Correction to: Safety and efficacy of Cerebrolysin in acute brain injury and neurorecovery: CAPTAIN I-a randomized, placebo-controlled, double-blind, Asian-Pacific trial.

The above article was published online with incorrect abbreviations in Figures 2 and 3 last sentence of the legend. HDA should be corrected to HADS.

Safety and efficacy of Cerebrolysin in acute brain injury and neurorecovery: CAPTAIN I-a randomized, placebo-controlled, double-blind, Asian-Pacific trial.

OBJECTIVE: To evaluate the safety and efficacy of Cerebrolysin as an add-on therapy to local standard treatment protocol in patients after moderate-to-severe traumatic brain injury. METHODS: The patients received the study medication in addition to standard care (50 mL of Cerebrolysin or physiological saline solution daily for 10 days, followed by two additional treatment cycles with 10 mL daily for 10 days) in a prospective, randomized, double-blind, placebo-controlled, parallel-group, multi-centre phase IIIb/IV trial. The primary endpoint was a multidimensional ensemble of 14 outcome scales pooled to be analyzed by means of the multivariate, correlation-sensitive Wei-Lachin procedure. RESULTS: In 46 enrolled TBI patients (Cerebrolysin 22, placebo 24), three single outcomes showed stand-alone statistically significant superiority of Cerebrolysin [Stroop Word/Dots Interference (p = 0.0415, Mann-Whitney(MW) = 0.6816, 95% CI 0.51-0.86); Color Trails Tests 1 and 2 (p = 0.0223/0.0170, MW = 0.72/0.73, 95% CI 0.53-0.90/0.54-0.91), both effect sizes lying above the benchmark for "large" superiority (MW > 0.71)]. While for the primary multivariate ensemble, statistical significance was just missed in the intention-to-treat population (pWei-Lachin < 0.1, MWcombined = 0.63, 95% CI 0.48-0.77, derived standardized mean difference (SMD) 0.45, 95% CI -0.07 to 1.04, derived OR 2.1, 95% CI 0.89-5.95), the per-protocol analysis showed a statistical significant superiority of Cerebrolysin (pWei-Lachin = 0.0240, MWcombined = 0.69, 95% CI 0.53 to 0.85, derived SMD 0.69, 95% CI 0.09 to 1.47, derived OR 3.2, 95% CI 1.16 to 12.8), with effect sizes of six single outcomes lying above the benchmark for "large" superiority. Safety aspects were comparable to placebo. CONCLUSION: Our trial suggests beneficial effects of Cerebrolysin on outcome after TBI. Results should be confirmed by a larger RCT with a comparable multidimensional approach.

The German trial on Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE): a multicenter, randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Comprehensive treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major clinical challenge. The current therapy gold standard is aciclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains around 20% and a majority of survivors suffer from severe disability. Experimental research and recent retrospective clinical observations suggest a favourable therapy response to adjuvant dexamethasone. Currently there is no randomized clinical trial evidence, however, to support the routine use of adjuvant corticosteroid treatment in HSVE. METHODS: The German trial of Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE) studied the effect of adjuvant dexamethasone versus placebo on top of standard aciclovir treatment in adult patients aged 18 up to 85 years with proven HSVE in German academic centers of Neurology in a randomized and double blind fashion. The trial was open from November 2007 to December 2012. The initially planned sample size was 372 patients with the option to increase to up to 450 patients after the second interim analysis. The primary endpoint was a binary functional outcome after 6 months assessed using the modified Rankin scale (mRS 0-2 vs. 3-6). Secondary endpoints included mortality after 6 and 12 months, functional outcome after 6 months measured with the Glasgow outcome scale (GOS), functional outcome after 12 months measured with mRS and GOS, quality of life as measured with the EuroQol 5D instrument after 6 and 12 months, neuropsychological testing after 6 months, cranial magnetic resonance imaging findings after 6 months, seizures up to day of discharge or at the latest at day 30, and after 6 and 12 months. RESULTS: The trial was stopped prematurely for slow recruitment after 41 patients had been randomized, 21 of them treated with dexamethasone and 20 with placebo. No difference was observed in the primary endpoint. In the full analysis set (n = 19 in each group), 12 patients in each treatment arm achieved a mRS of 0-2. Similarly, we did not observe significant differences in the secondary endpoints (GOS, mRS, quality of life, neuropsychological testing). CONCLUSION: GACHE being prematurely terminated demonstrated challenges encountered performing randomized, placebo-controlled trials in rare life threatening neurological diseases. Based upon our trial results the use of adjuvant steroids in addition to antiviral treatment remains experimental and is at the decision of the individual treating physician. Unfortunately, the small number of study participants does not allow firm conclusions. TRIAL REGISTRATION: EudraCT-Nr. 2005-003201-81.

[Neurological rehabilitation]. / Neurologische Rehabilitation.

This article describes state of the art concepts of neurological rehabilitation in Germany. In parallel to enormous growth of knowledge in the neurosciences also neurological rehabilitation has made significant progress. The increasing use of concepts of evidence based medicine and an early translation of knowledge from the neurosciences into clinical rehabilitation practice contribute to therapeutic advances. It is now widely accepted, that rehabilitation should start early and should be organized in a multidisciplinary professional team. Therapeutic procedures selected should be evidence based and have to be modified to find custom tailored solutions for individual patients. General rules derived from neuroscientific knowledge have been shown to be useful to design new therapeutic techniques. Neuromodulatory stimulation and special pharmacological treatments provide further options for enhancing results of rehabilitation.

TENS and optokinetic stimulation in neglect therapy after cerebrovascular accident: a randomized controlled study.

BACKGROUND: In a randomized controlled type Ib study, the effectiveness of three different forms of therapy for the treatment of visual neglect was assessed by comparing therapy outcomes in three groups of patients after cerebrovascular accidents. METHODS: A control group received only standard exploration training, whilst the second and third group received exploration training combined with either contralateral transcutaneous electrical nerve stimulation (TENS) or optokinetic stimulation (OKS) respectively. RESULTS: It was found that exploration training alone resulted in no improvement on both standard neglect tests (NTs) and everyday-relevant measures of reading and writing performance. In contrast, the groups receiving TENS or OKS showed significant improvements in both sets of measures with the difference that for the TENS group the improvement in NT scores at the end of therapy had disappeared 1-week later. However, both treatments resulted in significant improvements in reading and writing which were still present upon retesting 1-week after the end of therapy. CONCLUSION: Both methods can be recommended for neglect therapy and are superior to exploration therapy alone.

Benign symmetric lipomatosis with axonal neuropathy and abnormalities in specific mitochondrial tRNA regions.

Benign symmetric lipomatosis, also called Madelung's disease, is characterized by lipomata and fatty infiltrations. Involvement of the nervous system has occasionally been described, mitochondrial dysfunctions have been suggested. We report a 55 year old male suffering from benign symmetric lipomatosis with associated axonal neuropathy and hyperlipoproteinemia. He showed a remarkable phenotype of neuropathy i.e. no sensory disturbance, ubiquitous fasciculations and muscle cramps, furthermore reduced COX activity and abnormalities in specific mitochondrial tRNA regions.

Differential effect of Huntington's and Parkinson's diseases in programming motor sequences of varied lengths.

BACKGROUND: Parkinson's disease (PD) and Huntington's disease (HD) patients have difficulties executing sequential movements. Attention control and short-term memory probably play an important role in programming sequential movements. To investigate the contribution of these cognitive factors to programming and executing visuomotor sequences in HD and PD patients a computerized version of the Corsi Block Tapping-Test was employed. METHODS: the performance of 11 patients with early stage PD, 11 HD patients with borderline to mild caudate atrophy and 20 healthy subjects was compared. The task was a reaction time task where targets were illuminated in groups of sequences increasing from 2 items to 5 items. Subjects reproduced the sequence (pressing the illuminated target) in the same order of appearance. Reaction Times and movement times were recorded. RESULTS: PD patients had increasing difficulties in programming and executing series greater than three components. HD patients did not differ significantly from the controls, although they showed a tendency to lose accuracy in the longer series. Both patient groups did not differ in their attention span. CONCLUSIONS: In PD although the spatial information may be well stored, they have difficulty accessing it when their attention is overloaded, leading to poor encoding and slow information processing. This process interferes with programming and execution of movement sequences. HD patients in the early stages of the illness seem to have more attention resources than PD patients, so that they start to show more problems in executing visuomotor sequences with longer movement sequences than PD patients.

Cingulate cortex activation and competing responses: the role of preparedness for competition.

Regional cerebral blood flow (rCBF) was studied in a task, where a preparatory stimulus (S1) cued for an imperative second stimulus (S2) which was associated with a response. Two preparatory stimuli cued unequivocally each for one response. In contrast, a third preparatory stimulus cued for two response alternatives which appeared for the same ratio (each in 50% of all trials) introducing response competition. In a first experimental condition, non-arbitrary, unambiguous stimuli were used as S1 to enable the subjects to prepare their responses. In a second and third scan, arbitrary preparatory stimuli were used during different stages of awareness for the S1-S2 association. Subjects performed this task "naive" without knowledge about the S1-S2 association and also in an experimental condition being aware of the S1-S2 association. Button presses after unambiguous, non-arbitrary preparatory stimuli activated the right middle frontal gyrus and inferior parietal lobe if S1 was associated with a definite response. When the subjects did not know the S1-S2 relation, left prefrontal cortex activation was associated with trials including definite responses. Performing the same S1-S2 response condition after subjects knew their relation right prefrontal and left parietal areas became additionally engaged. However, in the first experimental condition using unambiguous, non-arbitrary stimuli and in the third, "aware" experimental condition when S1 was coupled with two response alternatives, the anterior cingulate cortex was activated. As these experimental conditions have in common, that the preparatory stimulus shares information about the upcoming competing response alternatives they highlight the evaluative role of the anterior cingulate cortex for competing actions.

Recruitment of contralesional motor cortex in stroke patients with recovery of hand function.

In neuroimaging studies of stroke patients, coactivation may account for increased recruitment of bilateral motor areas when moving the affected limb. Here we studied eight patients after stroke with fMRI and simultaneous EMG. Bilateral recruitment of premotor and primary motor cortices was evident in five patients with strictly unilateral performance per EMG. Because patients had excellent motor recovery, this increased recruitment suggests an adaptive response to the infarct.

Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS.

The authors report mutation screening of the p150 subunit of dynactin (DCTN1) and the cytoplasmic dynein heavy chain (DNCHC1) genes in 250 patients with ALS and 150 unrelated control subjects. Heterozygous missense mutations of the DCTN1 gene were detected in one apparently sporadic case of ALS (T1249I), one individual with familial ALS (M571T), two patients with familial ALS, and two unaffected relatives in the same kindred (R785W). The allelic variants of the DCTN1 gene may represent a previously unknown genomic risk factor for ALS.

[Levetiracetam in combined therapy for focal epilepsy: experience with 80 patients]. / Levetiracetam in der Kombinationsbehandlung fokaler Epilepsien. Erfahrungen bei 80 Patienten.

BACKGROUND: Levetiracetam was released in 2000 as an antiepileptic drug for add-on treatment of focal epilepsies. Its efficacy and tolerability were investigated in this retrospective study. METHODS: The effects of add-on treatment with levetiracetam on seizure frequency and side effects were analyzed retrospectively in 80 consecutive patients with focal epilepsy. RESULTS: With a mean follow-up of 12.3 months, 18.8% of patients treated with levetiracetam became seizure-free, and additional 15.0% and 3.8% had reductions in seizure frequency of 75% and 50%, respectively. Increasing the dosage to more than 3,500 mg/day did not improve efficacy but could induce a paradoxical increase in seizure frequency and psychic side effects. Levetiracetam was efficacious against all seizure types independently of focus localization. There was no evidence for the development of tolerance with longer periods of treatment. The most common adverse effects were somnolence and aggressiveness; tolerability did not decrease with rapid titration. CONCLUSIONS: Levetiracetam is a potent and generally well tolerable new antiepileptic drug which is also efficacious in patients with difficult-to-treat focal epilepsies.

Interstitial radiosurgery in the treatment of gelastic epilepsy due to hypothalamic hamartomas.

The authors evaluated a new stereotactic radiosurgical approach in seven patients with gelastic epilepsy due to hypothalamic hamartomas. Stereotactic implantation of 125I-seeds into the hamartoma was feasible in six patients. At follow-up at least 1 year after interstitial radiotherapy, two patients had become seizure-free within 2 months, and two others had only persisting auras. There were no major perioperative or postoperative side effects.

Effect of interstitial stereotactic radiosurgery on behavior and subjective handicap of epilepsy in patients with gelastic epilepsy.

Patients with symptomatic epilepsy due to hypothalamic hamartomas often are compromised not only by pharmacoresistant epileptic seizures but also by behavioral disturbances and cognitive dysfunction. We report the effect of successful treatment with stereotactic interstitial radiosurgery by intrahypothalamic implantation of 125I seeds on behavior and subjective handicap. In all patients rendered seizure-free or suffering only from auras, improvement of behavior was reported by parents and colleagues or schoolteachers. Parents' ratings according to the Child Behavior Checklist showed improvements with respect to social problems and attention. Self-ratings of quality of life by adult patients showed improvements in activities, working situation, and self-perception. These improvements were not observed in patients in whom clinically manifest seizures and interictal EEG discharges persisted after radiosurgery.

Conscious and subconscious sensorimotor synchronization--prefrontal cortex and the influence of awareness.

One of the most compelling challenges for modern neuroscience is the influence of awareness on behavior. We studied prefrontal correlates of conscious and subconscious motor adjustments to changing auditory rhythms using regional cerebral blood flow measurements. At a subconscious level, movement adjustments were performed employing bilateral ventral mediofrontal cortex. Awareness of change without explicit knowledge of the nature of change led to additional ventral prefrontal and premotor but not dorsolateral prefrontal activations. Only fully conscious motor adaptations to a changing rhythmic pattern showed prominent involvement of anterior cingulate and dorsolateral prefrontal cortex. These results demonstrate that while ventral prefrontal areas may be engaged in motor adaptations performed subconsciously, only fully conscious motor control which includes motor planning will involve dorsolateral prefrontal cortex.

[Interactive driving simulation--a new approach to diagnosis and rehabilitation of driving skills]. / Interaktive Fahrsimulation--ein neuer Weg zur Diagnose und Rehabilitation der Fahrtauglichkeit.

Until recently, major methodological problems were faced in the assessment and rehabilitation of driving ability in neurological patients, concerning practical driving lessons and driving tests as well as neuropsychological tests and therapies. The use of highly-advanced driving simulators may solve parts of this problem. However, a basic requirement for effective rehabilitation is the patients' acceptance of this method. In a semi-standardized interview with 56 patients we found that the driving simulator recently installed in the Neurological Rehabilitation Centre "Godeshöhe" was rated mainly positively. Also, patients experienced the simulator to be motivating, effective and informative. Hence, a very important prerequisite for successful use of driving simulators in neurological rehabilitation is given.

[Ad hoc change from carbamazepine to oxcarbazepine--effectiveness and tolerance. A retrospective analysis]. / Ad hoc-Umstellung von Carbamazepin auf Oxcarbazepin--Effektivität und Tolerabilität. Eine retrospektive Analyse.

Oxcarbazepine (OXC) has been licensed for monotherapy and add-on therapy of focal epilepsy in Germany since February 2000. It is chemically related to carbamazepine, and its anticonvulsant effect has been proven in placebo-controlled double blind studies to be comparable to standard antiepileptic drugs such as carbamazepine, valproate, and phenytoin. Patients whose epilepsy is not well controlled with carbamazepine or in whom side effects occur with carbamazepine can be switched to oxcarbazepine overnight, i.e., without a titration phase. In a retrospective analysis on 51 patients with focal epilepsy, the exchange of carbamazepine with oxcarbazepine was investigated. An exchange in a dosage ratio of 1:1-1:1.5 led to a reduction in seizure frequency by more than 50% in 51% of patients. Oxcarbazepine was better tolerated than carbamazepine. During exchange, CNS toxicity occurred more often with high initial dosages and with an exchange ratio of 1:1.5. In patients pretreated with high dosages of carbamazepine, an exchange ratio of 1:1 and rapid subsequent titration to the maximally tolerated dosage may thus be preferable. In 35% (18/51) of patients treated with oxcarbazepine, hyponatremia developed, which was symptomatic in three patients. Sodium levels should be controlled after exchange and if side effects occur. In conclusion, the overnight switch to oxcarbazepine is an attractive option in patients insufficiently controlled by carbamazepine.