Human lumbar cord circuitries can be activated by extrinsic tonic input to generate locomotor-like activity.

We have demonstrated that non-patterned electrical stimulation of the lumbar cord can induce stepping-like activity in the lower limbs of complete spinal cord injured individuals. This result suggested the existence of a human lumbar locomotor pattern generator, which can convert a tonic input to a rhythmic motor output. We have studied the human lumbar cord in isolation from supraspinal input but under extrinsic tonic input delivered by spinal cord stimulation. Large-diameter afferents within the posterior roots are directly depolarized by the electrical stimulation. These afferents project to motoneurons as well as to lumbar interneurons involved in the motor control of lower limbs. Stimulation at 25-50 Hz can elicit rhythmic alternating flexion/extension movements of the lower limbs in supine individuals. Reducing the tonic input frequency to 5-15 Hz initiates lower limb extension. Epidural stimulation applied during manually assisted treadmill stepping in complete spinal cord injured persons immediately increases the central state of excitability of lumbar cord networks and enhances stepping-like functional motor outputs. Sustained, non-patterned tonic input via the posterior roots can activate human lumbar cord networks. Pattern generating configurations of these multifunctional circuitries can be set-up depending on the stimulation parameters and particularly on the input frequency.

[Importance of intrathecal pain therapy]. / Stellenwert der intrathekalen Schmerztherapie.

Intraspinal drug infusion using implantable pumps and catheter systems is a safe and effective therapy for selected pain patients with severe chronic pain. It improves pain relief, reduces drug-related side effects, decreases the need for oral analgesia and enhances quality of life in a segment of chronic pain patients whose pain has not been controlled with more conservative therapies. Intrathecal drug therapy has therefore established its role in the treatment of malignant pain, benign pain and severe spasticity.Careful patient selection and management as well as a multidisciplinary approach are determinants of successful treatment. Current practices for patient selection and management, screening, drug selection, dosing and implantation for intrathecal drug delivery systems are discussed.

Stepping-like movements in humans with complete spinal cord injury induced by epidural stimulation of the lumbar cord: electromyographic study of compound muscle action potentials.

STUDY DESIGN: It has been previously demonstrated that sustained nonpatterned electric stimulation of the posterior lumbar spinal cord from the epidural space can induce stepping-like movements in subjects with chronic, complete spinal cord injury. In the present paper, we explore physiologically related components of electromyographic (EMG) recordings during the induced stepping-like activity. OBJECTIVES: To examine mechanisms underlying the stepping-like movements activated by electrical epidural stimulation of posterior lumbar cord structures. MATERIALS AND METHODS: The study is based on the assessment of epidural stimulation to control spasticity by simultaneous recordings of the electromyographic activity of quadriceps, hamstrings, tibialis anterior, and triceps surae. We examined induced muscle responses to stimulation frequencies of 2.2-50 Hz in 10 subjects classified as having a motor complete spinal cord injury (ASIA A and B). We evaluated stimulus-triggered time windows 50 ms in length from the original EMG traces. Stimulus-evoked compound muscle action potentials (CMAPs) were analyzed with reference to latency, amplitude, and shape. RESULTS: Epidural stimulation of the posterior lumbosacral cord recruited lower limb muscles in a segmental-selective way, which was characteristic for posterior root stimulation. A 2.2 Hz stimulation elicited stimulus-coupled CMAPs of short latency which were approximately half that of phasic stretch reflex latencies for the respective muscle groups. EMG amplitudes were stimulus-strength dependent. Stimulation at 5-15 and 25-50 Hz elicited sustained tonic and rhythmic activity, respectively, and initiated lower limb extension or stepping-like movements representing different levels of muscle synergies. All EMG responses, even during burst-style phases were composed of separate stimulus-triggered CMAPs with characteristic amplitude modulations. During burst-style phases, a significant increase of CMAP latencies by about 10 ms was observed. CONCLUSION: The muscle activity evoked by epidural lumbar cord stimulation as described in the present study was initiated within the posterior roots. These posterior roots muscle reflex responses (PRMRRs) to 2.2 Hz stimulation were routed through monosynaptic pathways. Sustained stimulation at 5-50 Hz engaged central spinal PRMRR components. We propose that repeated volleys delivered to the lumbar cord via the posterior roots can effectively modify the central state of spinal circuits by temporarily combining them into functional units generating integrated motor behavior of sustained extension and rhythmic flexion/extension movements. This study opens the possibility for developing neuroprostheses for activation of inherent spinal networks involved in generating functional synergistic movements using a single electrode implanted in a localized and stable region.

Initiating extension of the lower limbs in subjects with complete spinal cord injury by epidural lumbar cord stimulation.

We provide evidence that the human spinal cord is able to respond to external afferent input and to generate a sustained extension of the lower extremities when isolated from brain control. The present study demonstrates that sustained, nonpatterned electrical stimulation of the lumbosacral cord--applied at a frequency in the range of 5-15 Hz and a strength above the thresholds for twitches in the thigh and leg muscles--can initiate and retain lower-limb extension in paraplegic subjects with a long history of complete spinal cord injury. We hypothesize that the induced extension is due to tonic input applied by the epidural stimulation to primary sensory afferents. The induced volleys elicit muscle twitches (posterior root muscle-reflex responses) at short and constant latency times and coactivate the configuration of the lumbosacral interneuronal network, presumably via collaterals of the primary sensory neurons and their connectivity with this network. We speculate that the volleys induced externally to the lumbosacral network at a frequency of 5-15 Hz initiate and retain an "extension pattern generator" organization. Once established, this organization would recruit a larger population of motor units in the hip and ankle extensor muscles as compared to the flexors, resulting in an extension movement of the lower limbs. In the electromyograms of the lower-limb muscle groups, such activity is reflected as a characteristic spatiotemporal pattern of compound motor-unit potentials.

Epidural electrical stimulation of posterior structures of the human lumbosacral cord: 3. Control Of spasticity.

OBJECTIVES: The purpose of this study was to evaluate the effect of spinal cord stimulation (SCS) on severe spasticity of the lower limbs in patients with traumatic spinal cord injury (SCI) under close scrutiny of the site and parameters of stimulation. MATERIALS AND METHODS: Eight SCI patients (four women, four men) were included in the study. Levels of spasticity before and during stimulation were compared according to a clinical rating scale and by surface electrode polyelectromyography (pEMG) during passive flexion and extension of the knee, supplemented by a pendulum test with the stimulating device switched either on or off over an appropriate period. RESULTS: Both the clinical and the experimental parameters clearly demonstrated that SCS, when correctly handled, is a highly effective approach to controlling spasticity in spinal cord injury subjects. The success of this type of treatment hinges on four factors: (1) the epidural electrode must be located over the upper lumbar cord segment (L1, L2, L3); (2) the train frequency of stimulation must be in the range of 50 - 100 Hz, the amplitude within 2 - 7 V and the stimulus width of 210 micross; (3) the stimulus parameters must be optimized by clinically assessing the effect of arbitrary combinations of the four contacts of the quadripolar electrode; and (4) amplitudes of stimulation must be adjusted to different body positions. CONCLUSIONS: Severe muscle hypertonia affecting the lower extremities of patients with chronic spinal cord injuries can be effectively suppressed via stimulation of the upper lumbar cord segment.

No tissue damage by chronic deep brain stimulation in Parkinson's disease.

We report on the pathological findings in the brains of 8 Parkinson's disease patients treated with deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (6 cases) and subthalamic nucleus (2 cases). DBS was performed continuously for up to 70 months. All brains showed well-preserved neural parenchyma and only mild gliosis around the lead track compatible with reactive changes due to surgical placement of the electrode. We conclude that chronic DBS does not cause damage to adjacent brain tissue.

An open-label, multicentre clinical trial to determine the levodopa dose-sparing capacity of pramipexole in patients with idiopathic Parkinson's disease.

Ninety-three patients with idiopathic Parkinson's disease (PD) entered a 12 week open-label, baseline controlled, multicentre study. The study was designed to determine the levodopa sparing effect of pramipexole as add-on treatment in PD while maintaining an optimal clinical improvement in motor performance. The overall reduction in adjusted levodopa dose was the primary endpoint. Unified Parkinson's Disease Rating Scale (UPDRS) subscores as well as motor fluctuations, frequency and severity of dyskinesia (assessed by patient diaries) were secondary endpoints. Pramipexole permitted a median reduction of adjusted levodopa by 40% while maintaining or improving the UPDRS scores in 61 patients (per protocol [PP] analysis). The intent-to-treat (ITT) analysis (90 patients) similarly revealed a median reduction of 40%. An anticipated short-term levodopa dose reduction as substantiated by 95% confidence interval calculations lies within a range of 35% to 50%. If unadjusted levodopa doses were considered, a median reduction of 42% (PP) or 43% (ITT) was achieved. 47% patients (ITT) had a levodopa dose reduction (adjusted) of more than 40% while maintaining or improving their level of efficacy, and 72.2% had a reduction of at least 20%. Motor fluctuations improved compared to baseline according to patient diaries and UPDRS part IV. These findings suggest that pramipexole can markedly reduce the daily levodopa dosage without deterioration of motor response and support that this new selective D2/D3 receptor agonist also improves later levodopa-associated motor complications.

Does deep brain stimulation of the nucleus ventralis intermedius affect postural control and locomotion in Parkinson's disease?

The purpose of this study was to evaluate the effect of unilateral stimulation of the nucleus ventralis intermedius (VIM) on parkinsonian signs like postural stability and locomotion with respect to the severity of Parkinson's disease (PD). Seven patients with idiopathic PD were included in the study. Changes in visual cues on postural stability and step initiation were assessed on a fixed platform system with VIM stimulation switched either on (VIM ON) or off (VIM OFF), and compared with a control group of seven age-matched normal individuals. Sway scores (area and path) were significantly (p <0.05) higher in the parkinsonian patients with VIM OFF than with VIM ON as well as compared with the control subjects. No correlation was obtained between extent of sway scores and severity of contralateral tremor after cessation of VIM stimulation. Locomotion parameters, by contrast, were not influenced by VIM stimulation: latency until step initiation and walking-cycle time were the same among parkinsonian patients as among normal individuals, both in the presence and in the absence of VIM stimulation. In conclusion, our results indicate that tremor suppression by VIM stimulation improves postural stability.

Apomorphine test: a predictor for motor responsiveness to deep brain stimulation of the subthalamic nucleus.

The value of the apomorphine test as a predictor of the clinical outcome of deep brain stimulation of the subthalamic nucleus (STN) was evaluated in patients with advanced idiopathic Parkinson's disease (IPD) or multiple system atrophy (MSA). Thirteen IPD patients with severe diurnal fluctuations and one MSA patient not responding to dopaminergic drugs were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) and the timed finger tapping test (FTT), measured preoperatively on and off apomorphine and postoperatively on and off STN stimulation. UPDRS motor items 20-25 were assessed intraoperatively on and off STN stimulation when the clinically effective target was approached. The motor response to immediate intraoperative and long-term STN stimulation was correlated with results of the apomorphine test. The response to immediate intraoperative STN stimulation was accurately predicted by apomorphine challenge in all 13 IPD patients. Clinical outcome following long-term STN stimulation was correlated significantly with preoperative changes due to apomorphine measured with the UPDRS motor scores (r = 0.7125, P < 0.01) and FTT (r = 0.9276, P < 0.001). Moreover, comparison of long-term STN stimulation to preoperative drug treatment displayed a significant reduction in the duration of off-phases and a significant increase in the duration of on-phases. However, in the single patient with MSA no beneficial response was obtained either to apomorphine or to STN stimulation intraoperatively and during the postoperative externalized test period. Our results indicate that the apomorphine test can predict the outcome of immediate and long-term STN stimulation and may help in the selection of candidates for surgery.

Efficacy, safety, and tolerance of the non-ergoline dopamine agonist pramipexole in the treatment of advanced Parkinson's disease: a double blind, placebo controlled, randomised, multicentre study.

OBJECTIVES: Pramipexole, a non-ergot dopamine D2/D3 receptor agonist, was investigated as an add on drug in advanced parkinsonian patients with motor fluctuations to assess efficacy, safety, and tolerance. METHODS: Seventy eight patients of either sex with advanced Parkinson's disease and treatment complications such as motor fluctuations were enrolled into a double blind, placebo controlled, randomised, multicentre study (phase II) and assigned to add on treatment with pramipexole (n=34) versus placebo (n=44) to a previously stabilised antiparkinsonian medication (7 week dose titration interval, 4 week maintenance period). The primary end point of efficacy was the change from baseline in the total score of the unified Parkinson's disease rating scale (UPDRS) in the on "period" (2 hours after intake of study medication). Safety and tolerability were assessed on the basis of adverse events, vital signs, laboratory measurements, and ECG recordings. RESULTS: There was a significant improvement of the pramipexole group in UPDRS total scores, subscores part II, III (activities of daily living and motor examination), and IV (complications of therapy). Mean UPDRS total score decreased by 37.3% under pramipexole compared with 12.2% under placebo (p<0.001). Patients under pramipexole reported an overall reduction in "off" periods of 12%--resulting in 1.7 more hours "on" time a day--compared with an increase in "off" periods of 2% under placebo. There were no unexpected safety results. The adverse event profile disclosed a high tolerability. The most important adverse events under pramipexole were fatigue, dyskinesia, and vivid dreams. CONCLUSION: Pramipexole administration is an efficacious and well tolerated add on therapy in patients with advanced Parkinson's disease with an improvement in activities of daily living, motor function, and treatment associated complications.

Deep brain stimulation of the subthalamic nucleus for control of extrapyramidal features in advanced idiopathic parkinson's disease: one year follow-up.

UNLABELLED: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) with a quadripolar electrode was carried out in 9 patients with advanced idiopathic Parkinson's disease (PD) affected with severe diurnal motor fluctuations. The effect of bilateral STN stimulation was evaluated by clinical methods in all patients after 3 and 12 months. Assessment was based on the Unified Parkinson's Disease Rating Scale (UPDRS), timed motor tests, the Schwab and England Activities of Daily Living and a diary chart to document motor fluctuations. Alterations in parkinsonian signs, motor performance and functional outcome were recorded postoperatively (1) under temporary complete withdrawal of both STN stimulation and medication; (2) in the presence of STN stimulation only; and (3) in the presence of both STN stimulation and medication. The results were compared with the preoperative data assessed in defined on-phase and defined off-phase. STN stimulation on (compared to STN stimulation off) results in a significant improvement in UPDRS motor scores: after 3 months from 50.5 +/- 14.3 to 27.8 +/- 5.8, and after 12 months from 49.4 +/- 14.1 to 27.1 +/- 7.1 (p < 0.01). There was a significant decrease in the average duration of off-periods from 8.82 +/- 2.47 hours to 1.00 +/- 1.06 hours (p < 0.001), a marked increase in on-periods without dyskinesia from 4.62 +/- 2.72 to 14.62 +/- 1.51 hours (p < 0.01), and a sharp drop in on-periods with dyskinesia from 2.87 (+/- 4.18) to 0.25 (+/- 0.97) hours (p < 0.05), which remained stable up to 12 months (off-periods: 1.25 +/- 1.58 hours, p < 0.001; on-periods without: 13.87 +/- 1.95 hours, p < 0.001; and on-periods wth dyskinesia: 0.37 +/- 1.06 hours, p < 0.05). However, our first PD patient with an implanted DBS electrode within the STN died from cardiac infarction two days after surgery. This sudden death was not linked either to surgery nor to stimulation - and happened by chance. Our findings confirm that STN stimulation is a suitable functional neurosurgical procedure for the modulation and control of PD signs associated with severe motor fluctuations, in that they demonstrate a beneficial effect which was fully sustained over a one year follow-up period. KEYWORDS: Subthalamic nucleus, deep brain stimulation, Parkinson's disease.

Short-term effect of amantadine sulphate on motor performance and reaction time in patients with idiopathic Parkinson's disease.

In thirty patients with idiopathic Parkinson's disease (PD) we examined in a prospectively designed study the effect on motor performance and cognitive functions of amantadine sulphate, applied intravenously over a period of 14 days. Prior to the introduction of amantadine and post infusionem the motor function was measured by the Unified Parkinson Disease Rating Scale (UPDRS) and the Motor Performance Test Series (MPS); the simple and the choice reaction time were assessed using the Vienna Reaction Unit (VRU). The primary endpoint of efficacy was the change in the UPDRS part III (motor examination) after 14 days of amantadine sulphate administration compared with baseline. Secondary end-points were changes in the variables of-the MPS and VRU at the end of administration interval compared with baseline. Overall, after 14 days of intravenous amantadine administration (200mg/ day), a significant improvement was obtained in motor performance with respect to the semiquantitative motor scores of the UPDRS (p = 0.002) and the quantitative motor variables in the pertinent subtests of the MPS, reflecting precision and speed of arm-hand movement as well as manual and finger dexterity, for the right (p < 0.01) and the left hand (p < 0.05). However, all patients being viewed collectively, it was observed that there was a widely differing time delay of efficient motor response to amantadine from 4 to 9 days between individuals, whilst the quality of motor response remained stable for the follow-up period. Although simple reaction time showed no significant improvement, choice reaction time shortened significantly in less affected PD patients staging Hoehn and Yahr I to III (p < 0.05). We conclude that apart from efficacy on motor performance, amantadine sulphate - applied intravenously - has a positive effect on cognitive functions, particularly in less affected PD patients.

Evidence for a spinal central pattern generator in humans.

Non-patterned electrical stimulation of the posterior structures of the lumbar spinal cord in subjects with complete, long-standing spinal cord injury, can induce patterned, locomotor-like activity. We show that epidural spinal cord stimulation can elicit step-like EMG activity and locomotor synergies in paraplegic subjects. An electrical train of stimuli applied over the second lumbar segment with a frequency of 25 to 60 Hz and an amplitude of 5-9 V was effective in inducing rhythmic, alternating stance and swing phases of the lower limbs. This finding suggests that spinal circuitry in humans has the capability of generating locomotor-like activity even when isolated from brain control, and that externally controlled sustained electrical stimulation of the spinal cord can replace the tonic drive generated by the brain.

Transient increase of pancreatic enzymes evoked by apomorphine in Parkinson's disease.

In one of our first patients with severely disabling and fluctuating Parkinson's disease (PD) we observed a transient pancreatic enzymes increase 6 months after continuous apomorphine therapy. Since this adverse effect had not been previously reported, we systematically investigated the course of pancreas and liver functions in response to apomorphine: laboratory and neurological assessments were conducted before initiation of apomorphine therapy, during the increment phase up to the optimal motor effective level and at all follow-up visits. We found in five out of 29PD patients a transient increase of pancreatic enzymes during the initial phase of continuous subcutaneous apomorphine application. Peaks of pathological plasma levels were apparent from the first day up to the fifth day after apomorphine initiation, and returned to normal levels within 10 days in all 5 patients. Otherwise, this pancreatic enzymes increase was not accompanied by any raising in plasma levels of corresponding liver enzymes. No pathological signs in the endoscopic-retrograde cholangiopancreatography, the abdominal ultrasonography and the computed tomography of the abdomen were found in any of the affected PD patients. Furthermore, there was no evidence of pancreato-hepatal risk factors in the previous history in any of the PD patients studied. With respect to the course of PD, no differences were obtained upon comparison of affected and non-affected PD patients. Considering the patients' history, clinical course and current knowledge about the effect of apomorphine on pancreato-hepatal function, we conclude that a possible cumulative pathomechanism between transient pancreato-hepatal enzymes and continuous applied apomorpine, especially in the titrating phase, might cause this adverse event in about 20% of PD patients treated with apomorphine continuously.

Stimulation of the ventral intermediate thalamic nucleus in tremor dominated Parkinson's disease and essential tremor.

Based on Benabid's experimental and clinical findings that low-frequency (50 Hz) electrical stimulation of the ventral intermediate thalamic nucleus may increase tremor, while higher frequencies (> 100 Hz) lead to suppression of the tremor, we implanted a stimulation electrode in 33 thalami among 27 patients. Six patients were implanted bilaterally. 23 suffered from Parkinson's disease, 4 from essential tremor. All patients had a drug-resistant tremor. The Vim target was calculated based on stereotactic ventriculography. An intra-operative neurophysiological target control was performed on all patients. After a monopolar (12 thalami) or quadripolar (21 thalami) lead was implanted we then connected it to a percutaneous extension lead. In the days following the surgery a test stimulation was performed. In all but one patient stimulation resulted in a suppression of the tremor. In a second procedure, a pulse generator (ITREL II; MEDTRONIC) was implanted and connected subcutaneously to the thalamic lead. After implantation of the pulse generator all patients stimulate chronically while some turn off the stimulator at night. In 21 thalami total suppression of tremor was observed, 6 showed major improvement, 4 only minor improvement. There was no significant effect on any other existing symptom of Parkinson's disease. Due to the proximity of Vim to the sensory thalamus the majority of the patients (27 thalami) report slight temporary paraesthesias when the pulse generator is turned on. Two report permanent paraesthesias when stimulation is on. In 4 cases a slight dysarthria occurs under stimulation. In 2 the dysarthria is marked. In one case dysequilibrium occurs under stimulation. All these side effects are reversible when stimulation is turned off. In 3 patients, the lead was displaced due to an insufficient lead fixation, thus making a second procedure necessary to correct the electrode position. We had one complication due to bleeding at the burr hole side. Follow-up ranges from 3 to 48 months. So far in no cases has the effect of stimulation worn off. In conclusion we regard Vim neurostimulation as an effective and safe alternative to conventional thalamotomy and recommend that it should be considered in cases in which drug therapy has failed to affect Parkinsonian or essential tremor. Moreover, we believe that this procedure is a less invasive and equally efficient alternative to classic thalamotomy and thus should be given preference.

[Apomorphine test in Parkinson disease--dose and corresponding parameters]. / Apomorphintest bei Morbus-Parkinson--Dosis und korrespondierende Parameter.

The apomorphine test is a well known indicator of therapeutic responsiveness to dopaminergic substances and a reliable instrument for the differential diagnosis of idiopathic Parkinson's disease. The relationship between apomorphine dosage and the following parameters, namely age, duration of disease, body height, body surface, skinfold thickness of the abdominal wall and the upper arm as a measure of subcutaneous fatty tissue, and amount of administered L-dopa was studied in 45 patients with Parkinson's disease in whom the apomorphine test was positive. In addition we investigated whether different doses of apomorphine resulted in significant differences of the parameters studied. The determined parameters correlated with the given dose of apomorphine (p < 0.05) and thus, represent a potential indicator for optimal L-dopa dose determination and intermittent or continuous apomorphine administration.

Therapeutic effect of clozapine in psychotic decompensation in idiopathic Parkinson's disease.

Seven patients with idiopathic Parkinson's disease, aged 62 to 76 years, average duration of the disease approximately eleven years, suffering from severe hallucinosis and paranoid delusions of different degree, in whom conventional therapeutic strategies (administration of benzodiazepines and mild neuroleptics) had no antipsychotic effect, received clozapine, a non-classical highly potent neuroleptic, while blood count was strictly monitored. Paranoid ideas disappeared in all seven patients after a maximum of four days administration of 25-125 mg/day. No deterioration of parkinsonian symptoms, quantified according to UPDRS was seen. Given the protection of clozapine, we could increase the L-dopa dose in two cases, thereby improving the patients' motor function. Blood count showed no abnormalities in any of the patients during an average observation period of seventeen months. Our results support the assumption that clozapine has a potent antipsychotic effect in the treatment of psychotic decompensation in advanced Parkinson's disease in carefully selected patients. We saw no negative influence of the neuroleptic on extrapyramidal symptoms.

Speed and power of higher cerebral functions in parkinsonian patients.

We compared 21 idiopathic, pharmaceutically well managed parkinsonian patients, neurological stages I and II on the Hoehn and Yahr scale with 21 parkinsonian patients stage III and 19 healthy controls group-matched for age, sex and education to study to what extent impairments of fluid intelligence in parkinsonian patients are due to a slowing of cognitive processes, i.e. to bradyphrenia (a deficit in the speed component) or to a true performance deficit (a deficit in the power component). The Vienna Matrices Test, which is similar to Raven's Standard Progressive Matrices was presented to the patients in a modified form. The Cognitrone was used to measure the influence of vigilance and perception on the cerebral function assessed. With increasing neurological severity of the disease, the dimension examined showed true deficits in the power component. There was no bradyphrenia in the sense of slower performance which would otherwise be equal to that of the control subjects. Vigilance and perception did not change in the course of the disease.