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Background/Aim: A recommendation of radiotherapy for patients with malignant gliomas may trigger emotional distress. Frequency and risk factors of this complication were investigated. Patients and Methods: Prevalence of six emotional problems and 11 potential risk factors were evaluated in 103 patients irradiated for grade II-IV gliomas. p-Values

BACKGROUND AND PURPOSE Many drugs can worsen myasthenia symptoms. The clinician usually relies on cautionary lists compiled according to case reports. We intended to provide a quantitative basis for a risk comparison within the groups of antiepileptic, antidepressant, neuroleptic, and sedative drugs. METHODS We extracted adverse drug reaction (ADR) counts (total and myasthenia related) for drugs from these groups and calculated the reporting odds ratio (ROR) within the drug groups from the World Health Organization pharmacovigilance database. For a given drug, the ROR was increased above 1 if the proportion of myasthenia-related ADRs for this drug was larger than the same proportion for the rest of drugs in that same group. If the 95% confidence interval of ROR was >1, this was taken as a signal for a higher risk of the given drug as compared to the average of the respective group. RESULTS Gabapentin, sertraline, citalopram, lithium, and amisulpride had a signal for the ROR to be increased above 1 within their respective groups. Bupropion, desvenlafaxine, duloxetine, escitalopram, and paroxetine had ROR values

Intravenous thrombolysis (IVT) is rarely performed in dizzy patients with acute vestibular syndrome (AVS) or acute imbalance (AIS) even if posterior circulation stroke (PCS) is suspected. Decision-making may be affected by uncertainties in discriminating central from peripheral vestibulopathy or concerns of IVT-related harm, particularly intracerebral hemorrhage (ICH), but related studies are missing. Using an in-house register of dizzy patients coming to the emergency room, we identified 29 AVS/AIS patients who presented within 4.5 h after onset, revealed clinical signs indicative of PCS (central oculomotor signs, mild focal abnormalities), and had non-contrast computed tomography (NCCT). Patients treated with IVT (n = 15) were compared to NoIVT patients (n = 14) with regard to clinical and imaging (including perfusion computed tomography, CTP) parameters, occurrence of ICH and short-term clinical outcome (NIHSS improvement; ability to walk independently). IVT and NoIVT patients did not differ in baseline characteristics, central oculomotor signs, or clinical outcome. IVT patients more often exhibited disabling vestibular symptoms (severe dizziness/vertigo, inability to stand unsupported) and focal abnormalities than NoIVT patients. There was no ICH in either group. CTP was performed in 0% of NoIVT versus 80% of IVT patients, seven of twelve revealing posterior circulation hypoperfusion. Comparison of initial hypoperfusion (CTP) and final stroke (NCCT) revealed IVT-related benefit (smaller lesion) in three of seven IVT patients. In AVS/AIS patients with suspected PCS, disabling vestibular symptoms, focal neurological deficits, and hypoperfusion on CTP seem to direct decision-making pro IVT. In our small cohort, there were no significant IVT-related clinical benefits, no IVT-related ICHs, and salvage of brain tissue in some patients.

The usefulness of brain imaging studies in dizzy patients presenting to the emergency department (ED) is controversial. We aimed to assess the ‘real-world’ probability of ischemic stroke and other acute brain lesions (ABLs) in these patients to create an algorithm that helps decision-making on whether which and when brain imaging is needed. By reviewing medical records, we identified 610 patients presenting with dizziness, vertigo or imbalance to our university hospital’s ED and receiving neurological workup. We collected timing/triggers of symptoms, ABCD2 score, focal neurological abnormalities, HINTS (head impulse, nystagmus, test-of-skew) and other central oculomotor signs. ABLs were extracted from CT/MRI reports. Uni-/multivariate logistic regression analyses investigated associations between clinical parameters and ABLs. Finally, the likelihood of ABLs was assessed for different clinically defined subgroups (‘dizziness syndromes’). Early CT (day 1) was performed in 539 (88%) and delayed MR imaging (median: day 4) in 299 (49%) patients. ABLs (89% ischemic stroke) were revealed in 75 (24%) of 318 patients with adequate imaging (MRI or lesion-positive CT). The risk for ABLs increased with the presence of central oculomotor signs (odds ratio 2.8, 95% confidence interval 1.5–5.2) or focal abnormalities (OR 3.3, 95% CI 1.8–6.2). The likelihood of ABLs differed between dizziness syndromes, e.g., HINTS-negative acute vestibular syndrome: 0%, acute imbalance syndrome with ABCD2-score ≥ 4: 50%. We propose a clinical pathway, according to which patients with HINTS-negative acute vestibular syndrome should not receive brain imaging, whereas imaging is suggested in dizzy patients with acute imbalance, central oculomotor signs or focal abnormalities.

Background/Aim: Little is known regarding seizures during radiotherapy for brain tumors. This prospective study investigated seizure activity in patients irradiated for high-grade gliomas. Patients and Methods: Using a seizure diary, progression of seizure activity was evaluated in 22 patients receiving chemoradiation for grade III (n=1) or IV (n=21) gliomas. Progression was defined as increased frequency of any and/or generalized seizures (>50%) or increased anti-epileptic medication (≥25%). Patients’ satisfaction with the diary was assessed using a questionnaire (six scales of 1-7 points). Uni- and multivariable analyses were performed including baseline seizure activity, age, sex, resection, tumor site, performance score, and history of epilepsy/seizures. Results: Ten patients (45%) experienced progression of seizure activity during their radiotherapy course, mainly due to increased seizure frequency (nine patients=41%). Mean values of patients’ satisfaction scores ranged between 3.92 and 4.92 points. Conclusion: Radiotherapy of high-grade gliomas can increase seizure activity. Patients require close monitoring to initiate or adjust anti-epileptic medication.

Objective: The head impulse test (HIT) assesses the vestibulo-ocular reflex (VOR) and is used to differentiate vestibular neuritis (abnormal VOR) from stroke (normal VOR) in patients presenting with an acute vestibular syndrome (AVS). The video-oculography-based HIT (vHIT) quantifies VOR function and provides information imperceptible for the clinician during clinical bedside HIT. However, the vHIT—like an electrocardiogram—requires experienced interpretation, which is especially difficult in the emergency setting. This calls for a simple, reliable and rater-independent way of analysis.Methods: We retrospectively collected 171 vHITs performed in patients presenting with AVS to our emergency department. Three neuro-otological experts comprehensively assessed the vHITs including interpretability (artifacts), VOR gain (eye/head velocity ratio), velocity profile (abrupt decline) and corrective saccades (overt/covert). Their consensus rating (abnormal/peripheral vs. normal/central) was compared to a simple algorithm that automatically classified the vHITs based on a single VOR gain cutoff (0.7).Results: Inter-rater agreement between experts was high (Fleiss' kappa = 0.74). Five (2.9 %) vHITs were “uninterpretable” according to experts' consensus, 80 (46.8 %) were rated “normal” and 86 (50.3 %) “abnormal”. The algorithm had substantial agreement with the experts' consensus (Cohen's kappa = 0.75). Importantly, it correctly classified all of the normal/central vHITs denoted by the experts (100% specificity) and at the same time it had sufficient sensitivity (75.6%) in detecting abnormal/peripheral vHITs.Conclusion: A simple, automated, gain-based evaluation of the vHIT reliably detects normal/central VOR and may be a feasible and effective tool to screen AVS patients for potentially underlying stroke in the emergency setting.

Due to the elliptic shape of Earth's orbit around the Sun, the apparent diameter of the Sun varies throughout the year. With digital analysis of a number of images at a given date, the effect can be demonstrated with a digital single lens reflection camera (DSLR) and a standard telephoto lens even over a few days. In the analysis, the influence of image brightness and atmospheric refraction on apparent Sun size and shape have to be removed to reach the accuracy that is required.

The restoration of voluntary muscle activity in posttraumatic paraplegia in both animal experiments and other clinical applications requires reproducibility of a technically-demanding microsurgical procedure, limited by physicians’ understanding of Brunelli’s spinal cord grafting paradigm. The insufficient clinical investigation of the long-term benefits of the CNS-PNS graft application warrants additional inquiry. The objective of this study is to explore the potential benefits of the first replicated, graft-induced neuroregeneration of denervated skeletal muscle regarding long-term clinical outcomes and to investigate the effect of Cerebrolysin on neuromodulation. A randomized study evaluating 30 rats, approved by the National Animal Ethics Advisory Committee was performed. The medication was administered postoperatively. For 14 days, 12 rats received Cerebrolysin (serum), 11 received NaCl 0.9% (shams), and 7 were controls. For microsurgery, the lateral corticospinal tract T10 was grafted to the denervated internal obliquus abdominal muscle. On day 90, intraoperative proof of reinnervation was observed. On day 100, 15 rats were euthanized for fixation, organ removal, and extensive histology-morphology examination, and the Wei-Lachin statistical procedure was employed. After an open revision of 16 rats, 8 were CMAP positive. After intravenous Vecuronium application, two (Cerebrolysin, NaCl) out of two rats showed an incomplete compound muscle action potential (CMAP) loss due to glutamatergic and cholinergic co-transmission, while two others showed a complete loss of amplitude. Cerebrolysin medication initiated larger restored muscle fiber diameters and less scarring. FB+ neurons were not observed in the brain but were observed in the Rexed laminae. Brunelli’s concept was successfully replicated, demonstrating the first graft induced existence of cholinergic and glutamatergic neurotransmission in denervated grafted muscles. Statistics of the histometric count of muscle fibers revealed larger fiber diameters after Cerebrolysin. Brunelli’s CNS-PNS experimental concept is suitable to analyze graft-neuroplasticity focused on the voluntary restoration of denervated skeletal muscles in spinal cord injury. Neuroprotection by Cerebrolysin is demonstrated.

Background and purpose Some groups of cardiovascular drugs (beta-blocking drugs, Ca antagonists, antiarrhythmics) are listed as potentially worsening myasthenia. An empirical basis for alternative recommendations for antihypertensive and antiarrhythmic therapy in myasthenia patients has not yet been provided. Methods From the World Health Organization pharmacovigilance database, we retrieved total and myasthenia-related counts of adverse drug reactions for various groups of drugs used in cardiovascular disease and drugs with related mechanism of action used in other indications. We calculated the reporting odds ratio as a measure of a disproportional fraction of myasthenia-related events among all events. A 95% confidence interval of reporting odds ratio (ROR) >1 was taken as an indication for a higher risk. Because our approach involves a considerable number of tests, this situation is referred to as a signal that requires additional confirmation. Results A signal for an increased risk was noted for tizanidine, for alpha-blocking drugs, for beta-blocking drugs, and for Ca antagonists. ROR indicated a lower-than-average risk for salbutamol, angiotensin receptor antagonists, oral anticoagulants, thrombocytic function inhibitors, and heparins. Conclusions Angiotensin receptor antagonists, angiotensin-converting enzyme inhibitors, and diuretics seem to be safe in antihypertensive therapy. Surprisingly, and yet requiring confirmation by case reports, alpha receptor-blocking drugs seem to carry a risk of myasthenia worsening. Amiodarone seems to be a safe alternative in antiarrhythmic therapy in patients with myasthenia.

Background and purpose The bedside head impulse test (bHIT) is used to differentiate vestibular neuritis (VN) from posterior circulation stroke (PCS) in patients presenting with acute vestibular syndrome (AVS). If assessed by neuro-otological experts, diagnostic accuracy is high. We report on its diagnostic accuracy when applied by nonexperts during routine clinical practice in the emergency department (ED), its impact on patient management, and the potential diagnostic yield of the video-oculography-supported head impulse test (vHIT). Methods Medical chart review of 38 AVS patients presenting to our university medical center's ED, assessed by neurology residents. We collected bHIT results (abnormal/peripheral or normal/central) and whether patients were admitted to the stroke unit or general neurological ward. Final diagnosis (VN, n = 24; PCS, n = 14) was determined by clinical course, magnetic resonance imaging, and vHIT. Results The bHIT's accuracy was only 58%. Its sensitivity for VN was high (88%), but due to many false-abnormal bHITs in PCS (36%), the specificity was low (64%). The vHIT yielded excellent specificity (100%) and moderate sensitivity (67%). The decision on the patient's further care was almost arbitrary and independent from the bHIT: 58% of VN and 57% of PCS patients were admitted to the stroke unit. Conclusions The bHIT, applied by nonexperts during routine practice in the ED, has low accuracy, is too often mistaken as abnormal/peripheral, and is not consistently used for patients' in-hospital triage. As false-abnormal bHITs can lead to misdiagnosis/mistreatment of stroke patients, we recommend that bHIT applied by nonexperts should be reassessed by a neuro-otological expert or preferably quantitative vHIT in the ED.

BACKGROUND/AIM In a previous study investigating radiotherapy for newly diagnosed glioblastoma multiforme (GBM), significant or almost significant associations with survival were found for performance status, upfront resection, O6-methylguanine-DNA methyl-transferase (MGMT) promoter methylation and unifocal GBM. This study aimed to create a survival score based on these factors. PATIENTS AND METHODS Most of the 81 patients included received resection of GBM followed by radiochemotherapy (59.4 Gy/33 or 60 Gy/30 fractions). The previously identified predictors of survival were re-evaluated. Factors significantly associated with survival were used for the score. RESULTS All factors were significantly associated with survival. For each factor, 0 points (less favorable survival) or 1 point (more favorable survival) were assigned and added for each patient. Three groups were designed, 0-1 (n=10), 2 (n=21) and 3-4 points (n=50); 12-month survival rates were 0%, 38% and 78% (p

Objective Our aim was to identify the role of the investigators’ knowledge of the patient’s history of vestibular symptoms (PVH) in the clinical evaluation of the bedside head-impulse test (bHIT). We hypothesized that this knowledge will reduce uncertainty and improve bHIT accuracy when compared to quantitative analysis of the vestibulo-ocular reflex by video head-impulse test (vHIT). Methods We looked for changes in the clinical assessment of the bHIT in 594 consecutive patients before and after taking PVH. bHIT was performed by 12 clinical neurologists with various clinical experience in neuro-otological diseases (novices to long-standing experts). vHIT was analyzed by four experts being blinded for the patients’ clinical presentation and history of symptoms. The confidence of bHIT and vHIT was rated (0–100%). Results One hundred fifty-four (15%) of 1,030 bHIT of all eligible patients (n = 515) were rated pathological. Thirty-five (22.7%) of them were rated bilateral vestibulopathies. Sensitivity of bHIT reached 56.3%, its specificity 92.4%; the positive predictive value (PPV) was 41.5% and the negative predictive value 95.7%. These data did not differ between bHIT before and after PVH. bHIT after PVH (post-bHIT) differed from pre-bHIT in 44.3%, usually with regard to the level of confidence but also in polarity (5%). The accuracy of changes in bHIT depended on the direction of change: a “normal” post-bHIT was correct in 92.3% while only 39.8% of pathological post-bHIT were pathological on vHIT. However, sensitivity of a pathological post-bHIT depended on the clinical experience in taking PVH and bHIT: the PPV was 20.5% in novices as compared to 69.6% in experts. Conclusion The study shows that PVH changes the certainty and/or polarity of the clinical evaluation of bHIT. Unlike expected, the increase in confidence in post-bHIT is associated with a consistently high specificity but no increase in sensitivity. Accuracy of changes in post-bHIT depends on the investigators’ clinical experience: it increases only in experts but not novices. Since novices show only a poor PPV and moderate sensitivity of bHIT, pathological bHITs should be controlled by vHIT, even in patients with a positive PVH. By contrast, confirmed normal post-bHIT is usually correct.

Schwindel zahlt zu den haufigsten Symptomen, die Patienten in Deutschland zum Arzt fuhren. Die Diagnosestellung basiert auf einer gezielten Anamnese, klinischen Untersuchung und sinnvollen Zusatzdiagnostik. Zum Nachweis oder Ausschluss einer vestibularen Unterfunktion als Ursache des Schwindels kamen bisher v. a. die kalorische Erregung des Gleichgewichtsorgans, seltener Drehstuhluntersuchungen oder vestibular-evozierte myogene Potenziale zur Anwendung. Seit Kurzem steht eine vielversprechende neue diagnostische Methode zur Verfugung: der videobasierte Kopfimpulstest (vKIT). Dieser hat aufgrund seiner einfachen und schnellen Anwendbarkeit fur den Untersucher, seiner geringen Belastung fur den Patienten und seiner hohen Sensitivitat fur vestibulare Schadigungen das Potenzial, die Diagnostik und damit auch die Therapie von Schwindelerkrankungen in der breiten medizinischen Versorgung in Deutschland zu verbessern. Im Folgenden wird uber erste Erfahrungen mit dieser neuen Methode nach Untersuchung von > 1500 Patienten in der Lubecker Schwindelambulanz berichtet. Prinzip und Anwendung des vKIT in der taglichen Routine werden beschrieben sowie zahlreiche Vorteile, aber auch einige Fallstricke aufgezeigt.

Objective: Retest Brunelli’s graft induced glutamate neurotransmitter switch at the neuromuscular junction in rat for the translation of new aspects of central plasticity concepts for human reconstructive surgery in spinal cord lesions. Methods: Randomized double blind controlled study in rat, which was limited to 30 animals (Charles River, 220 to 280 g). Ethical research approval was obtained from the Animal Research Committee of the University Hospital Schleswig Holstein, UK-SH, Lubeck, D, and legitimated by the Governmental Department of Agriculture, Natural Environments and Agriculture Kiel, D, in compliance with the European Commission Recommendation to retest and review of graft-induced glutamatergic regeneration and /or cholinergic co-transmission at the neuromuscular junction for reinnervation of the skeletal obliquus abdominis internus muscle fibers. Assessments were performed to demonstrate pharmacological neuromodulation after attaching the lateral corticospinal tract at T10 to the bisected skeletal motor nerve. Medication was administered for 14 days postoperatively–a) verum Cerebrolysin® IP=12–b) shams NaCl 0.9% IP=11, and c) 7 controls (nil). 2nd Op at day 90 (16 surviving rats) for open proof of reinnervation and its type by a) CMAP, b)Vecuronium® application. Fast Blue® labeling were performed. 10 days later, on the 3rd Op N=15, euthanasia and organ fixation were performed. Extensive histology-morphology examinations were performed in Cluj. Results: Eight rats showed positive CMAPs. Reinnervation and neuromodulation were demonstrated by counting and comparison of the grafted muscle fibers diameter. Four CAMP- positive- rats received Vecuronium®: 1 CERE and 1 NaCl each demonstrated a loss of amplitude respectively two an incomplete muscle blockage due to the coexistence of glutamatergic and cholinergic neurotransmission. Confirmation of the VGluT2 in axons was observed by immunofluorescence. FB+ neurons were observed in many Rexed laminae in grafted spinal cord, but not in the brain. Conclusion: The coexistence of graft-induced cholinergic and glutamatergic neurotransmission and a great capacity of lower motor neurons and other types of spinal neurons to regenerate were observed. Because of limited animals, pharmacological neuromodulation requires further investigation.

The quantification of stimulation intensity in transcranial magnetic stimulation (TMS) as a function of depth is of interest in order to adjust stimulator output when non-motor regions are stimulated. Currently, a linear increase of stimulator output to correct for depth has been suggested. This is contrary to the physical properties of the electric field that is induced by the stimulation coil as measured in vitro. For two stimulation coils, we determined the characteristics of their field in air. We then measured motor thresholds for the abductor hallucis muscle of 10 healthy subjects. Coil position, distance from the scalp, and orientation were controlled with a head tracking robotic system that corrected for head movements. In both coils an approximately exponential increase, rather than a linear increase, of the threshold with the scalp-coil distance was measured. The slope of the increase was slightly smaller than expected from the field characteristic, but overall in good agreement. With respect to the depth of the TMS target, different results were obtained from the threshold ratios of the coils and from the slopes of the threshold increase with distance. For the adjustment of stimulator output to scalp-to-cortex distances exponential functions with parameters motivated by physical properties of the coils should be used. Estimation of the target depth from the thresholds, with different coils, is not reliable. Our results resolve a conflict between physiological data and physical properties of TMS coils. They provide a more reliable base for depth dependent corrections for TMS stimulator output.

Externally guided sensory-motor processes deteriorate with increasing age. Internally guided, for example, predictive, behavior usually helps to overcome sensory-motor delays. We studied whether predictive components of visuomotor transformation decline with age. We investigated smooth pursuit eye movements (SPEM) of 45 healthy subjects with paradigms of different degrees of predictability with respect to target motion onset, type (smoothed triangular, ramp stimulation), and direction by blanking the target at various intervals of the ramp stimulation. Using repetitive trials of SPEM stimulation, we could dissociate anticipatory and predictive components of extraretinal smooth pursuit behavior. The main results suggest that basic motor parameters decline with increasing age, whereas both anticipation and prediction of target motion did not change with age. We suggest that the elderly maintain their capability of using prediction in the immediate control of motor behavior, which might be a way to compensate for age-related delays in sensory-motor transformation, even in the absence of sensory signals.

This review is intended to assist in making a syndromal diagnosis of vertigo on the basis of details from the case history and clinical findings. Only in a few cases should it be necessary to confirm the diagnosis by means of examinations using particular apparatus systems.

Transcranial magnetic stimulation provides a mean to stimulate the brain non-invasively and painlessly. The effect of the stimulation hereby depends on the stimulation coil used and on its placement. This paper presents a mapping algorithm based on the assumption of a monotonous functional relationship between the applied electric field strength at the representation point of a muscle and the evoked motor potential. We combine data from coil characteristics, coil placement, and stimulation outcome to calculate a likelihood map for the representation of stimulated muscles in the brain. Hereby, correlation ratio (CR) and Kendall's rank coefficient tau are used to find areas in the brain where there is most likely a functional or monotonous relationship between electric field strength applied to this area and the muscle response. First results show a good accordance of our method with mapping from functional magnetic resonance imaging. In our case, classical evaluation of CR with binning is impossible, because sample data sets are too small and data are continuous. We therefore introduce a refined CR formula based on a Parzen windowing of the X-data to solve the problem. In contrast to usual windowing approaches, which require numeric integration, it can be evaluated directly in O(n2) time. Hence, its advantage lies in fast evaluation while maintaining robust applicability to small sample sets. We suggest that the presented formula can generally be used in CR-related problems where sample size is small and data range is continuous.

Altres ajuts: This study was funded by the Eugene Devic European Network (EDEN) project (ERA-Net ERARE 2: http://www.erare.eu/financed-projects/eden). Euroimmun AG provided assay kits for groups from Denmark and Hungary at 50% discount, and at no cost to both Italian groups. The work in Oxford was supported by the National Health Service National Specialised Commissioning Group for Neuromyelitis Optica and the National Institute for Health Research Oxford Biomedical Research Centre. Competing interests: AS is funded by Fundació la Marató de TV3 (101610). FT is enrolled in the doctoral programme SPIN funded by the Austrian Science Fund (FWF; project W1206). ZI is funded by Lundbeckfonden and Scleroseforeningen of Denmark. AB has received a grant from Bayer Healthcare on NMO. LZ would like to thank RH for her excellent technical assistance with the assay. RH was supported by a Schrödinger fellowship funded by the Austrian Science Fund (FWF; project J3230). CC acknowledges funding from Fundació la Marató de TV3 (493/C/2012). FP acknowledges funding from the Bundesministerium für Bildung und Forschung (Competence Network Multiple Sclerosis KKNMS). BW acknowledges funding from the Dietmar-Hopp-Stiftung and from Merck Serono. RM and AR acknowledge Nathalie Dufay from NeuroBioTec-Banques (Hospices Civils de Lyon, France) and funding from Association pour la Recherche sur la Sclerose en Plaques (ARSEP). PW has received speaker honoraria from Biogen Idec and Euroimmun AG; holds a patent with Oxford University for LGI1/CASPR2 antibodies, licensed to Euroimmun AG; and for GABAAR antibodies. MR reports other from University Hospital of Innsbruck (TILAK), during the conduct of the study; personal fees from Euroimmun, outside the submitted work. AS has received compensation for consulting services and speaking from Bayer-Schering, Merck-Serono, Biogen-Idec, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd and Novartis. HHN has received travel funding and speaker honoraria from Novartis Healthcare, Biogen Idec, Genzyme Denmark and Teva Denmark. ZI reports grants from Lundbeckfonden, Denmark; Scleroseforeningen, Denmark, during the conduct of the study; personal fees from compensation for consulting services and speaking from Bayer-Schering, Biogen-Idec, Merck-Serono, Novartis, Sanofi-Aventis, and Teva Pharmaceutical Industries Ltd, outside the submitted work. TB reports non-financial support from Euroimmun AG, during the conduct of the study. KR is shareholder and an employee of Euroimmun AG. AB reports grants from Bayer Heathcare, personal fees from Biogen Idec, personal fees from Merck Serono, personal fees from Teva, personal fees from Novartis, personal fees from Genzyme, other from Biogen Idec, other from Novartis, other from Genzyme, other from Roche, other from Alexion Pharmaceuticals, outside the submitted work. LG received congress and travel compensations from Euroimmun. AB received honoraria for serving in the scientific advisory boards of Almirall, Bayer, Biogen Idec, Genzyme, and received speaker honoraria from Biogen Idec, Genzyme, Novartis, TEVA with approval by the Director of AOU San Luigi University Hospital; his institution has received grant support from Bayer, BiogenIdec, Merck, Novartis, TEVA from the Italian Multiple Sclerosis Society, Associazione Ricerca Biomedica ONLUS and San Luigi ONLUS. LZ reports personal fees from Teva Pharmaceutical, personal fees from Novartis, outside the submitted work. MC has received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Genzyme, and Novartis. XM has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Phramaceuticals, Almirall and Roche. MT has received compensation for consulting services and speaking from Bayer-Schering, Merk-Serono, Biogen-Idec, Teva, Sanofi-Aventis, and Novartis. AS reports receiving grants from the Scientific and Technological Research Council of Turkey-Health Sciences Research (grants numbers 109S070 and 112S052); and also unrestricted grants from Bayer-Schering AG and Merck-Serono to their Neurology Department Clinical Neuroimmunology Unit. AS also reports receiving honoraria or consultation fees Biogen Idec, Novartis and Teva. He had received travel and registration coverage for attending several national or international congresses or symposia, from Merck Serono, Biogen Idec, Novartis, Teva, Bayer-Schering and Allergan. AA received grants to her department from The Scientific and Technological Research Institute of Turkey-Health Sciences (grants numbers 109S070 and 112S052), and she also received honoraria, research and travel grants from Teva, Merck-Serono, Gen Ilac, Bayer-Schering, Novartis. FP has received travel funding, speaker honoraria and personal compensation for activities on advisory boards and steering committees from Bayer, Biogen Idec, Alexion, Chugai, MedImmune, MerckSerono, Novartis, Teva, and Sanofi Genzyme. He has received grants from the Guthy Jackson Charitable Foundation and the National Multiple Sclerosis Society of the USA. OA reports grants from German Ministry for Education and Research (BMBF), during the conduct of the study; German Research Foundation (DFG); Hertie Foundation; Biogen; Novartis; Bayer; outside the submitted work; and Honoraria for consultancy and speaking by Biogen, Novartis, Bayer Schering, Teva, Chugai, Genzyme, MedImmune, and Merck Serono. BW reports personal fees from Bayer Healthcare, grants and personal fees from Biogen, Merck Serono; Genzyme, a Sanofi Company; Novartis Pharmaceuticals; TEVA Pharma; grants from Biotest, German Ministry of Education and Research; Dietmar Hopp Foundation; outside the submitted work. H-PH reports personal fees from MedImmune, outside the submitted work. MP is an employee of and holds stock in Euroimmun AG. PT reports non-financial support from Roche Pharmaceuticals, outside the submitted work. SS is an employee of Euroimmun AG. AV is on the Advisory Board for Neurology; was an associate editor for Brain; holds patents with Oxford University for MuSK, LGI1/CASPR2, and GABAAR antibodies, and receives a proportion of royalties. RM reports personal fees from MedImmune, personal fees and non-financial support from Biogen, non-financial support from Merck-Serono, non-financial support from Teva, non-financial support from Novartis, non-financial support from Sanofi, outside the submitted work. Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD). Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1). Results of tests on 92 controls identified 12assays as highly specific (0-1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5-100%) of all 21 assays. The specificities (85.8-100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples. The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.

Despite many reports on visual processing deficits in psychotic disorders, studies are needed on the integration of visual and non-visual components of eye movement control to improve the understanding of sensorimotor information processing in these disorders. Non-visual inputs to eye movement control include prediction of future target velocity from extrapolation of past visual target movement and anticipation of future target movements. It is unclear whether non-visual input is impaired in patients with schizophrenia. We recorded smooth pursuit eye movements in 21 patients with schizophrenia spectrum disorder, 22 patients with bipolar disorder, and 24 controls. In a foveo-fugal ramp task, the target was either continuously visible or was blanked during movement. We determined peak gain (measuring overall performance), initial eye acceleration (measuring visually driven pursuit), deceleration after target extinction (measuring prediction), eye velocity drifts before onset of target visibility (measuring anticipation), and residual gain during blanking intervals (measuring anticipation and prediction). In both patient groups, initial eye acceleration was decreased and the ability to adjust eye acceleration to increasing target acceleration was impaired. In contrast, neither deceleration nor eye drift velocity was reduced in patients, implying unimpaired non-visual contributions to pursuit drive. Disturbances of eye movement control in psychotic disorders appear to be a consequence of deficits in sensorimotor transformation rather than a pure failure in adding cognitive contributions to pursuit drive in higher-order cortical circuits. More generally, this deficit might reflect a fundamental imbalance between processing external input and acting according to internal preferences.

In obsessive-compulsive disorder (OCD), a dysfunction of neuronal circuits involving prefrontal areas and the basal ganglia is discussed that implies specific oculomotor deficits. Performance during reflexive and predictive saccades, antisaccades and predictive smooth pursuit was compared between patients with OCD (n=22), patients with schizophrenia (n=21) and healthy subjects (n=24). Eye movements were recorded by infrared reflection oculography. In both patient groups, higher frequencies of anticipatory saccades with reduced amplitudes in the predictive saccade task were observed. Additionally, reduced smooth pursuit eye velocity and increased frequencies of saccadic intrusions during smooth pursuit as well as increased error rates in the antisaccade task were demonstrated for patients suffering from schizophrenia. Patients with OCD and schizophrenia revealed different patterns of oculomotor impairment: whereas increased anticipation of predictive saccades provides evidence for a dysfunction of the circuit between the frontal eye field and the basal ganglia in both groups, results from the antisaccade task imply additional deficits involving the dorsolateral prefrontal cortex in schizophrenic patients. Furthermore, the cortical network for smooth pursuit (especially the frontal eye field) is also assumed to be disturbed in schizophrenia.

Patients with essential tremor (ET) or with cerebellar lesions have in common oculomotor abnormalities, with the exception of saccadic eye movements, which do not seem to be involved in ET. Since grasping is prolonged in ET and might be related to saccadic dysmetria, we tested whether simultaneous hand pointing could unmask it. Twelve ET patients and 14 controls performed saccades with and without simultaneous pointing movements to the same targets, and with and without a gap between the disappearance of the fixation point and the appearance of the target. Eye movements were recorded with the magnetic search-coil method, hand movements with an ultrasound-emitting probe. ET patients did not have saccadic dysmetria, and contrary to normal subjects their saccadic latency did not decrease during combined eye-hand movements compared with saccades performed in isolation. Hand movements had a longer duration in ET patients, with decreased peak acceleration, an increased latency of the peak velocity, and peak deceleration. In conclusion, this first study on eye-hand coordination in ET revealed abnormal kinematic changes in the early phase of pointing movements. These changes might be related to cerebellar disease but they are independent of the intention tremor component and saccade performance.

Hypersalivation ist eine haufige unerwunschte Nebenwirkung einer Behandlung mit Clozapin. Bisherige therapeutische Strategien zur Reduktion von Sialorrho zielten auf die Gabe antimuskarinerger (anticholinerger) und α2-agonistischer Substanzen. Die Verwendung dieser Substanzen ist aber limitiert durch deren teilweise mangelnde Wirksamkeit und durch ein ungunstiges Nebenwirkungsprofil. Eine neue und sichere Therapieoption der Clozapin-induzierten Hypersalivation ergibt sich durch die Injektion von Botulinum-Toxin. Im Folgenden beschreiben wir einen Patienten, bei dem Botulinum-Toxin B zur Reduktion von Hypersalivation eingesetzt wurde und geben eine Ubersicht uber bisherige Therapiestrategien zur Reduktion von Clozapin-induzierter Hypersalivation.

Background Neurological and psychiatric disorders show clinical overlap suggesting a shared pathophysiological background. We evaluated myoclonus-dystonia, a monogenic movement disorder as a disease model for inherited psychopathology. Method We investigated 12 SGCE mutation carriers using standardized neurological and psychiatric examinations to assign DSM-IV diagnoses. Furthermore, we analyzed all studies in the Medline database which included psychiatric information on SGCE mutation-positive patients. Results Of our twelve SGCE mutation carriers, 10 were older than 16 years. Two of them (20%) reported psychiatric diagnoses before our examination, which resulted in at least one psychiatric diagnosis in seven (70%) patients, most frequently anxiety (60%), depression (30%) or both. Substance abuse was observed in 20%, whereas obsessive-compulsive disorders were absent. One mutation carrier showed Axis 2 features. In the literature analysis, the ten studies using standardized tools covering DSM-IV criteria reported prevalences similar to those in our sample. This was three times the frequency of psychiatric disorders detected in 13 studies using clinical history or patient report only. Conclusion About two thirds of SGCE mutation carriers develop psychiatric comorbidity and >80% are previously undiagnosed.

Alterations in sensorimotor processing and predictive mechanisms have both been proposed as the primary cause of eye tracking deficits in schizophrenia. 20 schizophrenia patients and 20 healthy controls were assessed on blocks of predictably moving visual targets at constant speeds of 10, 15 or 30°/s. To assess internal drive to the eye movement system based on predictions about the ongoing target movement, targets were blanked off for either 666 or 1,000 ms during the ongoing pursuit movement in additional conditions. Main parameters of interest were eye deceleration after extinction of the visual target and residual eye velocity during blanking intervals. Eye deceleration after target extinction, reflecting persistence of predictive signals, was slower in patients than in controls, implying greater rather than diminished utilization of predictive mechanisms for pursuit in schizophrenia. Further, residual gain was not impaired in patients indicating a basic integrity of internal predictive models. Pursuit velocity gain in patients was reduced in all conditions with visible targets replicating previous findings about a sensorimotor transformation deficit in schizophrenia. A pattern of slower eye deceleration and unimpaired residual gain during blanking intervals implies greater adherence to top-down predictive models for pursuit tracking in schizophrenia. This suggests that predictive modeling is relatively intact in schizophrenia and that the primary cause of abnormal visual pursuit is impaired sensorimotor transformation of the retinal error signal needed for the maintenance of accurate visually driven pursuit. This implies that disruption in extrastriate and sensorimotor systems rather than frontostriatal predictive mechanisms may underlie this widely reported endophenotypes for schizophrenia.

Patients with Parkinson's disease (PD) have difficulties in the control of self-guided (i.e., internally driven) movements. The basal ganglia provide a nonspecific internal cue for the development of a preparatory activity for a given movement in the sequence of repetitive movements. Controversy surrounds the question of whether PD patients are capable of (1) anticipating (before an external trigger appears; i.e., anticipation) and (2) predicting movement velocity once a moving target shortly disappears from the visual scene (i.e., prediction). To dissociate between these two components, we examined internally driven (extraretinal generated) smooth pursuit eye movements in PD patients and age-matched healthy controls by systematically varying target blanking periods of a trapezoidally moving target in four paradigms (initial blanking, midramp blanking, blanking after a short ramp, and no blanking). Compared to controls, PD patients showed (1) decreased smooth pursuit gain (without blanking), (2) deficient anticipatory pursuit (prolonged pursuit initiation latency; reduced eye velocity before target onset in the early onset blanking paradigm), and (3) preserved extraretinal predictive pursuit velocity (midramp target blanking). Deficient anticipation of future target motion was not related to either disease duration or the general motor impairment (UPDRS). We conclude that PD patients have difficulties in anticipating future target motion, which may play a role for the mechanisms involved in deficient gait initiation and termination of PD. In contrast, they remain unimpaired in their capacity of building up an internal representation of continuous target motion. This may explain the clinical advantage of medical devices that use visual motion to improve gait initiation (e.g., "PD glasses").

Externally guided sensory-motor processes deteriorate with increasing age. Internally guided, for example, predictive, behavior usually helps to overcome sensory-motor delays. We studied whether predictive components of visuomotor transformation decline with age. We investigated smooth pursuit eye movements (SPEM) of 45 healthy subjects with paradigms of different degrees of predictability with respect to target motion onset, type (smoothed triangular, ramp stimulation), and direction by blanking the target at various intervals of the ramp stimulation. Using repetitive trials of SPEM stimulation, we could dissociate anticipatory and predictive components of extraretinal smooth pursuit behavior. The main results suggest that basic motor parameters decline with increasing age, whereas both anticipation and prediction of target motion did not change with age. We suggest that the elderly maintain their capability of using prediction in the immediate control of motor behavior, which might be a way to compensate for age-related delays in sensory-motor transformation, even in the absence of sensory signals.

Publisher Summary This chapter discusses that the testing of ocular motor functions is an important step in the diagnosis of vestibular and balance disorders for three reasons: First, most of these disorders are associated with the disorders of eye movements. Second, the classification of the eye movement disorder will often lead to localization of the neural structures involved. Third, eye movement disorders can cause impaired vision or dizziness, and thus might impair balance. The chapter outlines the technology and equipment needed for clinical electronystagmography (ENG), its basic recording and calibration procedures, possible artifacts, and its advantages and disadvantages versus clinical bedside tests. It also describes the testing procedures and interpretation for three categories of ocular motor functions: (1) stability of gaze; (2) smooth pursuit eye movements and optokinetic nystagmus; and (3) saccadic eye movements. For vertical eye movements, positive angles correspond to gaze up and negative angles to gaze down. It is assumed that the eye position is digitally available for numerical differentiation to obtain eye velocities.

Smooth pursuit eye movements enable us to focus our eyes on moving objects by utilizing well-established mechanisms of visual motion processing, sensorimotor transformation and cognition. Novel smooth pursuit tasks and quantitative measurement techniques can help unravel the different smooth pursuit components and complex neural systems involved in its control. The maintenance of smooth pursuit is driven by a combination of the prediction of target velocity and visual feedback about performance quality, thus a combination of retinal and extraretinal information that has to be integrated in various networks. Different models of smooth pursuit with specific in- and output parameters have been developed for a better understanding of the underlying neurophysiological mechanisms and to make quantitative predictions that can be tested in experiments. Functional brain imaging and neurophysiological studies have defined motion sensitive visual area V5, frontal (FEF) and supplementary (SEF) eye fields as core cortical smooth pursuit regions. In addition, a dense neural network is involved in the adjustment of an optimal smooth pursuit response by integrating also extraretinal information. These networks facilitate interaction of the smooth pursuit system with multiple other visual and non-visual sensorimotor systems on the cortical and subcortical level. Future studies with fMRI advanced techniques (e.g., event-related fMRI) promise to provide an insight into how smooth pursuit eye movements are linked to specific brain activation. Applying this approach to neurological and also mental illness can reveal distinct disturbances within neural networks being present in these disorders and also the impact of medication on this circuitry.