N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study.

BACKGROUND: Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded phase IIb clinical trial. Here, we describe the development of a study protocol (Sponsor Code "IB1001-301") for the chronic treatment of symptoms in adult and pediatric patients with NPC. METHODS: This multinational double-blind randomized placebo-controlled crossover phase III study will enroll patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites. Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments. DISCUSSION: Pre-clinical as well as observational and phase IIb clinical trials have previously demonstrated that IB1001 rapidly improved symptoms, functioning, and quality of life for pediatric and adult NPC patients and is safe and well tolerated. In this placebo-controlled cross-over trial, the risk/benefit profile of IB1001 for NPC will be evaluated. It will also give information about the applicability of IB1001 as a therapeutic paradigm for other rare and common neurological disorders. TRIAL REGISTRATIONS: The trial (IB1001-301) has been registered at www. CLINICALTRIALS: gov (NCT05163288) and www.clinicaltrialsregister.eu (EudraCT: 2021-005356-10). Registered on 20 December 2021.

A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia.

BACKGROUND: The lack of approved treatments for the majority of rare diseases is reflective of the unique challenges of orphan drug development. Novel methodologies, including new functionally relevant endpoints, are needed to render the development process more feasible and appropriate for these rare populations and thereby expedite the approval of promising treatments to address patients' high unmet medical need. Here, we describe the development of an innovative master protocol and primary outcome assessment to investigate the modified amino acid N-acetyl-L-leucine (Sponsor Code: IB1001) in three separate, multinational, phase II trials for three ultra-rare, autosomal-recessive, neurodegenerative disorders: Niemann-Pick disease type C (NPC), GM2 gangliosidoses (Tay-Sachs and Sandhoff disease; "GM2"), and ataxia telangiectasia (A-T). METHODS/DESIGN: The innovative IB1001 master protocol and novel CI-CS primary endpoints were developed through a close collaboration between the Industry Sponsor, Key Opinion Leaders, representatives of the Patient Communities, and National Regulatory Authorities. As a result, the open-label, rater-blinded study design is considerate of the practical limitations of recruitment and retention of subjects in these ultra-orphan populations. The novel primary endpoint, the Clinical Impression of Change in Severity© (CI-CS), accommodates the heterogenous clinical presentation of NPC, GM2, and A-T: at screening, the principal investigator appoints for each patient a primary anchor test (either the 8-m walk test (8MWT) or 9-hole peg test of the dominant hand (9HPT-D)) based on his/her unique clinical symptoms. The anchor tests are videoed in a standardized manner at each visit to capture all aspects related to the patient's functional performance. The CI-CS assessment is ultimately performed by independent, blinded raters who compare videos of the primary anchor test from three periods: baseline, the end of treatment, and the end of a post-treatment washout. Blinded to the time point of each video, the raters make an objective comparison scored on a 7-point Likert scale of the change in the severity of the patient's neurological signs and symptoms from video A to video B. To investigate both the symptomatic and disease-modifying effects of treatment, N-acetyl-L-leucine is assessed during two treatment sequences: a 6-week parent study and 1-year extension phase. DISCUSSION: The novel CI-CS assessment, developed through a collaboration of all stakeholders, is advantageous in that it better ensures the primary endpoint is functionally relevant for each patient, is able to capture small but meaningful clinical changes critical to the patients' quality of life (fine-motor skills; gait), and blinds the primary outcome assessment. The results of these three trials will inform whether N-acetyl-L-leucine is an effective treatment for NPC, GM2, and A-T and can also serve as a new therapeutic paradigm for the development of future treatments for other orphan diseases. TRIAL REGISTRATION: The three trials (IB1001-201 for Niemann-Pick disease type C (NPC), IB1001-202 for GM2 gangliosidoses (Tay-Sachs and Sandhoff), IB1001-203 for ataxia telangiectasia (A-T)) have been registered at www.clinicaltrials.gov (NCT03759639; NCT03759665; NCT03759678), www.clinicaltrialsregister.eu (EudraCT: 2018-004331-71; 2018-004406-25; 2018-004407-39), and https://www.germanctr.de (DR KS-ID: DRKS00016567; DRKS00017539; DRKS00020511).

The neurological update: therapies for cerebellar ataxias in 2020.

Cerebellar ataxias (CAs) represent a heterogeneous group of sporadic or inherited disorders. The clinical spectrum of CAs is continuously expanding. Our understanding of the mechanisms leading to the clinical deficits has improved over these last decades, in particular thanks to progress in genetics, neuroimaging and the advent of relevant animal models allowing the identification of the pathophysiological pathways leading to CAs. The rationale behind treatments is now established for most of the CAs encountered during daily practice worldwide. In this update, we will discuss the symptomatic, physical and occupational therapies now being trialled along with individualized exercises, and present key emerging issues on immune-mediated cerebellar ataxias, hereditary cerebellar ataxias. Finally, we will discuss novel therapeutic approaches, including cerebellar non-invasive stimulation and treatments acting on RNA/proteins. So far, no state-of-the art randomized placebo-controlled clinical trial has shown a convincing clinically relevant efficacy of any drug, with the exception of 4-aminopyridine for the symptomatic treatment of episodic ataxia type 2 and downbeat nystagmus (placebo-controlled trials).

[Pharmacotherapy of Vestibular Disorders, Nystagmus and Cerebellar Disorders]. / Medikamentöse Therapiemöglichkeiten bei vestibulären Störungen, Nystagmus und zerebellären Ataxien.

There are currently different groups of drugs for the pharmacotherapy of vertigo, nystagmus and cerebellar disorders: antiemetics; anti-inflammatories, antimenieres, and antimigraineous medications and antidepressants, anticonvulsants, aminopyridines as well as acetyl-DL-leucine. In acute unilateral vestibulopathy, corticosteroids improve the recovery of peripheral vestibular function, but currently there is not sufficient evidence for a general recommendation. There is insufficient evidence to support the view that 16 mg t. i. d. or 48 mg t. i. d. betahistine has an effect in Menière's disease. Therefore, higher dosages are recommended. In animal studies, it was shown that betahistine increases cochlear blood flow. In vestibular paroxysmia, oxcarbazepine was effective (one randomized controlled trial (RCT)). Aminopyridines are recommended for the treatment of downbeat nystagmus (two RCTs) and episodic ataxia type 2 (EA2, one RCT). There has been no RCT on the efficacy of beta-blockers or topiramate but one RCT on flunarizine in vestibular migraine. Based on clinical experience, a treatment analogous to that for migraine without aura can be recommended. Acetyl-DL-leucine improved cerebellar ataxia (two observational studies); it also accelerated central compensation in an animal model of acute unilateral lesion, but RCTs were negative. There are ongoing RCTs on treatment of 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).

[Diagnostic criteria for Menière's disease according to the Classification Committee of the Bárány Society]. / M. Menière: Diagnostische Kriterien des Internationalen Klassifikationskomitees der Bárány-Gesellschaft.

This paper presents diagnostic criteria for Menière's disease jointly formulated by the Classification Committee of the Bárány Society, The Japan Society for Equilibrium Research, the European Academy of Otology and Neurotology (EAONO), the Equilibrium Committee of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and the Korean Balance Society. The classification includes two categories: definite Menière's disease and probable Menière's disease. The diagnosis of definite Menière's disease is based on clinical criteria and requires the observation of an episodic vertigo syndrome associated with low- to medium-frequency sensorineural hearing loss and fluctuating aural symptoms (hearing, tinnitus and/or fullness) in the affected ear. Duration of vertigo episodes is limited to a period between 20 min and 12 h. Probable Menière's disease is a broader concept defined by episodic vestibular symptoms (vertigo or dizziness) associated with fluctuating aural symptoms occurring in a period from 20 min to 24 h.

Bilateral vestibulopathy.

The leading symptoms of bilateral vestibulopathy (BVP) are postural imbalance and unsteadiness of gait that worsens in darkness and on uneven ground. There are typically no symptoms while sitting or lying under static conditions. A minority of patients also have movement-induced oscillopsia, in particular while walking. The diagnosis of BVP is based on a bilaterally reduced or absent function of the vestibulo-ocular reflex (VOR). This deficit is diagnosed for the high-frequency range of the angular VOR by a bilaterally pathologic bedside head impulse test (HIT) and for the low-frequency range by a bilaterally reduced or absent caloric response. If the results of the bedside HIT are unclear, angular VOR function should be quantified by a video-oculography system (vHIT). An additional test supporting the diagnosis is dynamic visual acuity. Cervical and ocular vestibular-evoked myogenic potentials (c/oVEMP) may also be reduced or absent, indicating impaired otolith function. There are different subtypes of BVP depending on the affected anatomic structure and frequency range of the VOR deficit: impaired canal function in the low- and/or high-frequency VOR range only and/or otolith function only; the latter is very rare. The etiology of BVP remains unclear in more than 50% of patients: in these cases neurodegeneration is assumed. Frequent known causes are ototoxicity mainly due to gentamicin, bilateral Menière's disease, autoimmune diseases, meningitis and bilateral vestibular schwannoma, as well as an association with cerebellar degeneration (cerebellar ataxia, neuropathy, vestibular areflexia syndrome=CANVAS). In general, in the long term there is no improvement of vestibular function. There are four treatment options: first, detailed patient counseling to explain the cause, etiology, and consequences, as well as the course of the disease; second, daily vestibular exercises and balance training; third, if possible, treatment of the underlying cause, as in bilateral Menière's disease, meningitis, or autoimmune diseases; fourth, if possible, prevention, i.e., being very restrictive with the use of ototoxic substances, such as aminoglycosides. In the future vestibular implants may also be an option.

Normal pressure hydrocephalus: Increase of utricular input in responders to spinal tap test.

OBJECTIVE: To investigate whether there is a change in ocular (oVEMP) and cervical (cVEMP) vestibular evoked myogenic potentials in patients with normal pressure hydrocephalus (NPH) before and after spinal tap test (STT). METHODS: In 25 patients (6 females, age 62-83years) c/oVEMP were measured before and after STT. Patients with an increase of >20% of walking velocity were classified as responders (n=10). VEMP were also measured in a control group of 13 non-NPH patients. RESULTS: All patients had reproducible oVEMP; 68% had cVEMP. There was a significant increase of the peak-to-peak (pp) oVEMP amplitude after STT in responders (8.5±2.7 to 18.9±7.5µV (p=0.010)). No significant changes were found in non-responders (13.4±7.6 to 15.3±8.6µV) or controls (12.4±7.6 to 12.5±6.8µV). There were no significant differences in cVEMP before and after spinal tap test (STT). CONCLUSION: One third of patients with suspected NPH had impaired otolith function. Responders to STT only had a significant increase of oVEMP and thereby utricular input, probably due to a decrease of pressure. SIGNIFICANCE: Both findings indicate that otolith dysfunction may contribute to imbalance in NPH and that increased utricular function after STT may be relevant for gait improvement.

Real-time computer-based visual feedback improves visual acuity in downbeat nystagmus - a pilot study.

BACKGROUND: Patients with downbeat nystagmus syndrome suffer from oscillopsia, which leads to an unstable visual perception and therefore impaired visual acuity. The aim of this study was to use real-time computer-based visual feedback to compensate for the destabilizing slow phase eye movements. METHODS: The patients were sitting in front of a computer screen with the head fixed on a chin rest. The eye movements were recorded by an eye tracking system (EyeSeeCam®). We tested the visual acuity with a fixed Landolt C (static) and during real-time feedback driven condition (dynamic) in gaze straight ahead and (20°) sideward gaze. In the dynamic condition, the Landolt C moved according to the slow phase eye velocity of the downbeat nystagmus. The Shapiro-Wilk test was used to test for normal distribution and one-way ANOVA for comparison. RESULTS: Ten patients with downbeat nystagmus were included in the study. Median age was 76 years and the median duration of symptoms was 6.3 years (SD +/- 3.1y). The mean slow phase velocity was moderate during gaze straight ahead (1.44°/s, SD +/- 1.18°/s) and increased significantly in sideward gaze (mean left 3.36°/s; right 3.58°/s). In gaze straight ahead, we found no difference between the static and feedback driven condition. In sideward gaze, visual acuity improved in five out of ten subjects during the feedback-driven condition (p = 0.043). CONCLUSIONS: This study provides proof of concept that non-invasive real-time computer-based visual feedback compensates for the SPV in DBN. Therefore, real-time visual feedback may be a promising aid for patients suffering from oscillopsia and impaired text reading on screen. Recent technological advances in the area of virtual reality displays might soon render this approach feasible in fully mobile settings.

[Peripheral, central and functional vertigo syndromes]. / Periphere, zentrale und funktionelle Schwindelsyndrome.

Depending on the temporal course, three forms of vertigo syndrome can be differentiated: 1) vertigo attacks, e.g. benign paroxysmal positional vertigo (BPPV), Menière's disease and vestibular migraine, 2) acute spontaneous vertigo lasting for days, e.g. acute unilateral vestibulopathy, brainstem or cerebellar infarction and 3) symptoms lasting for months or years, e.g. bilateral vestibulopathy and functional vertigo. The specific therapy of the various syndromes is based on three principles: 1) physical treatment with liberatory maneuvers for BPPV and balance training for vestibular deficits, 2) pharmacotherapy, e.g. for acute unilateral vestibulopathy (corticosteroids) and Menière's disease (transtympanic administration of gentamicin or steroids and high-dose betahistine therapy); placebo-controlled pharmacotherapy studies are currently being carried out for acute unilateral vestibulopathy, vestibular paroxysmia, prophylaxis of BPPV, vestibular migraine, episodic ataxia type 2 and cerebellar ataxia; 3) psychotherapy for functional dizziness.

[Diagnosis and treatment options in vertigo syndromes]. / Diagnosestellung und Therapieoptionen bei Schwindelsyndromen.

The key to diagnosing vertigo and balance disorders is systematic analysis of case history with clinical examination of the vestibular, oculomotor, and cerebral systems in particular. Important criteria for differentiating between the various vertigo syndromes are 1) the time course of symptoms, 2) the type of symptoms, 3) modulating factors, and 4) associated symptoms. For clinical examination of the vestibular system, six important tests are available: assessment of spontaneous nystagmus, head impulse test, dynamic visual acuity, subjective visual verticality, positioning manoeuvre, and the Romberg test/gait analysis with eyes open and closed. On the basis of five clinical signs (vertical divergence, central fixation nystagmus, gaze-evoked nystagmus, saccades, normal head impulse test), the clinical examination is able to differentiate between acute central and peripheral vestibular syndromes with a sensitivity and specificity of over 90%. The most relevant laboratory examinations are caloric irrigation and the video head-impulse test for canal function and the vestibular evoked myogenic potentials for otolith function. Finally, treatment is based upon four therapeutic principles: physiotherapy, pharmacotherapy, psychotherapy, and in rare cases, surgery.

[Pharmacotherapy of Vestibular Disorders, Nystagmus and Cerebellar Disorders]. / Medikamentöse Therapiemöglichkeiten bei vestibulären Störungen, Nystagmus und zerebellären Ataxien.

There are currently different groups of drugs for the pharmacotherapy of vertigo, nystagmus and cerebellar disorders: antiemetics; anti-inflammatories, antimenieres, and antimigraineous medications and antidepressants, anticonvulsants, aminopyridines as well as acetyl-DL-leucine. In acute unilateral vestibulopathy, corticosteroids improve the recovery of peripheral vestibular function, but currently there is not sufficient evidence for a general recommendation. There is insufficient evidence to support the view that 16 mg t. i. d. or 48 mg t. i. d. betahistine has an effect in Menière's disease. Therefore, higher dosages are recommended. In animal studies, it was shown that betahistine increases cochlear blood flow. In vestibular paroxysmia, oxcarbazepine was effective (one randomized controlled trial (RCT)). Aminopyridines are recommended for the treatment of downbeat nystagmus (two RCTs) and episodic ataxia type 2 (EA2, one RCT). There has been no RCT on the efficacy of beta-blockers or topiramate but one RCT on flunarizine in vestibular migraine. Based on clinical experience, a treatment analogous to that for migraine without aura can be recommended. Acetyl-DL-leucine improved cerebellar ataxia (two observational studies); it also accelerated central compensation in an animal model of acute unilateral lesion, but RCTs were negative. There are ongoing RCTs on treatment of 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).

Long-term course of orthostatic tremor in serial posturographic measurement.

OBJECTIVE: Primary orthostatic tremor (OT) is a rare neurological disease of unknown pathophysiology characterized by a high-frequency tremor mainly of the legs when standing. The aim of this study was to examine its long-term course by subjective estimation and objective recording by serial posturography and to obtain further standardized epidemiological and clinical data on patients with OT. METHODS: A clinical cohort of 37 patients with the diagnosis of primary OT was screened for this longitudinal follow-up study. Eighteen patients consented to participate. During study visit all patients underwent a standardized neurological examination and completed subjective scales and scores. Posturographic recordings at follow-up were compared to prior clinical posturographic measurements in 15 cases. RESULTS: In our cohort the mean duration of symptoms was 14.1 ± 6.8 years. Subjectively, 78% of patients reported progression of the disease. Posturographic data (5.4 ± 4.0 years) revealed a significant increase of the total sway path (standing on firm ground with eyes open) from 2.4 ± 1.3 to 3.4 ± 1.4 m/min (p = 0.022) and of the total root mean square values from 9.8 ± 4.3 to 12.4 ± 4.8 mm (p = 0.028). None of these observations are explained by aging of the patients. Mean frequency of the tremor did not change over time (14.7 ± 1.9 Hz vs. 14.9 ± 2.0 Hz at follow-up). Clinically, most patients had signs of cerebellar dysfunction and a substantial portion also showed proprioceptive deficits in the long-term course. CONCLUSIONS: This long-term follow-up study indicates, that primary OT is a progressive disorder. Furthermore, the clinical observation of cerebellar dysfunction in most OT patients in the long-term course might indicate an important role of the cerebellum in its pathophysiology.

Central ocular motor disorders, including gaze palsy and nystagmus.

An impairment of eye movements, or nystagmus, is seen in many diseases of the central nervous system, in particular those affecting the brainstem and cerebellum, as well as in those of the vestibular system. The key to diagnosis is a systematic clinical examination of the different types of eye movements, including: eye position, range of eye movements, smooth pursuit, saccades, gaze-holding function and optokinetic nystagmus, as well as testing for the different types of nystagmus (e.g., central fixation nystagmus or peripheral vestibular nystagmus). Depending on the time course of the signs and symptoms, eye movements often indicate a specific underlying cause (e.g., stroke or neurodegenerative or metabolic disorders). A detailed knowledge of the anatomy and physiology of eye movements enables the physician to localize the disturbance to a specific area in the brainstem (midbrain, pons or medulla) or cerebellum (in particular the flocculus). For example, isolated dysfunction of vertical eye movements is due to a midbrain lesion affecting the rostral interstitial nucleus of the medial longitudinal fascicle, with impaired vertical saccades only, the interstitial nucleus of Cajal or the posterior commissure; common causes with an acute onset are an infarction or bleeding in the upper midbrain or in patients with chronic progressive supranuclear palsy (PSP) and Niemann-Pick type C (NP-C). Isolated dysfunction of horizontal saccades is due to a pontine lesion affecting the paramedian pontine reticular formation due, for instance, to brainstem bleeding, glioma or Gaucher disease type 3; an impairment of horizontal and vertical saccades is found in later stages of PSP, NP-C and Gaucher disease type 3. Gaze-evoked nystagmus (GEN) in all directions indicates a cerebellar dysfunction and can have multiple causes such as drugs, in particular antiepileptics, chronic alcohol abuse, neurodegenerative cerebellar disorders or cerebellar ataxias; purely vertical GEN is due to a midbrain lesion, while purely horizontal GEN is due to a pontomedullary lesion. The pathognomonic clinical sign of internuclear ophthalmoplegia is an impaired adduction while testing horizontal saccades on the side of the lesion in the ipsilateral medial longitudinal fascicule. The most common pathological types of central nystagmus are downbeat nystagmus (DBN) and upbeat nystagmus (UBN). DBN is generally due to cerebellar dysfunction affecting the flocculus bilaterally (e.g., due to a neurodegenerative disease). Treatment options exist for a few disorders: miglustat for NP-C and aminopyridines for DBN and UBN. It is therefore particularly important to identify treatable cases with these conditions.

Consensus paper: management of degenerative cerebellar disorders.

Treatment of motor symptoms of degenerative cerebellar ataxia remains difficult. Yet there are recent developments that are likely to lead to significant improvements in the future. Most desirable would be a causative treatment of the underlying cerebellar disease. This is currently available only for a very small subset of cerebellar ataxias with known metabolic dysfunction. However, increasing knowledge of the pathophysiology of hereditary ataxia should lead to an increasing number of medically sensible drug trials. In this paper, data from recent drug trials in patients with recessive and dominant cerebellar ataxias will be summarized. There is consensus that up to date, no medication has been proven effective. Aminopyridines and acetazolamide are the only exception, which are beneficial in patients with episodic ataxia type 2. Aminopyridines are also effective in a subset of patients presenting with downbeat nystagmus. As such, all authors agreed that the mainstays of treatment of degenerative cerebellar ataxia are currently physiotherapy, occupational therapy, and speech therapy. For many years, well-controlled rehabilitation studies in patients with cerebellar ataxia were lacking. Data of recently published studies show that coordinative training improves motor function in both adult and juvenile patients with cerebellar degeneration. Given the well-known contribution of the cerebellum to motor learning, possible mechanisms underlying improvement will be outlined. There is consensus that evidence-based guidelines for the physiotherapy of degenerative cerebellar ataxia need to be developed. Future developments in physiotherapeutical interventions will be discussed including application of non-invasive brain stimulation.

[Management of patients with the cardinal symptom dizziness or vertigo]. / Versorgungssituation von Patienten mit dem Leitsymptom Schwindel.

BACKGROUND: Vertigo and dizziness are common symptoms leading patients to consult a physician. The nationally representative "2003 Health Survey" depicts the epidemiology of the symptoms vertigo and dizziness across all of Germany. A breakdown of the data by region is not available. METHODS: Routine data of the Bavarian Association of Statutory Health Insurance Physicians accounting centre ("Kassenärztliche Vereinigung Bayerns", KVB) from 2008 were analysed using multilevel models to investigate individual and regional factors and the relevance of nonspecific regional heterogeneity. RESULTS: Altogether, 866,086 of 9,269,729 (9.34%) inhabitants received an ambulatory diagnosis of vertigo or dizziness, including 1.77 times as many women as men. Visits to the doctor because of vertigo or dizziness increased with age. After adjustments for age and sex, a North-South divide and a higher prevalence in the urban centres were apparent within Bavaria. The majority of patients were seen by their GP and nearby doctors. This held especially true for women. Also older patients were less likely to go to specialists further afield. CONCLUSION: This analysis of the KVB data of patients with vertigo or dizziness underlines the central role that is played by GPs in diagnosis and treatment. In order to correctly diagnose the underlying causes, treat patients or send them to specialists effectively, all doctors need to be trained about this relevant clinical symptom. The insufficient representation of clinically established vertigo disorders by the ICD-10 was problematic. The most frequently coded diagnosis was N95.1 "postmenopausal dizziness".

[Cardinal symptom vertigo from the neurologist's perspective]. / Leitsymptom Schwindel aus Sicht des Neurologen.

In most patients with vertigo, the first and clinically most important question posed to neurologists is whether it is a central or a peripheral syndrome. In more than 90 % of cases, this differentiation is made possible by systematically recording the patient history (asking about the type of vertigo, the duration, triggers and accompanying symptoms) and conducting a physical examination. Particularly in the case of acute vertigo disorders, a five-step procedure has proven useful: 1. A cover test to look for vertical divergence (skew deviation) as a central sign and component of the ocular tilt reaction (OTR); 2. Examination with and without Frenzel goggles to differentiate between peripheral vestibular spontaneous nystagmus and central fixation nystagmus; 3. Examination of smooth pursuit; 4. Examination of the gaze-holding function (particularly gaze-evoked nystagmus beating in the opposite direction to spontaneous nystagmus); 5. The head impulse test to look for a deficit in the vestibulo-ocular reflex (VOR). Considerable advances have been made in the pharmacotherapy of vertigo disorders during the last 10 years, including cortisone for the treatment of acute vestibular neuritis, betahistine as a high-dose long-term treatment for Menière's disease, carbamazepine to treat vestibular paroxysmia and aminopyridine for down- and upbeat nystagmus and episodic ataxia type 2.