Biomedical subjects
Publications and source records attributed to H Topka.
The authors report a mutation in exon 5 of GCH1 in a patient with adult-onset oromandibular dystonia and no obvious family history of dystonia. The patient responded positively to treatment with L-dopa. These findings demonstrate that GCH1 mutations must be considered even in patients with dystonic symptoms not typical of dopa-responsive dystonia.
A simple paradigm was used to investigate how patients with cerebellar lesions cope with the need to correct for joint interactions during a multi-joint movement. Normal subjects and patients with cerebellar degeneration performed fast unconstrained elbow flexions with the instruction to voluntarily fixate the shoulder joint. Angular kinematics and inverse dynamics analyses were performed. A susceptibility index quantified how strong-concomitant shoulder-motion depended on interactions from the elbow. Amplitudes of involuntary shoulder movements increased with elbow movement speed and were generally larger in patients. Susceptibility indices were smaller in patients, indicating a more variable compensatory response, however, increased with elbow movement speed. We conclude that patients were significantly less able to 'tune' their postural stabilizing response to match interaction torques. However, the velocity dependence of this effect points to a deficit in generating normal levels of phasic torque.
Trains of repetitive transcranial magnetic stimulation (TMS) at 10-30 Hz and intensities of 90-120% motor threshold were delivered through a figure of eight coil over the motor cortex while normal subjects made either rapid, self-terminated (ballistic) wrist movements or maintained the position of their wrist at a fixed angle. Movement kinematics and EMG activity in antagonistic forearm muscles were analysed. In the ballistic task, repetitive TMS had little effect on the velocity or acceleration of the initial segment of the movement, although it induced large terminal oscillations (tremor) around the target position at frequencies between 4.4 and 7.2 Hz. The likelihood that tremor would occur increased with increasing stimulus intensities or frequencies. It was maximal with stimulation over the forearm area, and decreased with stimulation over the leg area, or over parietal sites; there was no tremor during stimulation of cervical nerve roots. The frequency of the induced tremor was independent of the rate of stimulation and did not depend on the presence of excitatory and inhibitory motor responses to the stimulus. Stimulation could also induce tremor of the same frequency in the fixed task, but only during co-contraction of forearm muscles. The amplitude of tremor was proportional to the level of co-contraction. Clinically, the tremor induced by repetitive TMS appeared very similar to cerebellar tremors. In order to confirm this we investigated two cerebellar patients, one with autosomal dominant cerebellar ataxia and the other with multiple sclerosis. Both of them had a terminal tremor of 6-7 Hz in the wrist movement task. In the holding task, the amplitude of their postural tremor increased with the level of co-contraction in forearm muscles. Since the frequency of repetitive TMS-induced tremor was independent of stimulus parameters, we conclude that it represents some intrinsic property of the CNS. We suggest that the tremor is caused by disruption of cortical processes involved in terminating a voluntary movement or maintaining a posture. Similarities to cerebellar patients suggest that repetitive TMS may cause tremor by interfering with adaptive cerebellar afferent inflow to motor cortex. Repetitive TMS-induced tremor, therefore, may represent a model of some forms of cerebellar tremor in man.
Dystonias occur frequently as repetitive movements, persistent elevations of muscle tone, or tonic contortions, whereby the cause is assumed to be an impairment of basal ganglia function. Focal dystonias are especially known in musicians, although little is reported on focal dystonias in athletic stress. The present case report describes the case of a 34-yr-old professional tennis player with bilateral segmental dystonia. The symptoms were expressed in involuntary movements when he intended to hit the ball and in a progredient tremor, initially in one hand, later in both, making him unable to write. The altered mobility during athletic stress was confirmed by video analysis, the altered innervation with excessive, uncoordinated impulse influx by means of electromyography during sport-type specific stress, and writing incapacity during a writing test. The symptoms abated under therapy with trihexyphenidyl-HCL, so that the patient has been able to work as a tennis coach with improved athletic performance for the past 3 yr. It is concluded that the various forms of dystonia should be included in the differential diagnosis of impaired coordinative movements under athletic exercise, especially of the upper extremities.
To identify determinants of peripheral involvement in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) the influence of CAG repeat length, age of onset, disease duration and age on the results of nerve conduction studies was analysed in 58 patients with SCA3/MJD. Patients with SCA3/MJD showed marked reduction of compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes indicating axonal neuropathy of both motor and sensory fibres. In addition, there was moderate slowing of nerve conduction suggestive of mild peripheral demyelination. Multivariate regression showed that CMAP and SNAP amplitudes decreased with age, but were not affected by CAG repeat length, age of onset, or disease duration. The age related decline of CMAP and SNAP amplitudes in SCA3/MJD was greater than in normal subjects. The data suggest that the degree of peripheral damage in SCA3/MJD does not depend on CAG repeat length, age of onset, or disease duration, but is mainly related to the time period over which the SCA3/MJD mutation exerts its effect.
To explore the role of the cerebellum in learning a complex motor task, we studied nineteen patients with cerebellar degeneration and sixteen healthy subjects who attempted to improve their performance in generating a trajectory connecting five via points on a data tablet. Multijoint arm movements were performed at a constant total movement time, and spatial error was measured. Subjects performed 100 trials at a movement time of 3.5 s (slow movements), and another 100 trials at maximum speed (fast movements). With slow movements, patients and normal subjects reduced the error over trials to the same extent, but in patients, the rate of improvement was slightly slower. With fast movements, patients showed less improvement than normal subjects. When tested 24 h later, patients demonstrated significant retention of acquired skill and tended to improve more rapidly when performing both slow and fast movements than during the first session. We conclude that patients with cerebellar degeneration can exhibit almost normal performance in skill learning with slow movements, but with fast movements, their performance improves to a lesser extent. The problem may be difficulty in the refinement of motor execution, which is more of a requirement for fast movements than for slow ones.
Intramuscular injections of botulinum neurotoxin type A cause reversible chemodenervation and subsequent paralysis by blocking the presynaptic release of acetylcholine. Botulinum toxin type A has emerged as the most effective form of symptomatic treatment for abnormabilities in muscle movement (blepharospasm, hemifacial spasm, torticollis) and has been approved for use in these conditions. First results in the treatment of patients suffering from oromandibular dystonia, myogenic craniomandibular dysfunction and recurrent dislocation of the temporomandibular joint are presented. In most cases, therapeutic effects occurred within 1-6 days post-injection. Muscular hyperfunction was reliably reduced and involuntary activity patterns gradually ceased. No severe side effects of the local injections were noted.
Kinematic abnormalities of fast multijoint movements in cerebellar ataxia include abnormally increased curvature of hand trajectories and an increased hand path and are thought to originate from an impairment in generating appropriate levels of muscle torques to support normal coordination between shoulder and elbow joints. Such a mechanism predicts that kinematic abnormalities are pronounced when fast movements are performed and large muscular torques are required. Experimental evidence that systematically explores the effects of increasing movement velocities on movement kinematics in cerebellar multijoint movements is limited and to some extent contradictory. We, therefore, investigated angular and hand kinematics of natural multijoint pointing movements in patients with cerebellar degenerative disorders and healthy controls. Subjects performed self-paced vertical pointing movements with their right arms at three different target velocities. Limb movements were recorded in three-dimensional space using a two-camera infrared tracking system. Differences between patients and healthy subjects were most prominent when the subjects performed fast movements. Peak hand acceleration and deceleration were similar to normals during slow and moderate velocity movements but were smaller for fast movements. While altering movement velocities had little or no effect on the length of the hand path and angular motion of elbow and shoulder joints in normal subjects, the patients exhibited overshooting motions (hypermetria) of the hand and at both joints as movement velocity increased. Hypermetria at one joint always accompanied hypermetria at the neighboring joint. Peak elbow angular deceleration was markedly delayed in patients compared with normals. Other temporal movement variables such as the relative timing of shoulder and elbow joint motion onsets were normal in patients. Kinematic abnormalities of multijoint arm movements in cerebellar ataxia include hypermetria at both the elbow and the shoulder joint and, as a consequence, irregular and enlarged paths of the hand, and they are marked with fast but not with slow movements. Our findings suggest that kinematic movement abnormalities that characterize cerebellar limb ataxia are related to an impairment in scaling movement variables such as joint acceleration and deceleration normally with movement speed. Most likely, increased hand paths and decomposition of movement during slow movements, as described earlier, result from compensatory mechanisms the patients may employ if maximum movement accuracy is required.
In cerebellar ataxia, kinematic aberrations of multijoint movements are thought to originate from deficiencies in generating muscular torques that are adequate to control the mechanical consequences of dynamic interaction forces. At this point the exact mechanisms that lead to an abnormal control of interaction torques are not known. In principle, the generation of inadequate muscular torques may result from an impairment in generating sufficient levels of torques or from an inaccurate assessment and prediction of the mechanical consequences of movements of one limb segment on adjacent joints. We sought to differentiate the relative contribution of these two mechanisms and, therefore, analyzed intersegmental dynamics of multijoint pointing movements in healthy subjects and in patients with cerebellar degeneration. Unrestrained vertical arm movements were performed at three different target movement velocities and recorded using an optoelectronic tracking system. An inverse dynamics approach was employed to compute net joint torques, muscular torques, dynamic interaction torques and gravitational torques acting at the elbow and shoulder joint. In both groups, peak dynamic interaction forces and peak muscular forces were largest during fast movements. In contrast to normal subjects, patients produced hypermetric movements when executing fast movements. Hypermetric movements were associated with smaller peak muscular torques and smaller rates of torque change at elbow and shoulder joints. The patients' deficit in generating appropriate levels of muscular force were prominent during two different phases of the pointing movement. Peak muscular forces at the elbow were reduced during the initial phase of the movement when simultaneous shoulder joint flexion generated an extensor influence upon the elbow joint. When attempting to terminate the movement, gravitational and dynamic interaction forces caused overshooting extension at the elbow joint. In normal subjects, muscular torque patterns at shoulder and elbow joint were synchronized in that peak flexor and extensor muscular torques occurred simultaneously at both joints. This temporal pattern of muscular torque generation at shoulder and elbow joint was preserved in patients. Our data suggest that an impairment in generating sufficient levels of phasic muscular torques significantly contributes to the patients' difficulties in controlling the mechanical consequences of dynamic interaction forces during multijoint movements.
OBJECTIVE: The exact pathogenesis of peritumoral brain edema (PTBE) in meningiomas is still unknown. A number of different pathophysiological hypotheses have been considered. A detrimental effect of tumor-related venous obstruction has been suggested as one pathogenetic mechanism. We sought to characterize the significance of venous stasis in the development of PTBE in meningiomas. METHODS: Angiograms for 134 patients with 136 intracranial meningiomas were analyzed. Pathological changes affecting cortical veins, sylvian veins, bridging veins, deep veins, transmedullary veins, and dural sinuses were evaluated. From preoperative computed tomographic scans, the total tumor volume, the tumor/PTBE volume ratio (edema index [EI]), and the location of the edema were determined. For statistical evaluation, meningiomas associated with pathological venous drainage were compared with size-matched controls. RESULTS: The edema incidence and the mean EI were not different for meningiomas with unselected signs of obstructed venous drainage, compared with controls. In particular, lesions with involvement of cortical veins, bridging veins, and dural sinuses showed no higher edema incidence. However, meningiomas associated with venous changes in sylvian veins (EI = 4.9 versus EI = 2.7; P < 0.004) and with dysplastic transmedullary veins (EI = 3.3 versus EI = 1.7; P < 0.04) showed significantly higher mean EI values, compared with meningiomas without involvement of these vessels. CONCLUSION: Our data suggest that tumor-related venous obstruction does not play an essential role in the development of PTBE for the majority of meningiomas. For a small subgroup of meningiomas with involvement of sylvian veins or development of dysplastic transmedullary veins, changes in venous drainage may aggravate preexisting PTBE.
We studied the kinematic patterns of gait initiation in 31 patients with Parkinson's disease and in 20 age- and sex-matched normals by using an optoelectronic tracking system (ELITE). Position markers were attached to the skin overlying the ankle, knee, hip, elbow, shoulder, and zygomatic bone. Subjects were instructed to start walking immediately after an acoustic go signal. Gait initiation was defined as the phase between standing motionless and steady-state locomotion. This phase was subdivided into a movement preparation period (the time between go signal and movement onset) and a movement execution period (the time between movement onset and the end of the first stride). Onset and duration of ankle, knee, hip, trunk, and arm motion within the first stride were analyzed. Movement preparation time was significantly increased in Parkinson's disease (p = 0.01), whereas movement execution times were similar in both groups (p = 0.23). Initiation of ankle, knee, hip, arm, and trunk movements was delayed in patients as compared with healthy subjects, but the relative timing and the sequence of submovements was comparable in both groups, indicating that the overall pattern of submovements was preserved in the patients. Our data suggest that gait initiation deficits in Parkinson's disease cannot be explained by a disordered sequence of limb and trunk submovements. More likely, gait initiation problems originate from the basal ganglia's internal cueing deficit for movement sequences, delaying onset and slowing the execution of all subcomponents.
Forty-one patients suffering from autosomal dominant cerebellar ataxia type I (ADCA-I) were subjected to a genotype-phenotype correlation analysis using molecular genetic assignment to the spinocerebellar ataxia type 1, 2 or 3 (SCA1, -2 or -3) genetic locus, clinical examination and nerve conduction as well as evoked potential studies. Pyramidal tract signs, pale discs, and dysphagia were more frequent in SCA1 compared with SCA2 and SCA3 patients, while double vision occurred less frequently. Visual evoked potentials and motor evoked potentials following transcranial magnetic stimulation were abnormal in almost all SCA1 patients, but only in a minority of SCA2 and SCA3 patients. In contrast, somatosensory evoked potentials were delayed or absent in the majority of patients with no significant differences between the mutations. Abnormalities of brainstem auditory evoked potentials were found in about half of the patients irrespective of the underlying mutation. In addition, reduced sensory nerve action potentials, suggesting sensory axonal neuropathy were found in all three mutations. These findings provide electrophysiological evidence that pyramidal and visual pathways are differentially affected in SCA1, SCA2 and SCA3 patients.
Patients with Parkinson's disease (PD) show impairments of a range of motor learning tasks, including tracking or serial reaction time task learning. Our study investigated whether such deficits would also be seen on a simple type of motor learning, classic conditioning of the eyeblink response. Medicated and unmediated patients with PD showed intact unconditioned eyeblink responses and significant learning across acquisition; the learning rates did not differ from those of healthy control subjects. The overall frequency of conditioned responses was significantly higher in the medicated patients with PD relative to control subjects, and there was also some evidence of facilitation in the unmedicated patients with PD. Conditioning of electrodermal and electrocortical responses was comparable in all groups. The findings are discussed in terms of enhanced excitability of brainstem pathways in PD and of the involvement of different neuronal circuits in different types of motor learning.
We describe five patients presenting with high fever and isolated cerebellar gait ataxia. In all these patients, neurological examination revealed dysmetria, intention tremor and postural tremor during sustained posture, all restricted to the legs. Brain MRI was normal. In four of these patients, the recording of leg tremor during sustained postures showed a 3-Hz frequency. Cerebellar gait ataxia resolved within 3-10 days. We suggest that the ataxic gait was due to a reversible dysfunction of the spinocerebellar part of the anterior lobe.
Lethal catatonia and the malignant neuroleptic syndrome represent two potentially fatal disorders that require different therapeutic regimens. Clinical differentiation is considered difficult because of a number of similarities with respect to mode of onset, signs and symptoms, and outcome. Recent observations emphasizing similarities between the two disorders, however, suggest that catatonia and the malignant neuroleptic syndrome may not represent separate diagnostic entities. Instead, the malignant neuroleptic syndrome has been hypothesized to be a neuroleptic-aggravated form of catatonia. In the present paper, we report the case of a 22-year-old male who developed different forms of malignant neuroleptic syndromes subsequent to a catatonic episode and overlapping it. In addition, the course was complicated by the occurrence of heterotopic calcification within skeletal muscles. The clinical value of diagnostic criteria that help distinguish catatonia from neuroleptic malignant syndrome and their therapeutic consequences are discussed.
Nine young infants were followed longitudinally from 4 to 15 months of age. We recorded early spontaneous movements and reaching movements to a stationary target. Time-position data of the hand (endpoint), shoulder, and elbow were collected using an optoelectronic measurement system (ELITE). We analyzed the endpoint kinematics and the intersegmental dynamics of the shoulder and elbow joint to investigate how changes in proximal torque control determined the development of hand trajectory formation. Two developmental phases of hand trajectory formation were identified: a first phase of rapid improvements between 16 and 24 weeks of age, the time of reaching onset for all infants. During that time period the number of movement units per reach and movement time decreased dramatically. In a second phase (28-64 weeks), a period of "fine-tuning" of the sensorimotor system, we saw slower, more gradual changes in the endpoint kinematics. The analysis of the underlying intersegmental joint torques revealed the following results: first, the range of muscular and motion-dependent torques (relative to body weight) did not change significantly with age. That is, early reaching was not confined by limitations in producing task-adequate levels of muscular torque. Second, improvements in the endpoint kinematics were not accomplished by minimizing amplitude of muscle and reactive torques. Third, the relative timing of muscular and motion-dependent torque peaks showed a systematic development toward an adult timing profile with increasing age. In conclusion, the development toward invariant characteristics of the hand trajectory is mirrored by concurrent changes in the control of joint forces. The acquisition of stable patterns of intersegmental coordination is not achieved by simply regulating force amplitude, but more so by modulating the correct timing of joint force production and by the system's use of reactive forces. Our findings support the view that development of reaching is a process of unsupervised learning with no external or innate teacher prescribing the desired kinematics or kinetics of the movement.
BACKGROUND: A case of progressive irradiation-induced cerebral vasculopathy with abnormal netlike vessels and transdural anastomoses (moyamoya syndrome) is presented. Radiological findings in an additional 40 cases reported in the literature are analyzed, and their clinical relevance is discussed. CASE DESCRIPTION: A 19-year-old woman presented with recurrent ischemic brain lesions after radiation therapy for treatment of a craniopharyngioma during childhood. Cerebral angiography 6 and 12 years after completion of radiation therapy revealed progressive cerebral arterial occlusive disease involving the internal carotid artery on either side of the circle of Willis, with abnormal netlike vessels and transdural anastomoses (moyamoya syndrome). CONCLUSIONS: Extensive similarities between irradiation-induced cerebral vasculopathy and primary moyamoya syndrome (Nishimoto's disease) support the notion that both disorders share common pathophysiological mechanisms. The occurrence of moyamoya-like vascular changes may not depend on specific trigger mechanisms but may rather represent a nonspecific response of the developing vascular system to a number of various noxious events.
There is evidence from animal experiments that the cerebellum and its associated brainstem circuitry are involved in the acquisition of the conditioned response. In order to obtain evidence for their involvement in humans, we studied classical delay conditioning, using the eye-blink conditioned response, in five patients with pure cerebellar cortical atrophy and seven patients with olivopontocerebellar atrophy. The results were compared with those obtained in a group of neurologically healthy volunteers matched with the patients for age and sex. The two groups of patients had similar abnormalities in the acquisition of the conditioned response and produced fewer conditioned responses than in the control subjects in any given block of trials. Many of the patients' conditioned responses were inappropriately timed with respect to the conditioned stimulus. These results support the role of the cerebellum in the expression and timing of the conditioned response.