Objective: Additionally to the forearm rolling test to detect mild unilateral upper limb dysfunct... more Objective: Additionally to the forearm rolling test to detect mild unilateral upper limb dysfunction, the bed cycling test (BCT) for detection of mild to moderate lower limb dysfunction was developed, evaluated and compared to the leg holding test. Methods: In a prospective observer-blinded study, 60 patients with MRI/CT-proven focal cerebral hemisphere lesions and a mild to moderate unilateral paresis of the lower limb (graduated MRC 3-4/5), and 60 control persons with normal imaging were examined and filmed. Nine observers blinded to the diagnosis evaluated these videos. The sensitivity, specificity and the positive and negative predictive values of the clinical tests were analyzed. Results: The observers gave a correct evaluation of BCT in 35.5% of all patients with focal cerebral lesions compared to 26.0% for the leg holding test. On the other hand, observers had false negative results in 29.1% of cases with BCT and 44.7% with leg holding test. In 36.7% of patients, only BCT was pathological while leg holding test was unremarkable. The sensitivity of the combination of both tests was 0.68 (95% CI 0.61-0.75). The BCT is more sensitive (64.3%) than leg holding test (46.2%) while the specificity of leg holding test (85.6%) is higher than of BCT (70.1%) to detect a cerebral lesion affecting the lower limb. The inter-rater variability is high with no differences comparing different types of clinical experience. Conclusions: The BCT is a useful additional clinical bedside test to detect subtle unilateral cerebral lesions. The BCT is easy to perform and can be added to the routine neurological examination.
Objective: Analogously to the forearm rolling test to detect unilateral upper limb dysfunction a ... more Objective: Analogously to the forearm rolling test to detect unilateral upper limb dysfunction a so-called bed cycling test (BCT) was developed and evaluated to detect mild to moderate unilateral lower limb dysfunction and compared to the leg holding test (LHT). Background: In recent years the sensitivity and specificity of different clinical tests was systematically investigated. In clinical practice, it is important to make a fast clinical decision whether the patients suffers from paresis. Methods: In a prospective examiner-blinded study 60 patients with MRI or CT proven acute focal cerebral hemisphere lesions and a mild to moderate unilateral paresis of the lower limb (graduated 3 or 4 of 5 on MRC scale) and 60 control persons with normal imaging and without obvious focal signs were examined using a battery of clinical tests including the filmed BCT and LHT. Nine examiners, who were blinded to the diagnosis, evaluated these tests presented to them on videos. The sensitivity, specificity as well as positive and negative predictive values of each test were analyzed. Results: The BCT was rated right positive in 35.5 [percnt] compared to LHT in 26.0 [percnt]. On the other hand, examiners had false negative results in 29.1 [percnt] of cases using BCT and 44.7 [percnt] using LHT. In 36.7 [percnt] of patients only BCT was pathological while leg holding test was unremarkable, In conclusion the BCT is more sensitive (64.3 [percnt]) than LHT (46.2 [percnt]) while the specificity of leg holding test (85.6 [percnt]) is higher than of BCT (70.1 [percnt]) to detect a cerebral lesion affecting the lower limb. Conclusions: The BCT test is a useful additional clinical bedside test to detectsubtle unilateral cerebral lesions, especially when regular neurological examination is unremarkable. The BCT is easy to perform and can be added to the neurological routine examination. Disclosure: Dr. Feil has nothing to disclose. Dr. Boettcher has nothing to disclose. Dr. Lezius has nothing to disclose. Dr. Hoegen has nothing to disclose. Dr. Huettemann has nothing to disclose. Dr. Muth has nothing to disclose. Dr. Eren has nothing to disclose. Dr. Schoeberl has nothing to disclose. Dr. Zwergal has nothing to disclose. Dr. Bayer has nothing to disclose. Dr. Strupp has received personal compensation in an editorial capacity for the Journal of Neurology as Joint Chief Editor, Frontiers of Neuro-otology as Editor in Chief, and of F1000 as Section Editor.
ZusammenfassungSchwindel und Gleichgewichtsstörungen bei Kindern sind nicht selten. Bei der Häufi... more ZusammenfassungSchwindel und Gleichgewichtsstörungen bei Kindern sind nicht selten. Bei der Häufigkeitsverteilung der einzelnen Schwindelsyndrome ergeben sich erhebliche altersabhängige Unterschiede. Bei Kindern sind migräneassoziierte Schwindelformen (benigner paroxysmaler Schwindel des Kindesalters, vestibuläre Migräne) sehr häufig und machen etwa 50% der Diagnosen aus. Häufiger als im Erwachsenenalter sind akute einseitige Funktionsstörungen im Rahmen von infektiösen oder parainfektiösen Labyrinthiden, die Bewegungskrankheit und Perilymphfisteln. Die Innenohrbeteiligung mit bilateralen vestibulären Funktionsstörungen kommt bei einer Reihe seltener kongenitaler Syndrome vor. Subakut einsetzende zentral-vestibuläre Zeichen sollten wegen der relativen Häufigkeit von Hirnstamm-und Kleinhirntumoren im Kindesalter eine MRT-Untersuchung nach sich ziehen, die insgesamt bei kindlichem Schwindel eher zu häufig erfolgt.
In 2009 the German BMBF (German Ministry of Education and Research) established an Integrated Cen... more In 2009 the German BMBF (German Ministry of Education and Research) established an Integrated Center for Research and Treatment (IFB(LMU)) of Vertigo, Balance and Ocular Motor Disorders in Munich. After the 10-year period of funding by the BMBF, it is envisioned that the (IFB(LMU)) will continue over the long term with the joint support of the University Hospital, the Medical Faculty, and the Bavarian State. Vertigo is one of the most common complaints in medicine. Despite its high prevalence, patients with vertigo generally receive either inappropriate or inadequate treatment. This deplorable situation is internationally well known and its causes are multiple: insufficient interdisciplinary cooperation, no standardized diagnostics and therapy, the failure to translate findings of basic science into clinical applications, and the scarcity of clinical multicenter studies. The (IFB(LMU)) will constitute a suitable tool with which these structural, clinical, and scientific deficits can be overcome. It will also make possible the establishment of an international interdisciplinary referral center. Munich has become the site of a unique concentration of leading experts on vertigo, balance and ocular motor disorders, both in the clinical and basic sciences. Academic structures have paved the way for the creation of an interdisciplinary horizontal network that also allows structured, vertical academic career paths via the Bachelor's and Master's degree programs in Neuroscience, a Graduate School of Systemic Neurosciences, and the Munich Center for Neurosciences - Brain and Mind. The (IFB(LMU)) has the following objectives as regards structure and content: to create an independent patient-oriented clinical research center under the auspices of the Medical Faculty but with autonomous administration and budget; to overcome existing clinical and academic barriers separating the traditional specializations; to establish a standardized interdisciplinary longitudinal and transversal network at one site for the management of patients. This should professionalize both the management and the international recruitment of patients (integrated care, telemedicine); to organize the study infrastructure for prospective multicenter clinical studies as well as to free clinical scientists from administrative tasks; to promote translational research with a focus on the innovative topics of molecular, functional and structural imaging, experimental and clinical pharmacotherapy, clinical research of vertigo and balance disorders, mathematical modelling, interaction between biological and technical systems (robotics), and research on functionality and the quality of life; to offer new attractive educational paths and career images for medical doctors, students of the natural sciences, and engineers in clinical research in order to overcome traditional hierarchical structures. This should promote the principles of efficiency and self-reliance; to supplement the existing excellence with up to eight groups of young scientists and up to eight professorships (tenure track). This should also be seen as an incentive that will attract the best young scientists; to incorporate (IFB(LMU)) competence into the existing medical and biological graduate schools. The (IFB(LMU)) is a unique center - worldwide.
Cerebellar dizziness and vertigo account for approximately 10% of diagnoses in a tertiary dizzine... more Cerebellar dizziness and vertigo account for approximately 10% of diagnoses in a tertiary dizziness center. This term summarizes a large group of disorders with chronic (degenerative, hereditary, acquired cerebellar ataxias), recurrent (episodic ataxias), or acute (stroke, inflammation) presentations. Key to the diagnosis is a comprehensive examination of central ocular motor and vestibular function. Patients with cerebellar dizziness and vertigo usually show a pattern of deficits in smooth pursuit, gaze-holding, saccade accuracy, or fixation-suppression of the vestibulo-ocular reflex. Central fixation nystagmus (e.g., downbeat nystagmus), gaze-evoked nystagmus, central positional nystagmus, or head-shaking nystagmus with cross-coupling (i.e., horizontal head shaking causing inappropriate vertical nystagmus) occurs frequently. Overlap syndromes with peripheral vestibular disorders, such as cerebellar ataxia, neuropathy, and vestibular areflexia, exist rarely. Posturography and gait analysis can contribute to diagnostic differentiation, estimation of the risk of falls, as well as quantification of progression and treatment effects. Patients with cerebellar dizziness and vertigo should receive multimodal treatment, including balance training, occupational therapy, and medication.
Introduction: Vertigo and dizziness are common chief complaints of vestibular and ocular motor di... more Introduction: Vertigo and dizziness are common chief complaints of vestibular and ocular motor disorders (lifetime prevalence 30%). Treatment relies on physical, pharmacological, psychological and rarely surgical approaches. Eight groups of drugs are currently used in vestibular and ocular motor disorders, namely anti-vertiginous, anti-inflammatory, anti-menière's, anti-migrainous medications, antidepressants, anti-convulsants, aminopyridines and agents that enhance vestibular plasticity. Areas covered: The purpose of this review is to summarize the pharmacological characteristics and clinical applications of medications that are used for peripheral, central and functional vestibular and ocular motor disorders. The level of evidence for the respective drugs is described alongside the pathophysiological premises supporting their use. The authors place particular focus on translation and back-translation in vestibular pharmacological research and the repurposing of known drugs for new indications and rare disorders. Expert opinion: The use of drugs in vestibular and ocular motor disorders is often based on open-label, non-controlled studies and expert opinion. In the future, strong evidence derived from RCTs is needed to support the effectiveness and tolerability of these therapies in well-defined vestibular and ocular motor disorders. Vestibular pharmacological research must be guided by a better understanding of the molecular targets relevant in the pathophysiology of vestibular and ocular motor disorders.
Annals of the New York Academy of Sciences, Apr 1, 2015
There are currently eight groups of drugs for the pharmacotherapy of vertigo, nystagmus, and cere... more There are currently eight groups of drugs for the pharmacotherapy of vertigo, nystagmus, and cerebellar disorders: antiemetics; anti-inflammatories, antimenieres, and antimigraineous medications; antidepressants, anticonvulsants, aminopyridines, and acetyl-DL-leucine ("the eight A's"). In acute unilateral vestibulopathy, corticosteroids improve the recovery of peripheral vestibular function, but there is not sufficient current evidence for a general recommendation. There is also insufficient evidence that 48 or 144 mg/day betahistine has an effect in Ménière's disease. Therefore, higher dosages are currently recommended; in animal studies, it was shown that betahistine increases cochlear blood flow. In vestibular paroxysmia, oxcarbazepine was effective (one yet not randomized controlled trial (RCT)). Aminopyridines are recommended for the treatment of downbeat nystagmus (two RCTs) and episodic ataxia type 2 (EA2, one RCT). There are so far no RCTs on vestibular migraine, so currently no treatment can be recommended. Acetyl-dl-leucine improves cerebellar ataxia (three observational studies); it also accelerates central compensation in an animal model of acute unilateral lesion, but RCTs were negative. There are ongoing RCTs on vestibular paroxysmia with carbamazepine (VESPA), acute unilateral vestibulopathy with betahistine (BETAVEST), vestibular migraine with metoprolol (PROVEMIG), benign paroxysmal positional vertigo with vitamin D (VitD@BPPV), EA2 with 4-aminopyridine versus acetazolamide (EAT-2-TREAT), and cerebellar ataxias with acetyl-DL-leucine (ALCAT).
Annals of the New York Academy of Sciences, May 1, 2009
Information from the vestibular nuclei ascending through the brainstem to the oculomotor and troc... more Information from the vestibular nuclei ascending through the brainstem to the oculomotor and trochlear nuclei (NIII, NIV), the interstitial nucleus of Cajal (INC), the pretectum, or thalamus, is thought to be distributed in at least five different pathways. They include the medial longitudinal fasciculus (MLF), the ascending tract of Deiters (ATD), possibly the brachium conjuctivum (BC), the crossing ventral tegmental tracts (CVTT), and a recently observed ipsilateral pathway close to the medial lemniscus, possibly the equivalent of the ipsilateral vestibulo-thalamic tract (IVTT). This short review describes the location of these ascending tracts, their function with respect to ocular motor control and perception, and their clinical relevance. There is evidence that the MLF carries mainly information from the canals to NIII, NIV, INC, and possibly the thalamus, whereas otolith signals may ascend in the CVTT, along with excitatory anterior canal connections. The evidence for BC as a specific vestibulo-oculomotor pathway is weak and could be the result of the initial observations of CVTT. The ATD carries mostly ipsilateral otolithic information to the medial and inferior recti subgroups in NIII and the Edinger-Westphal nucleus. In the rostral pons an ipsilateral vestibular pathway was seen lying close to the medial lemniscus. This anatomical projection could be the equivalent of the IVTT, bypassing the ocular motor centers and projecting to the thalamus. The IVTT mediates perception of verticality and may be part of a fast three-neuron vestibulo-thalamo-cortical pathway, which provides the multisensory cortical system for spatial orientation and self-motion-perception with information about head acceleration.
Background and ObjectivesBilateral vestibulopathy (BVP) is a chronic debilitating neurologic diso... more Background and ObjectivesBilateral vestibulopathy (BVP) is a chronic debilitating neurologic disorder with no monogenic cause established so far despite familiar presentations. We hypothesized that replication factor complex subunit 1 (RFC1) repeat expansions might present a recurrent monogenic cause of BVP.MethodsThe study involved RFC1 screening and in-depth neurologic, vestibulo-oculomotor, and disease evolution phenotyping of 168 consecutive patients with idiopathic at least “probable BVP” from a tertiary referral center for balance disorders, with127 of them meeting current diagnostic criteria of BVP (Bárány Society Classification).ResultsBiallelic AAGGG repeat expansions in RFC1 were identified in 10/127 patients (8%) with BVP and 1/41 with probable BVP. Heterozygous expansions in 10/127 patients were enriched compared with those in reference populations. RFC1-related BVP manifested at a median age of 60 years (range 34–72 years) and co-occurred predominantly with mild polyneuropathy (10/11). Additional cerebellar involvement (7/11) was subtle and limited to oculomotor signs in early stages, below recognition of classic cerebellar ataxia, neuropathy, and vestibular areflexia syndrome. Clear dysarthria, appendicular ataxia, or cerebellar atrophy developed 6–8 years after onset. Dysarthria, absent patellar reflexes, and downbeat nystagmus best discriminated RFC1-positive BVP from RFC1-negative BVP, but neither sensory symptoms nor fine motor problems. Video head impulse gains of patients with RFC1-positive BVP were lower relative to those of patients with RFC1-negative BVP and decreased until 10 years disease duration, indicating a potential progression and outcome marker for RFC1-disease.DiscussionThis study identifies RFC1 as the first—and frequent—monogenic cause of BVP. It characterizes RFC1-related BVP as part of the multisystemic evolution ofRFC1spectrum disease, with implications for designing natural history studies and future treatment trials.Classification of EvidenceThis study provides Class II evidence that RFC1 repeat expansions cause BVP.
Schwindel gehört zu den häufigsten Leitsymptomen in der Notaufnahme. Die zugrunde liegenden Ursac... more Schwindel gehört zu den häufigsten Leitsymptomen in der Notaufnahme. Die zugrunde liegenden Ursachen können in drei Untergruppen eingeteilt werden: neuro-otologische, internistische und selten auch psychiatrische Erkrankungen. Die diagnostische Einordnung in der Notfallsituation beruht vor allem auf einer strukturierten Anamnese (Begleitsymptome, Trigger, kardiovaskuläre Risikofaktoren), einer systematischen klinischen Untersuchung der vestibulären, okulomotorischen und cerebellären Systeme (Kopfimpulstest, Spontan-, Kopfschüttel-, Lagerungsnystagmus, Augenposition mit der Frage nach einer vertikalen Divergenz, Gang- und Standtests) sowie einem Notfallmonitoring (Vitalzeichen, 12-Kanal-EKG). Bei der Differenzierung zwischen peripheren und zentralen Ursachen des akuten vestibulären Syndroms ist die Überprüfung der sogenannten HINTS-Trias (Kopfimpulstest, Blickrichtungsnystagmus, vertikale Divergenz) diagnostisch wegweisend. Bei akutem Schwindel ohne einen Nystagmus können diagnostische Indextests (Kombinationen aus anamnestischen und klinischen Zeichen) bei der Abschätzung des Schlaganfallrisikos helfen. Von einer unkritischen Anwendung bildgebender Verfahren wird aufgrund des geringen diagnostischen Mehrwerts insbesondere in der Akutphase abgeraten. Die symptomatische Therapie mit Antiemetika sollte nur kurz (< 72 h) sein. Wichtiger ist die kausale Therapie, insbesondere bei Verdacht auf eine vertebro-basiläre Ischämie.
Fortschritte Der Neurologie Psychiatrie, Sep 30, 2015
prophylaktika, Aminopyridine (Kaliumkanalblocker) und Acetyl-DL-Leucin (eine modifizierte essenzi... more prophylaktika, Aminopyridine (Kaliumkanalblocker) und Acetyl-DL-Leucin (eine modifizierte essenzielle Aminosäure). Die Behandlung des Symptoms Schwindel und der begleitenden vegetativen Beschwerden wie Übelkeit, Brechreiz oder Erbrechen sollte zeitlich stets begrenzt werden. Bei einem akuten einseitigen Vestibularisausfall verbessern Kortikosteroide die Erholung der peripher vestibulären Funktion, ohne ausreichende Evidenz für eine allgemeine Empfehlung. Für die Wirksamkeit von Betahistin (16 mg dreimal täglich oder 48 mg dreimal täglich) bei Morbus Menière gibt es bislang keine ausreichende Evidenz, ggf. sollten hierbei höhere Dosierungen angestrebt werdeninsbesondere, da in tierexperimentellen Studien eine Verbesserung der Durchblutung des Innenohrs nachgewiesen wurde. Bei der Vestibularisparoxysmie sind Carbamazepin/ Oxcarbazepin wahrscheinlich wirksam, es fehlen aber noch randomisierte kontrollierte Studien (RCTs) dazu. Bei der vestibulären Migräne gibt es bislang keine RCTs zur Wirksamkeit von Betablockern oder Topiramat, so dass hier aufgrund von klinischen Erfahrungen die Therapie in Analogie zur Migräne ohne Aura empfohlen wird. Aminopyridine werden für die Behandlung von Patienten mit Downbeat-Nystagmus (2 RCTs) und der episodischen Ataxie Typ 2 (EA2, 1 RCT) empfohlen. Die Wirksamkeit von Aminopyridinen wurde in tierexperimentellen und funktionellen Bildgebungsstudien evaluiert. Acetyl-DL-Leucin, eine modifizierte essenzielle Aminosäure, verbessert die klinischen Symptome der zerebellären Ataxie (bisher 3 Beobachtungsstudien). Nach tierexperimentellen Studien beschleunigt
Introduction: Betahistine is widely used for the treatment of various vestibular disorders. Howev... more Introduction: Betahistine is widely used for the treatment of various vestibular disorders. However, the approved oral administration route and maximum daily dose are evidently not e ective in clinical trials, possibly due to a major first-pass metabolism by monoamine oxidases (MAOs). The current study aimed to test di erent application routes (i.v./s.c./p.o.), doses, and concurrent medication (with the MAO-B inhibitor selegiline) for their e ects on behavioral recovery and cerebral target engagement following unilateral labyrinthectomy (UL) in rats. Methods: Sixty rats were subjected to UL by transtympanic injection of bupivacaine/arsanilic acid and assigned to five treatment groups: i.v. low-dose betahistine (mg/kg bid), i.v. high-dose betahistine (mg/kg bid), p.o. betahistine (mg/kg bid)/selegiline (mg/kg once daily), s.c. betahistine (continuous release of. mg/day), and i.v. normal saline bid (sham treatment; days-post-UL), respectively. Behavioral testing of postural asymmetry, nystagmus, and mobility in an open field was performed seven times until day post-UL and paralleled by sequential cerebral [ F]-FDG-µPET measurements. Results: The therapeutic e ects of betahistine after UL di ered in extent and time course and were dependent on the dose, application route, and selegiline co-medication: Postural asymmetry was significantly reduced ondays post-UL by i.v. high-dose and s.c. betahistine only. No changes were observed in the intensity of nystagmus across groups. When compared to sham treatment, movement distance in the open field increased up to-fold from to days post-UL in the s.c., i.v. high-dose, and p.o. betahistine/selegiline groups. [ F]-FDG-µPET showed a dose-dependent rCGM increase in the ipsilesional vestibular nucleus until day post-UL for i.v. high-vs. low-dose betahistine and sham treatment, as well as for p.o. betahistine/selegiline and s.c. betahistine vs. sham treatment. From to days post-UL, rCGM increased in the thalamus bilaterally for i.v. high-dose betahistine, s.c. betahistine, and p.o. betahistine/selegiline vs. saline treatment. Discussion: Betahistine has the potential to augment the recovery of dynamic deficits after UL if the administration protocol is optimized toward higher e ective Frontiers in Neurology frontiersin.org Antons et al.. /fneur.. plasma levels. This may be achieved by higher doses, inhibition of MAO-based metabolism, or a parenteral route. In vivo imaging suggests a drug-target engagement in central vestibular networks.
ZusammenfassungDie episodische Ataxie Typ 2 (EA2) ist eine seltene autosomal dominant vererbte Ka... more ZusammenfassungDie episodische Ataxie Typ 2 (EA2) ist eine seltene autosomal dominant vererbte Kanalopathie mit einem typischen Erstmanifestationsalter zwischen zwei und 20 Jahren. Die Hauptsymptome bestehen in rezidivierenden Attacken von Schwindel, Gang-und Standataxie, die durch körperliche Anstrengung und emotionalen Stress ausgelöst werden können. Im attackenfreien Intervall finden sich eine leichtgradige, im Verlauf meist langsam progrediente zerebelläre Ataxie und zentrale Okulomotorikstörung (mit Downbeat Nystagmus). Weiterhin leiden betroffene Patienten häufig unter Migränekopfschmerzen, selten unter myasthenen Symptomen und epileptischen Anfällen. Die wichtigste Differenzialdiagnose ist die vestibuläre Migräne. Bei ca. 60% der Fälle von EA2 finden sich missense-Mutationen des Kalziumkanalgens CACNA1A verbunden mit einem Funktionsverlust des hauptsächlich auf zerebellären Purkinjezellen lokalisierten spannungsabhängigen P/Q-Typ Kalziumkanals. Dadurch kommt es zur Reduktion der tonischen GABAergen zerebellären Efferenzen. Aufbauend auf diesem pathogenetischen Verständnis wurden zwei effektive pharmakologische Therapieansätze entwickelt: Acetazolamid und 4-Aminopyridin.
Objective: Additionally to the forearm rolling test to detect mild unilateral upper limb dysfunct... more Objective: Additionally to the forearm rolling test to detect mild unilateral upper limb dysfunction, the bed cycling test (BCT) for detection of mild to moderate lower limb dysfunction was developed, evaluated and compared to the leg holding test. Methods: In a prospective observer-blinded study, 60 patients with MRI/CT-proven focal cerebral hemisphere lesions and a mild to moderate unilateral paresis of the lower limb (graduated MRC 3-4/5), and 60 control persons with normal imaging were examined and filmed. Nine observers blinded to the diagnosis evaluated these videos. The sensitivity, specificity and the positive and negative predictive values of the clinical tests were analyzed. Results: The observers gave a correct evaluation of BCT in 35.5% of all patients with focal cerebral lesions compared to 26.0% for the leg holding test. On the other hand, observers had false negative results in 29.1% of cases with BCT and 44.7% with leg holding test. In 36.7% of patients, only BCT was pathological while leg holding test was unremarkable. The sensitivity of the combination of both tests was 0.68 (95% CI 0.61-0.75). The BCT is more sensitive (64.3%) than leg holding test (46.2%) while the specificity of leg holding test (85.6%) is higher than of BCT (70.1%) to detect a cerebral lesion affecting the lower limb. The inter-rater variability is high with no differences comparing different types of clinical experience. Conclusions: The BCT is a useful additional clinical bedside test to detect subtle unilateral cerebral lesions. The BCT is easy to perform and can be added to the routine neurological examination.
Objective: Analogously to the forearm rolling test to detect unilateral upper limb dysfunction a ... more Objective: Analogously to the forearm rolling test to detect unilateral upper limb dysfunction a so-called bed cycling test (BCT) was developed and evaluated to detect mild to moderate unilateral lower limb dysfunction and compared to the leg holding test (LHT). Background: In recent years the sensitivity and specificity of different clinical tests was systematically investigated. In clinical practice, it is important to make a fast clinical decision whether the patients suffers from paresis. Methods: In a prospective examiner-blinded study 60 patients with MRI or CT proven acute focal cerebral hemisphere lesions and a mild to moderate unilateral paresis of the lower limb (graduated 3 or 4 of 5 on MRC scale) and 60 control persons with normal imaging and without obvious focal signs were examined using a battery of clinical tests including the filmed BCT and LHT. Nine examiners, who were blinded to the diagnosis, evaluated these tests presented to them on videos. The sensitivity, specificity as well as positive and negative predictive values of each test were analyzed. Results: The BCT was rated right positive in 35.5 [percnt] compared to LHT in 26.0 [percnt]. On the other hand, examiners had false negative results in 29.1 [percnt] of cases using BCT and 44.7 [percnt] using LHT. In 36.7 [percnt] of patients only BCT was pathological while leg holding test was unremarkable, In conclusion the BCT is more sensitive (64.3 [percnt]) than LHT (46.2 [percnt]) while the specificity of leg holding test (85.6 [percnt]) is higher than of BCT (70.1 [percnt]) to detect a cerebral lesion affecting the lower limb. Conclusions: The BCT test is a useful additional clinical bedside test to detectsubtle unilateral cerebral lesions, especially when regular neurological examination is unremarkable. The BCT is easy to perform and can be added to the neurological routine examination. Disclosure: Dr. Feil has nothing to disclose. Dr. Boettcher has nothing to disclose. Dr. Lezius has nothing to disclose. Dr. Hoegen has nothing to disclose. Dr. Huettemann has nothing to disclose. Dr. Muth has nothing to disclose. Dr. Eren has nothing to disclose. Dr. Schoeberl has nothing to disclose. Dr. Zwergal has nothing to disclose. Dr. Bayer has nothing to disclose. Dr. Strupp has received personal compensation in an editorial capacity for the Journal of Neurology as Joint Chief Editor, Frontiers of Neuro-otology as Editor in Chief, and of F1000 as Section Editor.
ZusammenfassungSchwindel und Gleichgewichtsstörungen bei Kindern sind nicht selten. Bei der Häufi... more ZusammenfassungSchwindel und Gleichgewichtsstörungen bei Kindern sind nicht selten. Bei der Häufigkeitsverteilung der einzelnen Schwindelsyndrome ergeben sich erhebliche altersabhängige Unterschiede. Bei Kindern sind migräneassoziierte Schwindelformen (benigner paroxysmaler Schwindel des Kindesalters, vestibuläre Migräne) sehr häufig und machen etwa 50% der Diagnosen aus. Häufiger als im Erwachsenenalter sind akute einseitige Funktionsstörungen im Rahmen von infektiösen oder parainfektiösen Labyrinthiden, die Bewegungskrankheit und Perilymphfisteln. Die Innenohrbeteiligung mit bilateralen vestibulären Funktionsstörungen kommt bei einer Reihe seltener kongenitaler Syndrome vor. Subakut einsetzende zentral-vestibuläre Zeichen sollten wegen der relativen Häufigkeit von Hirnstamm-und Kleinhirntumoren im Kindesalter eine MRT-Untersuchung nach sich ziehen, die insgesamt bei kindlichem Schwindel eher zu häufig erfolgt.
In 2009 the German BMBF (German Ministry of Education and Research) established an Integrated Cen... more In 2009 the German BMBF (German Ministry of Education and Research) established an Integrated Center for Research and Treatment (IFB(LMU)) of Vertigo, Balance and Ocular Motor Disorders in Munich. After the 10-year period of funding by the BMBF, it is envisioned that the (IFB(LMU)) will continue over the long term with the joint support of the University Hospital, the Medical Faculty, and the Bavarian State. Vertigo is one of the most common complaints in medicine. Despite its high prevalence, patients with vertigo generally receive either inappropriate or inadequate treatment. This deplorable situation is internationally well known and its causes are multiple: insufficient interdisciplinary cooperation, no standardized diagnostics and therapy, the failure to translate findings of basic science into clinical applications, and the scarcity of clinical multicenter studies. The (IFB(LMU)) will constitute a suitable tool with which these structural, clinical, and scientific deficits can be overcome. It will also make possible the establishment of an international interdisciplinary referral center. Munich has become the site of a unique concentration of leading experts on vertigo, balance and ocular motor disorders, both in the clinical and basic sciences. Academic structures have paved the way for the creation of an interdisciplinary horizontal network that also allows structured, vertical academic career paths via the Bachelor&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s and Master&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s degree programs in Neuroscience, a Graduate School of Systemic Neurosciences, and the Munich Center for Neurosciences - Brain and Mind. The (IFB(LMU)) has the following objectives as regards structure and content: to create an independent patient-oriented clinical research center under the auspices of the Medical Faculty but with autonomous administration and budget; to overcome existing clinical and academic barriers separating the traditional specializations; to establish a standardized interdisciplinary longitudinal and transversal network at one site for the management of patients. This should professionalize both the management and the international recruitment of patients (integrated care, telemedicine); to organize the study infrastructure for prospective multicenter clinical studies as well as to free clinical scientists from administrative tasks; to promote translational research with a focus on the innovative topics of molecular, functional and structural imaging, experimental and clinical pharmacotherapy, clinical research of vertigo and balance disorders, mathematical modelling, interaction between biological and technical systems (robotics), and research on functionality and the quality of life; to offer new attractive educational paths and career images for medical doctors, students of the natural sciences, and engineers in clinical research in order to overcome traditional hierarchical structures. This should promote the principles of efficiency and self-reliance; to supplement the existing excellence with up to eight groups of young scientists and up to eight professorships (tenure track). This should also be seen as an incentive that will attract the best young scientists; to incorporate (IFB(LMU)) competence into the existing medical and biological graduate schools. The (IFB(LMU)) is a unique center - worldwide.
Cerebellar dizziness and vertigo account for approximately 10% of diagnoses in a tertiary dizzine... more Cerebellar dizziness and vertigo account for approximately 10% of diagnoses in a tertiary dizziness center. This term summarizes a large group of disorders with chronic (degenerative, hereditary, acquired cerebellar ataxias), recurrent (episodic ataxias), or acute (stroke, inflammation) presentations. Key to the diagnosis is a comprehensive examination of central ocular motor and vestibular function. Patients with cerebellar dizziness and vertigo usually show a pattern of deficits in smooth pursuit, gaze-holding, saccade accuracy, or fixation-suppression of the vestibulo-ocular reflex. Central fixation nystagmus (e.g., downbeat nystagmus), gaze-evoked nystagmus, central positional nystagmus, or head-shaking nystagmus with cross-coupling (i.e., horizontal head shaking causing inappropriate vertical nystagmus) occurs frequently. Overlap syndromes with peripheral vestibular disorders, such as cerebellar ataxia, neuropathy, and vestibular areflexia, exist rarely. Posturography and gait analysis can contribute to diagnostic differentiation, estimation of the risk of falls, as well as quantification of progression and treatment effects. Patients with cerebellar dizziness and vertigo should receive multimodal treatment, including balance training, occupational therapy, and medication.
Introduction: Vertigo and dizziness are common chief complaints of vestibular and ocular motor di... more Introduction: Vertigo and dizziness are common chief complaints of vestibular and ocular motor disorders (lifetime prevalence 30%). Treatment relies on physical, pharmacological, psychological and rarely surgical approaches. Eight groups of drugs are currently used in vestibular and ocular motor disorders, namely anti-vertiginous, anti-inflammatory, anti-menière's, anti-migrainous medications, antidepressants, anti-convulsants, aminopyridines and agents that enhance vestibular plasticity. Areas covered: The purpose of this review is to summarize the pharmacological characteristics and clinical applications of medications that are used for peripheral, central and functional vestibular and ocular motor disorders. The level of evidence for the respective drugs is described alongside the pathophysiological premises supporting their use. The authors place particular focus on translation and back-translation in vestibular pharmacological research and the repurposing of known drugs for new indications and rare disorders. Expert opinion: The use of drugs in vestibular and ocular motor disorders is often based on open-label, non-controlled studies and expert opinion. In the future, strong evidence derived from RCTs is needed to support the effectiveness and tolerability of these therapies in well-defined vestibular and ocular motor disorders. Vestibular pharmacological research must be guided by a better understanding of the molecular targets relevant in the pathophysiology of vestibular and ocular motor disorders.
Annals of the New York Academy of Sciences, Apr 1, 2015
There are currently eight groups of drugs for the pharmacotherapy of vertigo, nystagmus, and cere... more There are currently eight groups of drugs for the pharmacotherapy of vertigo, nystagmus, and cerebellar disorders: antiemetics; anti-inflammatories, antimenieres, and antimigraineous medications; antidepressants, anticonvulsants, aminopyridines, and acetyl-DL-leucine (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;the eight A&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;). In acute unilateral vestibulopathy, corticosteroids improve the recovery of peripheral vestibular function, but there is not sufficient current evidence for a general recommendation. There is also insufficient evidence that 48 or 144 mg/day betahistine has an effect in Ménière&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease. Therefore, higher dosages are currently recommended; in animal studies, it was shown that betahistine increases cochlear blood flow. In vestibular paroxysmia, oxcarbazepine was effective (one yet not randomized controlled trial (RCT)). Aminopyridines are recommended for the treatment of downbeat nystagmus (two RCTs) and episodic ataxia type 2 (EA2, one RCT). There are so far no RCTs on vestibular migraine, so currently no treatment can be recommended. Acetyl-dl-leucine improves cerebellar ataxia (three observational studies); it also accelerates central compensation in an animal model of acute unilateral lesion, but RCTs were negative. There are ongoing RCTs on vestibular paroxysmia with carbamazepine (VESPA), acute unilateral vestibulopathy with betahistine (BETAVEST), vestibular migraine with metoprolol (PROVEMIG), benign paroxysmal positional vertigo with vitamin D (VitD@BPPV), EA2 with 4-aminopyridine versus acetazolamide (EAT-2-TREAT), and cerebellar ataxias with acetyl-DL-leucine (ALCAT).
Annals of the New York Academy of Sciences, May 1, 2009
Information from the vestibular nuclei ascending through the brainstem to the oculomotor and troc... more Information from the vestibular nuclei ascending through the brainstem to the oculomotor and trochlear nuclei (NIII, NIV), the interstitial nucleus of Cajal (INC), the pretectum, or thalamus, is thought to be distributed in at least five different pathways. They include the medial longitudinal fasciculus (MLF), the ascending tract of Deiters (ATD), possibly the brachium conjuctivum (BC), the crossing ventral tegmental tracts (CVTT), and a recently observed ipsilateral pathway close to the medial lemniscus, possibly the equivalent of the ipsilateral vestibulo-thalamic tract (IVTT). This short review describes the location of these ascending tracts, their function with respect to ocular motor control and perception, and their clinical relevance. There is evidence that the MLF carries mainly information from the canals to NIII, NIV, INC, and possibly the thalamus, whereas otolith signals may ascend in the CVTT, along with excitatory anterior canal connections. The evidence for BC as a specific vestibulo-oculomotor pathway is weak and could be the result of the initial observations of CVTT. The ATD carries mostly ipsilateral otolithic information to the medial and inferior recti subgroups in NIII and the Edinger-Westphal nucleus. In the rostral pons an ipsilateral vestibular pathway was seen lying close to the medial lemniscus. This anatomical projection could be the equivalent of the IVTT, bypassing the ocular motor centers and projecting to the thalamus. The IVTT mediates perception of verticality and may be part of a fast three-neuron vestibulo-thalamo-cortical pathway, which provides the multisensory cortical system for spatial orientation and self-motion-perception with information about head acceleration.
Background and ObjectivesBilateral vestibulopathy (BVP) is a chronic debilitating neurologic diso... more Background and ObjectivesBilateral vestibulopathy (BVP) is a chronic debilitating neurologic disorder with no monogenic cause established so far despite familiar presentations. We hypothesized that replication factor complex subunit 1 (RFC1) repeat expansions might present a recurrent monogenic cause of BVP.MethodsThe study involved RFC1 screening and in-depth neurologic, vestibulo-oculomotor, and disease evolution phenotyping of 168 consecutive patients with idiopathic at least “probable BVP” from a tertiary referral center for balance disorders, with127 of them meeting current diagnostic criteria of BVP (Bárány Society Classification).ResultsBiallelic AAGGG repeat expansions in RFC1 were identified in 10/127 patients (8%) with BVP and 1/41 with probable BVP. Heterozygous expansions in 10/127 patients were enriched compared with those in reference populations. RFC1-related BVP manifested at a median age of 60 years (range 34–72 years) and co-occurred predominantly with mild polyneuropathy (10/11). Additional cerebellar involvement (7/11) was subtle and limited to oculomotor signs in early stages, below recognition of classic cerebellar ataxia, neuropathy, and vestibular areflexia syndrome. Clear dysarthria, appendicular ataxia, or cerebellar atrophy developed 6–8 years after onset. Dysarthria, absent patellar reflexes, and downbeat nystagmus best discriminated RFC1-positive BVP from RFC1-negative BVP, but neither sensory symptoms nor fine motor problems. Video head impulse gains of patients with RFC1-positive BVP were lower relative to those of patients with RFC1-negative BVP and decreased until 10 years disease duration, indicating a potential progression and outcome marker for RFC1-disease.DiscussionThis study identifies RFC1 as the first—and frequent—monogenic cause of BVP. It characterizes RFC1-related BVP as part of the multisystemic evolution ofRFC1spectrum disease, with implications for designing natural history studies and future treatment trials.Classification of EvidenceThis study provides Class II evidence that RFC1 repeat expansions cause BVP.
Schwindel gehört zu den häufigsten Leitsymptomen in der Notaufnahme. Die zugrunde liegenden Ursac... more Schwindel gehört zu den häufigsten Leitsymptomen in der Notaufnahme. Die zugrunde liegenden Ursachen können in drei Untergruppen eingeteilt werden: neuro-otologische, internistische und selten auch psychiatrische Erkrankungen. Die diagnostische Einordnung in der Notfallsituation beruht vor allem auf einer strukturierten Anamnese (Begleitsymptome, Trigger, kardiovaskuläre Risikofaktoren), einer systematischen klinischen Untersuchung der vestibulären, okulomotorischen und cerebellären Systeme (Kopfimpulstest, Spontan-, Kopfschüttel-, Lagerungsnystagmus, Augenposition mit der Frage nach einer vertikalen Divergenz, Gang- und Standtests) sowie einem Notfallmonitoring (Vitalzeichen, 12-Kanal-EKG). Bei der Differenzierung zwischen peripheren und zentralen Ursachen des akuten vestibulären Syndroms ist die Überprüfung der sogenannten HINTS-Trias (Kopfimpulstest, Blickrichtungsnystagmus, vertikale Divergenz) diagnostisch wegweisend. Bei akutem Schwindel ohne einen Nystagmus können diagnostische Indextests (Kombinationen aus anamnestischen und klinischen Zeichen) bei der Abschätzung des Schlaganfallrisikos helfen. Von einer unkritischen Anwendung bildgebender Verfahren wird aufgrund des geringen diagnostischen Mehrwerts insbesondere in der Akutphase abgeraten. Die symptomatische Therapie mit Antiemetika sollte nur kurz (< 72 h) sein. Wichtiger ist die kausale Therapie, insbesondere bei Verdacht auf eine vertebro-basiläre Ischämie.
Fortschritte Der Neurologie Psychiatrie, Sep 30, 2015
prophylaktika, Aminopyridine (Kaliumkanalblocker) und Acetyl-DL-Leucin (eine modifizierte essenzi... more prophylaktika, Aminopyridine (Kaliumkanalblocker) und Acetyl-DL-Leucin (eine modifizierte essenzielle Aminosäure). Die Behandlung des Symptoms Schwindel und der begleitenden vegetativen Beschwerden wie Übelkeit, Brechreiz oder Erbrechen sollte zeitlich stets begrenzt werden. Bei einem akuten einseitigen Vestibularisausfall verbessern Kortikosteroide die Erholung der peripher vestibulären Funktion, ohne ausreichende Evidenz für eine allgemeine Empfehlung. Für die Wirksamkeit von Betahistin (16 mg dreimal täglich oder 48 mg dreimal täglich) bei Morbus Menière gibt es bislang keine ausreichende Evidenz, ggf. sollten hierbei höhere Dosierungen angestrebt werdeninsbesondere, da in tierexperimentellen Studien eine Verbesserung der Durchblutung des Innenohrs nachgewiesen wurde. Bei der Vestibularisparoxysmie sind Carbamazepin/ Oxcarbazepin wahrscheinlich wirksam, es fehlen aber noch randomisierte kontrollierte Studien (RCTs) dazu. Bei der vestibulären Migräne gibt es bislang keine RCTs zur Wirksamkeit von Betablockern oder Topiramat, so dass hier aufgrund von klinischen Erfahrungen die Therapie in Analogie zur Migräne ohne Aura empfohlen wird. Aminopyridine werden für die Behandlung von Patienten mit Downbeat-Nystagmus (2 RCTs) und der episodischen Ataxie Typ 2 (EA2, 1 RCT) empfohlen. Die Wirksamkeit von Aminopyridinen wurde in tierexperimentellen und funktionellen Bildgebungsstudien evaluiert. Acetyl-DL-Leucin, eine modifizierte essenzielle Aminosäure, verbessert die klinischen Symptome der zerebellären Ataxie (bisher 3 Beobachtungsstudien). Nach tierexperimentellen Studien beschleunigt
Introduction: Betahistine is widely used for the treatment of various vestibular disorders. Howev... more Introduction: Betahistine is widely used for the treatment of various vestibular disorders. However, the approved oral administration route and maximum daily dose are evidently not e ective in clinical trials, possibly due to a major first-pass metabolism by monoamine oxidases (MAOs). The current study aimed to test di erent application routes (i.v./s.c./p.o.), doses, and concurrent medication (with the MAO-B inhibitor selegiline) for their e ects on behavioral recovery and cerebral target engagement following unilateral labyrinthectomy (UL) in rats. Methods: Sixty rats were subjected to UL by transtympanic injection of bupivacaine/arsanilic acid and assigned to five treatment groups: i.v. low-dose betahistine (mg/kg bid), i.v. high-dose betahistine (mg/kg bid), p.o. betahistine (mg/kg bid)/selegiline (mg/kg once daily), s.c. betahistine (continuous release of. mg/day), and i.v. normal saline bid (sham treatment; days-post-UL), respectively. Behavioral testing of postural asymmetry, nystagmus, and mobility in an open field was performed seven times until day post-UL and paralleled by sequential cerebral [ F]-FDG-µPET measurements. Results: The therapeutic e ects of betahistine after UL di ered in extent and time course and were dependent on the dose, application route, and selegiline co-medication: Postural asymmetry was significantly reduced ondays post-UL by i.v. high-dose and s.c. betahistine only. No changes were observed in the intensity of nystagmus across groups. When compared to sham treatment, movement distance in the open field increased up to-fold from to days post-UL in the s.c., i.v. high-dose, and p.o. betahistine/selegiline groups. [ F]-FDG-µPET showed a dose-dependent rCGM increase in the ipsilesional vestibular nucleus until day post-UL for i.v. high-vs. low-dose betahistine and sham treatment, as well as for p.o. betahistine/selegiline and s.c. betahistine vs. sham treatment. From to days post-UL, rCGM increased in the thalamus bilaterally for i.v. high-dose betahistine, s.c. betahistine, and p.o. betahistine/selegiline vs. saline treatment. Discussion: Betahistine has the potential to augment the recovery of dynamic deficits after UL if the administration protocol is optimized toward higher e ective Frontiers in Neurology frontiersin.org Antons et al.. /fneur.. plasma levels. This may be achieved by higher doses, inhibition of MAO-based metabolism, or a parenteral route. In vivo imaging suggests a drug-target engagement in central vestibular networks.
ZusammenfassungDie episodische Ataxie Typ 2 (EA2) ist eine seltene autosomal dominant vererbte Ka... more ZusammenfassungDie episodische Ataxie Typ 2 (EA2) ist eine seltene autosomal dominant vererbte Kanalopathie mit einem typischen Erstmanifestationsalter zwischen zwei und 20 Jahren. Die Hauptsymptome bestehen in rezidivierenden Attacken von Schwindel, Gang-und Standataxie, die durch körperliche Anstrengung und emotionalen Stress ausgelöst werden können. Im attackenfreien Intervall finden sich eine leichtgradige, im Verlauf meist langsam progrediente zerebelläre Ataxie und zentrale Okulomotorikstörung (mit Downbeat Nystagmus). Weiterhin leiden betroffene Patienten häufig unter Migränekopfschmerzen, selten unter myasthenen Symptomen und epileptischen Anfällen. Die wichtigste Differenzialdiagnose ist die vestibuläre Migräne. Bei ca. 60% der Fälle von EA2 finden sich missense-Mutationen des Kalziumkanalgens CACNA1A verbunden mit einem Funktionsverlust des hauptsächlich auf zerebellären Purkinjezellen lokalisierten spannungsabhängigen P/Q-Typ Kalziumkanals. Dadurch kommt es zur Reduktion der tonischen GABAergen zerebellären Efferenzen. Aufbauend auf diesem pathogenetischen Verständnis wurden zwei effektive pharmakologische Therapieansätze entwickelt: Acetazolamid und 4-Aminopyridin.
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