Jan Raethjen

Treatment of patients with essential tremor

Essential tremor is a common movement disorder. Tremor severity and handicap vary widely, but most patients with essential tremor do not receive a diagnosis and hence are never treated. Furthermore, many patients abandon treatment because of side-effects or poor efficacy. A newly developed algorithm, based on the logarithmic relation between tremor amplitude and clinical tremor ratings, can be used to compare the magnitude of effect of available treatments. Drugs with established efficacy (propranolol and primidone) produce a mean tremor reduction of about 50%. Deep brain stimulation (DBS) in the thalamic nucleus ventrointermedius or neighbouring subthalamic structures reduces tremor by about 90%. However, no controlled trials of DBS have been done, and the best target is still uncertain. Better drugs are needed, and controlled trials are required to determine the safety and efficacy of DBS in the nucleus ventrointermedius and neighbouring subthalamic structures.

The pathophysiology of parkinsonian tremor: a review.

Abstract Parkinsonian tremor is most likely due to oscillating neuronal activity within the CNS. Summarizing all the available evidence, peripheral factors only play a minor role in the generation, maintenance and modulation of PD tremor. Recent studies have shown that not a single but multiple oscillators and responsible. The most likely candidate producing these oscillations is the basal ganglia loop and its topographic organization might be responsible for the separation into different oscillators which, nevertheless, usually produce the same frquency. The neuronal mechanisms underlying these oscillations are not yet clear, but three hypotheses would be compatible with the presently available data from animal models and data recorded in patients. The first is a cortico-subthalamo-pallido-thalamic loop, the second is a pacemaker consisting of the external pallidum and the subthalamic nucleus, and the third is abnormal synchronization due to unknown mechanisms within the whole striato-pallido-thalamic pathway leading to a loss of segregation. Assuming the oscillator within the basal ganglia pathway, the mechanism of stereotactic surgery might be a desynchronization of the activity of the basal ganglia-thalamo-cortical or the cerebello-thalamo-cortical pathway.

Multiple oscillators are causing parkinsonian and essential tremor

The tremors of Parkinsons disease (PD) and essential tremor (ET) are traditionally considered to depend on a central oscillator producing rhythmic activation of the motoneurones of all extremities. To test this hypothesis, we have compared electromyographic tremor activity in different muscles of the affected limbs using cross spectral analysis, including coherence and phase. Surface electromyographic recordings from both arms, legs, and the neck were analyzed in 22 patients with PD and 28 patients with ET. Volume conduction between neighboring muscles producing artificial “coherence” has been found to be an important methodologic problem. We have developed a mathematical test to exclude data that could distort the results. According to this test, 10% or 25% of muscle combinations from the same limb had to be excluded from further analysis in PD or ET, respectively. In both, patients with PD and ET, we found a considerable number of muscle combinations oscillating at virtually the same frequency (▵ frequency <0.4 Hz) without showing a significant coherence. Thus, the frequency difference between different muscles is not sufficient to measure the correlation between two muscles. Significant coherencies between muscles within the same arm or leg were found in 70% or 90% of patients with PD or ET, respectively, whereas only one patient with PD and not a single patient with ET showed significant coherencies between muscles from different limbs. The phase between coherent muscles of the same arm of patients with PD showed a preference of either a reciprocal alternating pattern for antagonistic muscles in forearm flexor and upper arm extensor as opposed to a co‐contraction pattern between the hand flexors and the triceps brachii. In patients with ET such clear differences were lacking. We conclude that multiple oscillators are responsible for the tremor in different extremities of patients with PD and ET. Differences between PD and ET concerning the phase relation within the arm may either be related to the topography within the basal ganglia or to differently involvedspinal pathways.

Effects of bilateral subthalamic nucleus stimulation on parkinsonian gait

Gait analysis was carried out to assess the effects of l-dopa and bilateral subthalamic nucleus stimulation on gait velocity, cadence, stride length, and gait kinematics in nine patients with PD. Substantial effects of bilateral subthalamic nucleus stimulation on gait, with an increase in gait velocity and stride length comparable to that of a suprathreshold l-dopa dose, were found. Interestingly, stride length was more improved by l-dopa and cadence more by subthalamic nucleus stimulation. In two patients with freezing during the “on” period, subthalamic nucleus stimulation failed to reduce this symptom effectively.

Typical features of cerebellar ataxic gait

Background: Although gait disturbance is one of the most pronounced and disabling symptoms in cerebellar disease (CD), quantitative studies on this topic are rare. Objectives: To characterise the typical clinical features of cerebellar gait and to analyse ataxia quantitatively. Methods: Twelve patients with various cerebellar disorders were compared with 12 age matched controls. Gait was analysed on a motor driven treadmill using a three dimensional system. A tandem gait paradigm was used to quantify gait ataxia. Results: For normal locomotion, a significantly reduced step frequency with a prolonged stance and double limb support duration was found in patients with CD. All gait measurements were highly variable in CD. Most importantly, balance related gait variables such as step width and foot rotation angles were increased in CD, indicating the need for stability during locomotion. The tandem gait paradigm showed typical features of cerebellar ataxia such as dysmetria, hypometria, hypermetria, and inappropriate timing of foot placement. Conclusions: Typical features of gait in CD are reduced cadence with increased balance related variables and an almost normal range of motion (with increased variability) in the joints of the lower extremity. The tandem gait paradigm accentuates all the features of gait ataxia and is the most sensitive clinical test.

Extracting model equations from experimental data

This letter wants to present a general data-driven method for formulating suitable model equations for nonlinear complex systems. The method is validated in a quantitative way by its application to experimentally found data of a chaotic electric circuit. Furthermore, the results of an analysis of tremor data from patients suffering from Parkinsons disease, from essential tremor, and from normal subjects with physiological tremor are presented, discussed and compared. They allow a distinction between the different forms of tremor.

The oscillating central network of Essential tremor

Essential tremor (ET) is a centrally driven tremor. It is meanwhile well established that it does not emerge from one single oscillator but an oscillatory network comprising most parts of the physiological central motor network. Several lines of evidence hint at the olivocerebellar system and the thalamus as key structures within this network whereas the cortical motor regions are only intermittently entrained in the tremor rhythm in thalamocortical loops. Dynamic changes in network composition and the interaction in symmetric loops seem to be specific to the generation of tremor. The same network in voluntary motor control is more fixed and subcortico-cortical interactions are preferentially via thalamocortical relays. Thus it is not primarily the network topography but the dynamics and interaction within the network that determines whether involuntary tremor or voluntary movements emerge. And this may be the basis for the selective effect of deep brain stimulation on tremor.

Camptocormia in idiopathic Parkinson's disease: A focal myopathy of the paravertebral muscles†

The objective of our study was to describe the clinical features of camptocormia, an involuntary, marked flexion of the thoracolumbar spine in idiopathic Parkinsons disease (PD) and to understand its etiology. In a prospective, cross‐sectional study, we examined 15 patients with PD and camptocormia using laboratory parameters, EMG, muscle magnetic resonance imaging, and biopsy of the paravertebral muscles. The clinical data were compared with a matched control group of PD patients without camptocormia, and the biopsies were compared with muscles from age‐matched autopsies. Almost all the patients (median age, 68.0 years; 7 women) with camptocormia suffered from advanced PD. Camptocormia occurred at a median of 9.0 years after the PD diagnosis. Compared with our clinical control group, back pain was more frequent and less dopa‐sensitive in the patients with camptocormia who suffered more often from additional diseases of the back. On EMG, we found mainly a myopathic pattern. The MRI of the paravertebral muscles showed localized changes ranging from edema with contrast enhancement, which are considered to be early signs, to atrophy and/or fatty degeneration, interpreted as late degenerative changes. Early signs were seen mainly during the first year and degenerative changes after 1.5 years. Biopsies revealed consistently myopathic changes and in some cases fatty degeneration. Clinical or electromyographic features favoring dystonia were absent. Camptocormia is a major disabling, non‐fluctuating and levodopa‐resistant complication of advanced PD. The cause of camptocormia in idiopathic PD is a focal myopathy. Our findings suggest that the myopathy has a progressive course, which finally leads to degeneration of the paravertebral muscles.

Monosymptomatic resting tremor and Parkinson's disease: A multitracer positron emission tomographic study

We sought to elucidate the relationship between monosymptomatic resting tremor (mRT) and Parkinsons disease (PD). We studied eight mRT patients (mean Hoehn and Yahr [H&Y], 1.1 ± 0.4), eight patients with PD (mean H&Y, 1.5 ± 0.8), who showed all three classic parkinsonian symptoms, and seven age‐matched healthy subjects. Subjects underwent cerebral magnetic resonance imaging (MRI) and multitracer positron emission tomography (PET) with 6‐[18F]fluoro‐L‐dopa (F‐dopa), [18F]fluorodeoxyglucose (FDG), and [11C]raclopride (RACLO). PD and mRT patients did not show significant differences in F‐dopa‐, RACLO‐, or FDG‐PET scans. In F‐dopa‐ and RACLO‐PET, significant differences between the pooled patient data and control subjects were found for the following regions: anterior and posterior putamen ipsilateral and contralateral to the more affected body side, and ipsilateral and contralateral putaminal gradients of the Ki values. Furthermore, we found a difference for the normalized glucose values of the whole cerebellum between the control group (0.94 ± 0.06) and PD patients (1.01 ± 0.04; P < 0.05) but not for the mRT group (0.97 ± 0.03). Our findings indicate that monosymptomatic resting tremor represents a phenotype of Parkinsons disease, with a nearly identical striatal dopaminergic deficit and postsynaptic D2‐receptor upregulation in both patient groups. We suggest that the cerebellar metabolic hyperactivity in PD is closer related to akinesia and rigidity rather than to tremor.

Gait ataxia in essential tremor is differentially modulated by thalamic stimulation

Patients with advanced stages of essential tremor frequently exhibit tandem gait ataxia with impaired balance control and imprecise foot placement, resembling patients with a cerebellar deficit. Thalamic deep brain stimulation, a surgical therapy for otherwise intractable cases, has been shown to improve tremor, but its impact on cerebellar-like gait difficulties remains to be elucidated. Eleven patients affected by essential tremor (five females; age 69.8 ± 3.9 years; disease duration 24.4 ± 11.2 years; follow-up after surgery 24.7 ± 20.3 months) were evaluated during the following conditions: stimulation off, stimulation on and supra-therapeutic stimulation. Ten age-matched healthy controls served as the comparison group. Locomotion by patients and controls was assessed with (i) overground gait and tandem gait; (ii) balance-assisted treadmill tandem gait and (iii) unassisted treadmill gait. The two treadmill paradigms were kinematically analysed using a 3D opto-electronic motion analysis system. Established clinical and kinesiological measures of ataxia were computed. During stimulation off, the patients exhibited ataxia in all assessment paradigms, which improved during stimulation on and worsened again during supra-therapeutic stimulation. During over ground tandem gait, patients had more missteps and slower gait velocities during stimulation off and supra-therapeutic stimulation than during stimulation on. During balance-assisted tandem gait, stimulation on reduced the temporospatial variability in foot trajectories to nearly normal values, while highly variable (ataxic) foot trajectories were observed during stimulation off and supra-therapeutic stimulation. During unassisted treadmill gait, stimulation on improved gait stability compared with stimulation off and supra-therapeutic stimulation, as demonstrated by increased gait velocity and ankle rotation. These improvements in ataxia were not a function of reduced tremor in the lower limbs or torso. In conclusion, we demonstrate the impact of thalamic stimulation on gait ataxia in patients with essential tremor with improvement by stimulation on and deterioration by supra-therapeutic stimulation, despite continued control of tremor. Thus, cerebellar dysfunction in these patients can be differentially modulated with optimal versus supra-therapeutic stimulation. The cerebellar movement disorder of essential tremor is due to a typical cerebellar deficit, not to trembling extremities. We hypothesize that deep brain stimulation affects two major regulating circuits: the cortico-thalamo-cortical loop for tremor reduction and the cerebello-thalamo-cortical pathway for ataxia reduction (stimulation on) and ataxia induction (supra-therapeutic stimulation).