[Post-stroke-depression. Algorithm for a standardized diagnostic approach in clinical routine]. / Post-Stroke-Depression. Algorithmus für ein standardisiertes diagnostisches Vorgehen in der klinischen Routine.

Depression is a frequent and important complication after stroke. The occurrence of a post-stroke-depression (PSD) has a significant impact on the functional and cognitive deficit, on mortality and on quality of life after stroke. In contrast to the clinical importance, PSD is often ignored in routine management of stroke patients and remains often untreated if diagnosed. The diagnostic uncertainty is aggravated by the lack of appropriate diagnostic criteria for PSD in the International Classification of Diseases (ICD-10) used in Germany. For the first time, we present an algorithm, which allows for a standardized examination of stroke patients on the presence of PSD. All stroke patients should be examined initially by a short and simple screening tool and are subjected to more extensive procedures only if PSD is assumed based on the screening result. Furthermore potentials and limitations to convert the diagnosis of PSD into a diagnostic related group (DRG) that is used to calculate the hospital's reimbursement are highlighted. Finally pharmacological treatment options for PSD are discussed.

Dopaminergic function in a family with the PARK6 form of autosomal recessive Parkinson's syndrome.

A G309D mutation in the PINK1 gene in a consanguineous Spanish kindred with seven siblings, three of whom are clinically affected, has recently been shown to be a cause of the PARK6 form of autosomal-recessive Parkinson's syndrome. In this family, we studied pre- and postsynaptic dopaminergic function using 123I-FP-CIT- and 123I-iodobenzamide-SPECT to determine binding to the presynaptic dopamine transporter (DAT) and postsynaptic D2 receptors respectively. All three PARK6 patients showed reduced striatal DAT binding with posterior preponderance similar to sporadic idiopathic PD, but only one patient showed significant striatal asymmetry. In two of the siblings, DAT binding was markedly increased. IBZM-SPECT was normal in both patients and sibs. Our findings indicate that 123I-FP-CIT-SPECT shows similar DAT binding in PARK6 patients compared to idiopathic Parkinson's disease. The increased DAT binding in heterozygous PARK6 carriers may be a new very early preclinical finding, but its significance is still unclear.

Survival and quality of life outcome after mechanical ventilation in elderly stroke patients.

OBJECTIVES: Mortality is high and functional outcome poor in mechanically ventilated stroke patients. In addition, age >65 years is an independent predictor of death at 2 months among these patients. Our objective was to determine survival rates, functional outcome, and quality of life (QoL) in stroke patients older than 65 years requiring mechanical ventilation. METHODS: A prospective cohort study with an additional cross-sectional survey in 65 patients aged 65 years and older (mean age (SD): 75.6 (6.0) years) with ischaemic or haemorrhagic stroke who underwent mechanical ventilation. Main outcome measures were survival rate at 6 months, and Barthel Index (BI), modified Rankin Scale, and QoL at 15.8 (SD 8.0) months. RESULTS: Survival rate at 6 months was 40%. Elective intubation (odds ratio (OR) 13.6; p = 0.002) was the only independent positive predictor for survival, while age >77.5 years (OR 0.1; p = 0.004) and white blood count >10/nl at admission (OR 0.31; p = 0.032) were independent negative predictors for survival at 6 months. At the time of the cross-sectional survey, BI was >70 in five out of 22 patients, 35-70 in three and <35 in the remaining 14 patients. QoL was impaired primarily in the physical domain, whereas the psychosocial domain was less affected. CONCLUSIONS: Although only 40% of elderly patients intubated in the acute phase of stroke survived at least 6 months, one in four survivors recovered to a good functional outcome with a reasonable QoL. Elderly stroke patients need to be selected carefully for intensive care treatment, but elective intubation to allow diagnostic procedures should not be withheld primarily based on their age.

Differential effects of various treatment combinations on cardiovascular dysfunction in patients with Parkinson's disease.

OBJECTIVES: Patients with Parkinson's disease (PD) frequently suffer from cardiovascular dysfunction, which may be enhanced to various extents by different antiparkinsonian drugs. MATERIALS AND METHODS: We analysed electrocardiogram (ECG) abnormalities, cardiovascular reflexes (CVR) and orthostatic hypotension (OH) in 148 patients with idiopathic PD assigned to five different combination therapies of levodopa (LD) plus either bromocriptine (BRO), ropinirole (ROP), selegiline (SEL), anticholinergic (ACH) or amantadine (AMA) or to LD monotherapy before and after a 1-week washout of the add-on drug. Patients were matched for age and disease severity (Hoehn and Yahr stage 2-3). Rater-blinded cardiovascular testing was performed at baseline, and following a 1-week washout period of the add-on drugs. RESULTS: We found that the incidence of cardiovascular dysfunction was generally higher in patients receiving a combination therapy compared with patients on LD monotherapy. ECG abnormalities were found in 40-52% of patients in combination therapy, but in only 20% of the patients receiving LD monotherapy. After discontinuation of BRO and SEL, there were significant improvements in ECG, OH and CVR. After washout of ACH and AMA, a significant improvement was found only in the CVR score. AMA and ROP were the add-on drugs with the least adverse cardiovascular effects. CONCLUSION: We conclude that pre-existing cardiovascular autonomic dysfunction should be investigated and taken into account when deciding which combination therapy to choose in the treatment of parkinsonian patients.

[Brain infarctions caused by paradoxical embolism during long-distance flights]. / Paradox-embolische Hirninfarkte bei Langstreckenflügen.

HISTORY AND ADMISSION FINDINGS: Over the period of one year three long-distance airline passengers (aged 21, 63, and 64 years) were admitted to our department because of a first-time acute neurological deficit having occurred during their long-distance flights. INVESTIGATIONS: In all three cases acute stroke MRI showed embolic cerebral ischemia, and transesophageal echocardiography revealed a persistent foramen ovale (PFO). Venous duplex and compression ultrasonography of the legs showed no signs of thrombosis. Extra- and transcranial Doppler, Holter ECG recording, routine blood analysis and additional tests for thrombophilia (incl. lupus anticoagulans, APC resistance, protein C, S, and AT III) revealed no signs of cardiovascular disease or other stroke causes. Only in case 3 the prothrombin gene G 20210A was found. DIAGNOSIS, TREATMENT AND COURSE: Ischemic stroke due to paradoxical embolism through a PFO was diagnosed in all three patients. One patient recovered fully within 2 days, one was discharged with a persistent motor deficit and the third patient died subsequently as a result of multiple cerebral infarctions accompanied by massive pulmonary embolism. CONCLUSION: These three cases illustrate that paradoxical embolic stroke is a possible severe complication of long-distance air travel in passengers with a PFO and this should be taken into account when deciding upon individual risk-adjusted prophylactic measures.

Long-term treatment of cervical dystonia with botulinum toxin A: efficacy, safety, and antibody frequency. German Dystonia Study Group.

Data from 616 patients suffering from idiopathic cervical dystonia were analyzed to determine the efficacy and safety of treatment with botulinum neurotoxin type A (BoNT/A). Since the specific purpose of this study was to determine the long-term effects of this treatment, the analysis focused specifically on the patients (n = 303) having received six or more injections. Statistical analysis of a standardized documentation showed sustained significant benefit as measured by a disease severity score independent of the type of cervical dystonia. Furthermore, pronounced individual differences were found in response to this treatment although initial clinical scores and doses of BoNT/A were similar. There was no indication of previously unknown adverse events, the only risk being the development of serum antibodies against the toxin. As in previous studies on short-term effects of BoNT/A treatment, the most frequent adverse event was dysphagia, which occurred on average 9.7 days after injection and lasted on average 3.5 weeks. While secondary nonresponse was seen in approx. 5% of patients, antibody tests revealed neutralizing serum antibodies in only 2%. On the basis of the present data, therapy of cervical dystonia with BoNT/A seems to be safe and yields good stable results even after 5 years of treatment.

Phenotypic variability of the DYT1 mutation in German dystonia patients.

Primary dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained involuntary muscle contractions causing repetitive movements and/or abnormal postures. Recently, the gene locus (DYT1) and mutation responsible for a substantial number of cases suffering from early-onset primary dystonia was described. Here we report 2 German families and 1 sporadic patient with early-onset dystonia due to the DYT1 mutation in order to illustrate the variability of clinical manifestation within this molecularly defined entity. We demonstrate that writer's cramp or focal cervical dystonia is a clinical presentation of DYT1 as well as generalized dystonia.

Sinusoidal forearm tracking with delayed visual feedback. I. Dependence of the tracking error on the relative delay.

During forearm tracking of a sinusoidally moving target matching of proprioceptive and visual feedback was altered by introducing different visual delays. In five normal subjects seven target frequencies were tested ranging from 0.3 to 1.5 Hz. For each target frequency nine different delays were used ranging from 0 to 120% of the cycle duration with target frequency and delay being varied randomly. Tracking error revealed a cyclic behaviour with an increase up to delays of about 50% of the target cycle duration and an improvement for delays larger than 50%. Modulation of response frequency was less pronounced compared with tracking error variation but also was dependent on relative phase. The response frequency matched the target frequency at delays of 0 and 100% of cycle duration and was slightly lower than the target frequency with relative delays of about 50%. The introduction of a visual delay during sinusoidal forearm tracking leads to a spatial in addition to the temporal mismatch between proprioception and vision. The temporal and the spatial incompatibility influence the tracking performance differentially.

What is the optimal dose of botulinum toxin A in the treatment of cervical dystonia? Results of a double blind, placebo controlled, dose ranging study using Dysport. German Dystonia Study Group.

OBJECTIVES: Botulinum toxin injections have become a first line therapeutic approach in cervical dystonia. Nevertheless, published dosing schedules, responder rates, and frequency of adverse events vary widely. The present prospective multicentre placebo controlled double blind dose ranging study was performed in a homogenous group of previously untreated patients with rotational torticollis to obtain objective data on dose-response relations. METHODS: Seventy five patients were randomly assigned to receive treatment with placebo or total doses of 250, 500, and 1000 Dysport units divided between one splenius capitis (0, 175, 350, 700 units) and the contralateral sternocleidomastoid (0, 75, 150, 300 units) muscle. Assessments were obtained at baseline and weeks 2, 4, and 8 after treatment and comprised a modified Tsui scale, a four point pain scale, a checklist of adverse events, global assessment of improvement, and a global rating taking into account efficacy and adverse events. At week 8 the need for retreatment was assessed and then the code was unblinded. For those still responding, there was an open follow up until retreatment to assess the duration of effect. RESULTS: Seventy nine per cent reported subjective improvement at one or more follow up visits. Decreases in the modified Tsui score were significant at week 4 for the 500 and 1000 unit groups versus placebo (p<0.05). Additionally positive dose-response relations were found for the degree of subjective improvement, duration of improvement, improvement on clinical global rating, and need for reinjection at eight weeks. A significant dose relation was also established for the number of adverse events overall and for the incidence of neck muscle weakness and voice changes. CONCLUSION: Magnitude and duration of improvement was greatest after injections of 1000 units Dysport; however, at the cost of significantly more adverse events. Therefore a lower starting dose of 500 units Dysport is recommended in patients with cervical dystonia, with upward titration at subsequent injection sessions if clinically necessary.

Frequency of familial inheritance among 488 index patients with idiopathic focal dystonia and clinical variability in a large family.

Idiopathic torsion dystonia is characterized by involuntary twisting movements and postures. One molecularly defined form with generalized dystonia has been shown to be autosomal dominantly inherited with reduced penetrance in chromosome 9q34.1, especially in Ashkenazi Jewish families, while other generalized families from Europe and families with other subtypes of dystonia have been excluded from linkage to this locus. Genealogical studies suggest that the much more frequent focal dystonia follows an autosomal dominant inheritance with reduced penetrance as well. For our study, 488 patients with focal dystonia, without a tendency for generalization, were interviewed for their family history. Evidence for hereditary disposition was found in 88 individuals. In a second step, all available family members of 17 of the 488 index patients (chosen for cooperation) were clinically examined. Objective diagnosis of affected relative was established in 13 families, whereas only 4 of the 17 index patients had previously admitted a positive family history. Furthermore, a large three-generation family with focal dystonia linked to chromosome 18p (linkage data described elsewhere) was identified. The familial pattern of all reported families is compatible with autosomal dominant inheritance with reduced penetrance. Assessment only on patients' report leads to underestimation of the frequency of familial idiopathic focal dystonia.

Evidence for DYT7 being a common cause of cervical dystonia (torticollis) in Central Europe.

Adult-onset focal idiopathic torsion dystonias (AFITD), such as torticollis, have a prevalence similar to that of multiple sclerosis and usually seem sporadic. Only recently has one large AFITD pedigree "K" with autosomal dominant inheritance and reduced penetrance from Northwest Germany provided the opportunity to identify a gene locus on chromosome 18p. We have now tested the relevance of this DYT7 gene locus in a collective of 18 nuclear AFITD families from Central Europe who were genotyped with chromosome 18p microsatellites. In three families, the affected relatives did not share a chromosome 18p haplotype, suggesting locus heterogeneity in AFITD. In the remaining 15 families, significant allelic association was observed for marker D18S1098. This result suggests that DYT7 is a common cause for AFITD at least in Central Europe, that many patients are descended from a common ancestor, and that the DYT7 gene is mapped in a 4.4 centimorgan subregion of chromosome 18p.

Sporadic focal dystonia in northwest Germany: molecular basis on chromosome 18p.

Idiopathic focal dystonia (IFD) is the most common form of idiopathic torsion dystonia in the Euroamerican population, with a prevalence of about 30 per 100,000. Although most patients claim a negative family history, we recently mapped this syndrome to chromosome 18p as an autosomal dominant trait in Family K from Northwest Germany. We now have investigated sporadic patients with IFD from the same geographic area both clinically and molecularly with chromosome 18p markers. The data indicate that most of these apparently sporadic patients have inherited the same mutation as Family K from a common ancestor and, in fact, owe their disease to autosomal dominant inheritance at low penetrance. The data also indicate that this dystonia mutation (DYT7) is the predominant cause of IFD, at least in this area of Northwest Germany, and that its location can be narrowed from a 30- to a 6-centimorgan region close to marker D18S1098.

The motor syndrome associated with exaggerated inhibition within the primary motor cortex of patients with hemiparetic.

Following transcranial magnetic stimulation (TMS) at stimulation strength of 1.5 times the resting motor threshold, a silent period (SP) of approximately 180 ms duration can be observed in surface EMG-registrations of tonically activated small hand muscles. This SP is believed to be generated cortically and can be prolonged in stroke patients, but it is not known whether a prolongation of the SP has any functional significance. In order to answer the question of whether enhanced cortical inhibition can contribute to pathophysiology of motor dysfunction we studied stroke patients with clearly prolonged SP durations in the first dorsal interosseus muscle (> 2 times that of the intact side), but with normal magnetically evoked motor potentials. Sixteen patients out of a cohort of 174 consecutive patients presenting with acute hemiparetic stroke fulfilled the inclusion criteria. Serial TMS investigations were performed for up to 2 years post-stroke. In all patients, the SP duration decreased in parallel with clinical improvement. In two patients, intermittent clinical deterioration was accompanied by an increase in the SP duration. In four patients, in addition to a markedly prolonged SP duration, the phenomenon of a complete inability to initiate voluntary muscle activity for several seconds, following TMS, could be observed in a number of trials ('motor arrest'). Detailed clinical analysis revealed that, in addition to hemiparesis, distinct motor disturbances in patients with SP prolongation could be observed. These motor disturbances resembled those of motor neglect and were characterized by motivationally dependent under-utilization of the affected arm, impairment of movement initiation, inability to maintain a constant force level and to scale forces, and impairment of individual finger movements. In 12 of the 16 patients at least one additional behavioural manifestation of neglect was present. We suggest that in stroke patients severe motor dysfunction may be caused by hyperactivity of cortical inhibitory interneurons rather than by direct lesions of descending motor tracts. Cortical hyperinhibition may, in turn, result from damage to any of a number of afferent pathways to the motor cortex which modulate local interneuronal activity.

Botulinum toxin: from poison to remedy.

Botulinum toxins, exotoxins of Clostridium botulinum, are the most toxic naturally occurring substances known to man. For more than a century they are known to be the cause of botulism, a nowadays rare intoxication with spoiled food that leads to generalized flaccid weakness of striated muscle including pharyngeal and respiratory musculature. The toxins act primarily at peripheral cholinergic motor nerve endings by blocking the release of the neurotransmitter acetylcholine. As a consequence, action potentials in the motor nerve can no longer be transmitted to the muscle. This lack in transmission, clinically appearing as weakness, may disable or actually critically endanger affected patients. However, in certain neurological diseases characterized by an abnormal increase in muscle tone or activity, for example dystonia or spasticity, a reduction in signal transmission may actually be beneficial. Around 1980 local injections of minute amounts (in the order of 0.5 ng) of Botulinum toxin type A were first successfully used in a neurological disorder named blepharospasm which is characterized by an involuntary squinting of the eyes. Since then Botulinum toxin has developed rapidly from a frightful poison to a safe therapeutic agent with a remarkable beneficial impact on the quality of life of many thousands of patients worldwide. This review tries to outline in brief the characteristics of Botulinum toxins, their mechanism of action and the various indications for clinical use as a therapeutic agent.

The EBD test--a clinical test for the detection of antibodies to botulinum toxin type A.

Approximately 5 to 10% of patients with cervical, segmental or multifocal dystonia receiving repetitive local injections with botulinum toxin A (BTX A) are estimated to develop secondary loss of treatment benefit (nonresponding) because of the formation of circulating serum antibodies against the neurotoxin. Because other reasons may account for loss of benefit during the course of treatment, the group of secondary nonresponders because of antibody formation need to be separated from the antibody-negative group by appropriate testing. We present an easy clinical antibody test based on a test injection of BTX A into an indicator muscle, the extensor digitorum brevis (EDB), combined with amplitude measurements of compound muscle action potentials (CMAPs) elicited by electrical nerve stimulation of the peroneal nerve before and after the injection. The results show that in a group of clinically defined secondary nonresponders, who were serologically proven to be antibody negative, a marked decrease in CMAP amplitude can consistently be detected in the injected EDB 4 weeks after BTX A injection. In contrast, antibody-positive patients are characterized by a lack of such decrease in amplitude. In all cases, results of the EDB test were in keeping with the standard mouse bioassay test. We conclude that the EDB test is a useful tool for clinicians faced with the question of whether a secondary nonresponding patient has in fact developed antibodies to BTX A.

Transcallosally mediated inhibition of interneurons within human primary motor cortex.

The objective of this study was to investigate interhemispheric transcallosal connections between primary motor cortices noninvasively in awake human subjects. For this purpose, focal transcranial magnetic stimulation was performed on eight healthy, right-handed subjects and one patient with congenital collosal agenesis. Using two magnetic stimulators, we investigated the effect of a conditioning magnetic stimulus applied to the motor cortex of one hemisphere on the duration of the silent period (SP) evoked in the first dorsal interosseus (FDI) muscle by a magnetic test stimulus given over the opposite motor cortex. It is well established that SP reflects activation of inhibitory interneurons within primary motor cortex. In all normal subjects, a conditioning stimulus to one hemisphere produced a significant shortening of SP evoked by the test stimulus when the conditioning-test-interval was 10-20 ms. The effect was also observed when an electrical test stimulus was used. The conditioning coil had to be placed over the hand motor area to obtain the maximal effect. The threshold for eliciting this decrease of SP duration was higher than the threshold for eliciting an early excitatory muscle response in the contralateral FDI. Increasing the intensity of the conditioning stimulus led to linear reduction of SP duration. In the patient with callosal agenesis, no such decreasing effect on SP duration was observed. These results suggest that inhibitory interneurons within primary hand motor cortex receive transcallosal inhibitory input from the opposite motor cortex. We propose that modulation of motor cortical interneurons via transcallosal pathways may provide a gain control for the motor cortical output system and subserve interhemispheric coordination in complex, nonsymmetrical bimanual movements.

Idiopathic torsion dystonia: assignment of a gene to chromosome 18p in a German family with adult onset, autosomal dominant inheritance and purely focal distribution.

Idiopathic torsion dystonia (ITD) is a group of movement disorders which is usually inherited in an autosomal dominant manner with reduced penetrance. Most patients with ITD present with focal dystonia at adult age. However, thus far, this common subform remained unmapped chromosomally. In contrast, a rare early onset, more generalized form of ITD has been mapped to chromosome 9q34. Our linkage study in a large pedigree with seven definitely affected, six possibly affected and 16 phenotypically unaffected family members assigns an ITD gene for the common focal form with a maximal lod score of 3.17 to the region telomeric of D18S1153 on chromosome 18p.

Role of the cerebellum in visuomotor coordination. I. Delayed eye and arm initiation in patients with mild cerebellar ataxia.

The initiation of coupled eye and arm movements was studied in six patients with mild cerebellar dysfunction and in six age-matched control subjects. The experimental paradigm consisted of 40 deg step-tracking elbow movements made under different feedback conditions. During tracking with the eyes only, saccadic latencies in patients were within normal limits. When patients were required to make coordinated eye and arm movements, however, eye movement onset was significantly delayed. In addition, removal of visual information about arm versus target position had a pronounced differential effect on movement latencies. When the target was extinguished for 3 s immediately following a step change in target position, both eye and arm onset times were further prolonged compared to movements made to continuously visible targets. When visual information concerning arm position was removed, onset times were reduced. Eye and arm latencies in control subjects were unaffected by changes in visual feedback. The results of this study clearly demonstrate that, in contrast to earlier reports of normal saccadic latencies associated with cerebellar dysfunction, initiation of both eye and arm movements is prolonged during coordinated visuomotor tracking thus supporting a coordinative role for the cerebellum during oculo-manual tracking tasks.