P<0.001) or healthy controls (38%, range 28-53%, P=0.002). Abnormalities in ipsilateral and transcallosal inhibition appear to facilitate the spread of the cortical myoclonic activity responsible for bilateral and generalized jerks. However, these abnormalities in inhibition do not play a major role in the development of generalized seizures in patients with cortical myoclonus.

Adolescent↗
PubMed1996

The basal ganglia and apraxia.

Ever since Liepmann's original descriptions at the beginning of the century apraxia has usually been attributed to damage confined to the cerebral cortex and/or cortico-cortical connecting pathways. However, there have been suggestions that apraxia can be due to deep subcortical lesions, which raises the question as to whether damage to the basal ganglia or thalamus can cause apraxia. We therefore analysed 82 cases of such 'deep' apraxias reported in the literature. These reports consisted of a small number (n=9) of cases studied neuropathologically, and a much larger group (n=73) in which CT or MRI was used to identify the size and extent of the lesion. The reports were subdivided into (i) those with small isolated lesions which involved nuclei of the basal ganglia or thalamus only, and not extending to involve periventricular or peristriatal white matter; (ii) those with large lesions which involved two or more of the nuclei, or one or more of these deep structures plus damage to closely adjacent areas including the internal capsule, periventricular or peristriatal white matter; and (iii) lesions sparing basal ganglia and thalamus but involving adjacent white matter. The main conclusions to be drawn from this meta-analysis are that lesions confined to the basal ganglia (putamen, caudate nucleus and globus pallidus) rarely, if ever, cause apraxia. Lesions affecting the lenticular nucleus or putamen nearly always intruded into the adjacent lateral white matter to involve association fibres, in particular those of the superior longitudinal fasciculus and frontostriatal connections. Apraxia occurred with deep lesions of the basal ganglia apparently sparing white matter in only eight out of the 82 cases. Apraxia was most commonly seen when there were lesions in the lenticular nucleus or putamen (58 out of 72 cases) with additional involvement of capsular, and particularly of periventricular or peristriatal, white matter. Lesions of the globus pallidus (no cases) or caudate nucleus (three cases) rarely caused apraxia. The caudate lesions also had white matter involvement. Indeed, involvement of periventricular white matter alone caused apraxia. The vast majority of cases described with apraxia associated with deep lesions were in the left, dominant hemisphere. Ideomotor apraxia was described in most reports (72 out of 82 cases). Orofacial apraxia was less common (37 cases), usually with ideomotor apraxia. Ideational apraxia was rare (five cases), all with ideomotor apraxia. Apraxia was either bilateral or involved the left hand if there was a right hemiparesis, in those cases where descriptions were available. Lesions of the thalamus can sometimes cause apraxia (26 cases), even if there is no apparent involvement of white matter (12 cases). Small lesions confined to the thalamus can also sometimes cause apraxia (eight cases). The role of the thalamus in higher order motor control and apraxia remains to be determined. It is suggested that the term limb-kinetic apraxia should be retained to describe motor deficits in planning 'what to do', 'how to do it' and 'when to do it'; decisions which appear to involve activation of a complex distributed network of dorsolateral prefrontal cortex, supplementary motor areas, anterior cingulate regions and lateral premotor cortex. Such deficits need to be quantified. If they are present in patients with basal ganglia disease, over and above classical akinesia, bradykinesia and hypokinesia, then such patients could be said to exhibit limb-kinetic apraxia.

Apraxias↗
PubMed1996

Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK.

Epilepsia partialis continua (EPC) is defined clinically as a syndrome of continuous focal jerking of a body part, usually localized to a distal limb, occurring over hours, days or even years. The anatomical and physiological origin of EPC has been the subject of much speculation. It has been argued that EPC is a form of focal cortical myoclonus, but subcortical mechanisms have also been proposed. We describe a series of 36 patients ascertained over a period of 1 year in the UK using the British Neurological Surveillance Unit. The commonest aetiologies identified were Rasmussen's syndrome (n = 7; 19%) and cerebrovascular disease (n = 5; 14%). Rasmussen's syndrome was the most common diagnosis in patients under 16 years. In seven patients the cause remained unknown. Eight patients (22%) had focal epileptiform scalp EEG abnormalities, and 56% had generalized background scalp EEG disturbances. Lesions on MRI or CT were found in 20 cases (56%), half of whom showed predominant cortical involvement. The muscle jerking resolved in four patients (with no treatment in one), with a partial response to treatment in seven (19%) patients. A cognitive or neurological decline had been noted retrospectively in 13 (36%) patients (and in all of the patients with Rasmussen's syndrome). We personally saw 16 patients who underwent detailed clinical and neurophysiological assessments. Only six of the patients had EEG and EMG evidence for a cortical origin of their jerks; five others had indirect evidence for a cortical origin, from EMG, magnetic stimulation, and other investigations. Two patients did not have myoclonus of cortical origin, but some other source (brainstem and basal ganglia). The origin in the remaining three patients was uncertain. The clinical appearance of the muscle jerks was similar in all patients despite the different origins. We propose that the definition of EPC is best restricted to "continuous muscle jerks of cortical origin'. Continuous muscle jerking that arises from other sites in the nervous system should be termed "myoclonia continua'.

Adolescent↗
PubMed1996

Single-joint rapid arm movements in normal subjects and in patients with motor disorders.

In normal subjects the execution of single rapid one-joint movements is characterized by an electromyographic (EMG) pattern composed of three discrete bursts of activity; two bursts (first and second agonist bursts, or AG1 and AG2) are present in the agonist muscle separated by an almost complete period of electrical silence. During this pause, another burst (antagonist burst, or ANT) occurs in the antagonist muscle. If a rapid movement is executed during tonic activation of the agonist muscle, tonic activity is inhibited just prior to AG1 onset (agonist inhibition). Similarly, if the movement is performed during tonic activation of the antagonist muscle, such activity is also inhibited prior to AG1 onset (antagonist inhibition). Antagonist inhibition also starts prior to AG1 onset and lasts until ANT onset. A general descriptor of the kinematic features related to the EMG pattern described above is a symmetrical and unimodal velocity profile that is bell-shaped and shows an acceleration time roughly equal to the deceleration time. This holds true for movements performed under low accuracy constraints; as accuracy demands become stricter and stricter, the peak velocity decreases but, as long as the movement is made with one continuous trajectory, the velocity profile remains roughly symmetrical. In general terms, the function of AG1 is to provide the impulsive force to start the movement; the function of ANT is to halt the movement at the desired end-point; and the function of AG2 is to dampen out the oscillations which might occur at the end of the movement. The timing and size of the bursts vary according to the speed and amplitude of the movement. The origin of the EMG pattern is a central programme, but afferent inputs can modulate the voluntary activity. In this paper, we also review the EMG and kinematic abnormalities that are present during the execution of single-joint, rapid arm movements in patients with Parkinson's disease, Huntington's disease, Sydenham's chorea, dystonia, athetosis, cerebellar deficits, upper motor neuron syndrome, essential tremor and large-fibre sensory neuropathy. The data from these studies lead us to the following conclusions: (i) the basal ganglia have a role in scaling the size of AG1, reinforcing the voluntary command and inhibiting inappropriate EMG activity; (ii) the cerebellum has a role in timing the voluntary bursts and probably in implementing muscle force phasically; (iii) the corticospinal tract has a role in determining spatial and temporal recruitment of motor units; (iv) proprioceptive feedback is not necessary to produce the triphasic pattern but it contributes to the accuracy of both the trajectory and the end-point of rapid movements.

Arm↗
PubMed1996

Tremor associated with benign IgM paraproteinaemic neuropathy.

The clinical and neurophysiological features of six patients with action tremor of the upper limbs associated with IgM paraproteinaemic neuropathy are described. Symptomatic tremor was confined to the upper limbs and was broadly symmetrical. The frequency of associated rhythmic muscle activity ranged from 2.8 to 5.5 Hz in abductor pollicis brevis and from 3.7 to 5.5 Hz in the forearm flexor muscles. Magnetic brain stimulation, somatosensory evoked potentials (SEPs) and stretch reflex studies did not provide evidence for delayed conduction within central pathways. There was marked slowing of the maximum motor conduction velocities in peripheral nerves. Forearm stretch reflexes were present but their latencies were prolonged. Somatosensory evoked potentials were obtained in the majority of patients, but were delayed. Wrist tremor could be modulated by mechanical perturbations or median nerve electrical shocks. Simple voluntary wrist movements were of normal duration and peak velocity, but the kinematic profile was asymmetric. Each movement was associated with a triphasic EMG pattern in agonist-antagonist-agonist muscles but the durations of the bursts were prolonged and the onset of the second agonist was delayed. These results support the hypothesis that distorted, mistimed peripheral inputs reach a central processor (probably the cerebellum) which although intact is misled into producing tremor in certain parts of the body.

Aged↗
PubMed1996

Alterations in peptide levels in Parkinson's disease and incidental Lewy body disease.

The levels of the neuropeptides Met- and Leu-enkephalin (MET-ENK, LEU-ENK), substance P and neurotensin were measured by a combined high performance liquid chromatography/radioimmunoassay (HPLC/RIA) method in postmortem samples of basal ganglia from Parkinson's disease patients, incidental Lewy body disease patients (pre-symptomatic Parkinson's disease) and matched controls. Dopamine (DA) levels were reduced in the caudate nucleus and putamen in Parkinson's disease, but unaltered in incidental Lewy body disease. The levels of MET-ENK were reduced in the caudate nucleus, putamen and substantia nigra in Parkinson's disease. Met-enkephalin levels were reduced in the caudate nucleus and in the putamen in incidental Lewy body disease. Leu-enkephalin levels were decreased in the putamen and were undetectable in the substantia nigra in Parkinson's disease. Leu-enkephalin levels were unchanged in incidental Lewy body disease, although there was a tendency to a reduction in putamen. Substance P levels were reduced in the putamen in Parkinson's disease. No significant changes in substance P content were observed in incidental Lewy body disease. Neurotensin levels were increased in the substantia nigra in Parkinson's disease. Neurotensin levels in incidental Lewy body disease were not altered significantly, but tended to parallel the changes in Parkinson's disease. The changes in basal ganglia peptide levels in incidental Lewy body disease generally followed a trend similar to those seen in Parkinson's disease, but were less marked. This suggests that they are an integral part of the pathology of the illness and not secondary to DA neuronal loss or a consequence of prolonged drug therapy.

Aged↗
PubMed1996

Rhythmic cortical and muscle discharge in cortical myoclonus.

Seven patients with cortical action myoclonus were studied. Six of these also had cortical reflex myoclonus. Surface and needle recordings were made from intrinsic hand muscles. Reflex and action jerks often consisted of a series of EMG bursts, some of which were polyphasic. The interval between repetitive EMG bursts was most commonly approximately 20 ms. The first EMG burst following median nerve stimulation varied in latency by a few milliseconds. Needle recordings of this reflex response showed more than one peak in half of the post-stimulus time histograms (PSTH) collected. Multiple peaks were narrow and separated by as little as 4 ms. Single trials of the EEG activity over the sensorimotor cortex were recorded during stimulation or voluntary movement of the contralateral limb in five patients. Activity typically consisted of a rhythmic series of giant positive spike-slow negative wave complexes. Intervals between spikes tended to cluster at approximately 20 ms. Frequency histograms of spike to EMG burst intervals confirmed that spikes preceded muscle discharges but they showed more than one peak. These peaks were narrow and separated by as little as 3 ms. Thus, in patients with cortical myoclonus rhythmic muscle responses are driven by the sensorimotor cortex, which has a tendency to oscillatory activity. Two types of cortical rhythmicity are present. The first determines the frequency of repetitive EEG spikes and EMG bursts. The second is of higher frequency and underlies the multiple peaks separated by short intervals in PSTHs and histograms of spike to EMG burst intervals. Both phenomena may have their correlate in normal functioning.

Adult↗
PubMed1996

Dopa-responsive dystonia in British patients: new mutations of the GTP-cyclohydrolase I gene and evidence for genetic heterogeneity.

Dopa-responsive dystonia (DRD) was originally described in a series of Japanese patients, but is now increasingly recognized in other countries. Recently the GTP cyclohydrolase I (GTPCH) gene was isolated as the first causative gene for dopa-responsive dystonia (DRD). Mutations were identified in three Japanese families with autosomal dominantly inherited DRD and in one sporadic Japanese patient. Characterisation of the exon-intron boundaries of this gene has now allowed the analysis of mutations at the level of genomic DNA. Amplifying all six exons, we analyzed the GTPCH gene in nine British families with 33 affected family members and in three sporadic cases and found six new mutations. Only point mutations were found, causing a stop codon in one family and an amino acid change in highly conserved regions of the gene in a further four families and in one sporadic case. None of these mutations were detected more than once and none of the mutations previously described were found in our patients. No mutations were identified in four families and in two sporadic cases.

Dopamine Agents↗
PubMed1996

Botulinum toxin in the treatment of writer's cramp.

Forty-four patients with disabling writer's cramp (WC) and one with a musician's cramp were treated with botulinum toxin (BT) injections for a mean period of 12 (range, 3-48) months. The forearm muscles causing the dystonic position were identified by inspection while writing; BT was then administered under electromyographic (EMG) guidance. The degree of improvement in writing and amelioration of pain were rated with self-assessment scales. Patients reported significant improvement in writing after 56% treatment sessions (TS) and in pain after 62% TS. Mild weakness occurred after 32% TS. Twenty-nine patients discontinued treatment, generally after the initial BT injection. In 16 patients who remained on treatment with a mean follow-up of 21 (range, 3-48) months, the improvement in writing and pain was present after 76 and 79% of the TS, respectively. We conclude that BT injections offered a worthwhile and sustained functional improvement to 36% of our patients with WC.

Adult↗
PubMed1996

Dyskinetic cerebral palsy: a clinical and genetic study.

The clinical features and family histories of 20 adults with dyskinetic cerebral palsy from 20 families were studied. The majority of the patients showed progressive neurological deterioration in adult life. In only three did the condition stabilise by 10 years of age and in seven there was deterioration after the age of 30. Two patients developed a secondary cervical spondylotic myelopathy. Four patients had affected relatives and there were similar proportions of affected parents and siblings. The family data suggest genetic heterogeneity with autosomal recessive and dominant variants. The existence of an X-linked form cannot be excluded, and the demonstration of an increased paternal age effect among single cases suggests that some of these may arise because of fresh dominant genetic mutation.

Adolescent↗
PubMed1996

Sex prevalence of focal dystonias.

The sex prevalence of idiopathic focal dystonia is reported from a data base review of all patients seen at the National Hospital of Neurology, Queen Square and King's College, London up to 1993. There was a higher prevalence of females to males in all categories of focal dystonia involving the craniocervical region. The female to male ratio for cranial dystonia was 1.92:1 (P < 0.01) and 1.6:1 (P < 0.001) for spasmodic torticollis. On the other hand, twice as many men than women had writer's cramp (M:F = 2.0:1, P < 0.01). At present, there is no clear explanation to account for this differences in the sex prevalence of different types of focal dystonia.

Dystonia↗
PubMed1996

Disordered axial movement in Parkinson's disease.

Axial motor impairments are a common cause of disability in patients with Parkinson's disease, become more prominent with longer disease duration, and have been said to be less responsive to levodopa replacement therapy. The ability to turn in bed while lying supine before and after dopaminergic stimulation was studied in a group of 36 patients with Parkinson's disease; 23 were in Hoehn and Yahr stages 3-5 when "off", and 13 were in stages 1-2. Turning was also compared with postural stability and gait before ("off") and after ("on") dopaminergic stimulation. Failure to turn in bed was noted in 19 of the 36 patients in the "off" state, with significant associations between disturbances of gait, postural stability, rising from a chair, whole body bradykinesia, and axial rigidity. Gait, postural stability, rising from a chair, whole body bradykinesia, and axial rigidity were significantly correlated in the "off" state. Disorder of axial movement, gait, and postural stability were not dependent on age at onset of Parkinson's disease, but did relate to duration of disease. After a levodopa challenge, turning in bed returned to normal in all but one patient, and gait, postural stability, rising from a chair, whole body bradykinesia, and axial rigidity also improved in nearly all. It is concluded that in the later stages of Parkinson's disease at least some aspects of axial motor control can remain dopamine responsive.

Adult↗
PubMed1995

Inhibition of complex I by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Mitochondrial respiratory failure secondary to complex I inhibition may contribute to the neurodegenerative process underlying nigral cell death in Parkinson's disease (PD). Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) may be inhibitors of complex I, and have been implicated in the cause of PD as endogenous neurotoxins. To determine the potency and structural requirements of isoquinoline derivatives to inhibit mitochondrial function, we examined the effects of 22 neutral and quaternary compounds from three classes of isoquinoline derivatives (11 isoquinolines, 2 dihydroisoquinolines, and 9 1,2,3,4-tetrahydroisoquinolines) and MPP+ on the enzymes of the respiratory chain in mitochondrial fragments from rat forebrain. With the exception of norsalsolinol and N,n-propylisoquinolinium, all compounds inhibited complex I in a time-independent, but concentration-dependent manner, with IC50s ranging from 0.36-22 mM. Several isoquinoline derivatives were more potent inhibitors of complex I than 1-methyl-4-phenylpyridinium ion (MPP+) (IC50 = 4.1 mM), the most active being N-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline (IC50 = 0.36 mM) and 6-methoxy-1,2,3,4-tetrahydroisoquinoline (IC50 = 0.38 mM). 1,2,3,4-Tetrahydroisoquinoline was the least potent complex I inhibitor (IC50 approximately 22 mM). At 10 mM, only isoquinoline (23.1%), 6,7-dimethoxyisoquinoline (89.6%), and N-methylsalsolinol (34.8%) inhibited (P < 0.05) complex II-III, but none of the isoquinoline derivatives inhibited complex IV. There were no clear structure-activity relationships among the three classes of isoquinoline derivatives studied, but lipophilicity appears to be important for complex I inhibition. The effects of isoquinoline derivatives on mitochondrial function are similar to those of MPTP/MPP+, so respiratory inhibition may underlie their reported neurotoxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗