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2.  Vestibular migraine: the most frequent entity of episodic vertigo 
Journal of Neurology  2016;263:82-89.
Vestibular migraine (VM) is the most common cause of episodic vertigo in adults as well as in children. The diagnostic criteria of the consensus document of the International Bárány Society for Neuro-Otology and the International Headache Society (2012) combine the typical signs and symptoms of migraine with the vestibular symptoms lasting 5 min to 72 h and exclusion criteria. Although VM accounts for 7 % of patients seen in dizziness clinics and 9 % of patients seen in headache clinics it is still underdiagnosed. This review provides an actual overview on the pathophysiology, the clinical characteristics to establish the diagnosis, the differential diagnosis, and the treatment of VM.
doi:10.1007/s00415-015-7905-2
PMCID: PMC4833782  PMID: 27083888
Vestibular migraine; Episodic vertigo; Migrainous vertigo; Dizziness; International Headache Society; Bárány Society; Review
3.  Vestibular assistance systems: promises and challenges 
Journal of Neurology  2016;263:30-35.
The handicap resulting from a bilateral vestibular deficit is often underestimated. In most cases the deficit settles gradually. Patients do not understand what is happening to them and have many difficulties to describe their symptoms. They have to consult several doctors with different medical specialties before diagnosis. Once the diagnosis is made there is no biological way to “repair” the deficient vestibular apparatus and vestibular exercises are mildly effective. Attempts have been made to help patients using substitution devices replacing the defective vestibular information by tactile or acoustic cues. Currently, efforts are being made towards the development of a vestibular implant, conceptually similar to the cochlear implant for the rehabilitation of deaf patients. In recent years, several experiments on animal models have demonstrated the feasibility of this project. This paper reports the steps accomplished in human experiments and the main results obtained in our laboratory.
doi:10.1007/s00415-015-7922-1
PMCID: PMC4833784  PMID: 27083882
Vertigo
4.  Vestibular paroxysmia: a treatable neurovascular cross-compression syndrome 
Journal of Neurology  2016;263:90-96.
The leading symptoms of vestibular paroxysmia (VP) are recurrent, spontaneous, short attacks of spinning or non-spinning vertigo that generally last less than one minute and occur in a series of up to 30 or more per day. VP may manifest when arteries in the cerebellar pontine angle cause a segmental, pressure-induced dysfunction of the eighth nerve. The symptoms are usually triggered by direct pulsatile compression with ephaptic discharges, less often by conduction blocks. MR imaging reveals the neurovascular compression of the eighth nerve (3D constructive interference in steady state and 3D time-of-flight sequences) in more than 95 % of cases. A loop of the anterior inferior cerebellar artery seems to be most often involved, less so the posterior inferior cerebellar artery, the vertebral artery, or a vein. The frequent attacks of vertigo respond to carbamazepine or oxcarbazepine, even in low dosages (200–600 mg/d or 300–900 mg/d, respectively), which have been shown to also be effective in children. Alternative drugs to try are lamotrigine, phenytoin, gabapentin, topiramate or baclofen or other non-antiepileptic drugs used in trigeminal neuralgia. The results of ongoing randomized placebo-controlled treatment studies, however, are not yet available. Surgical microvascular decompression of the eighth nerve is the “ultima ratio” for medically intractable cases or in exceptional cases of non-vascular compression of the eighth nerve by a tumor or cyst. The International Barany Society for Neuro-Otology is currently working on a consensus document on the clinical criteria for establishing a diagnosis of VP as a clinical entity.
doi:10.1007/s00415-015-7973-3
PMCID: PMC4833786  PMID: 27083889
Vestibular paroxysmia; Neurovascular cross-compression; Vestibular nerve; Episodic vertigo; Carbamazepine; Review
5.  Genetics of vestibular disorders: pathophysiological insights 
Journal of Neurology  2016;263:45-53.
The two most common vestibular disorders are motion sickness and vestibular migraine, affecting 30 and 1–2 % of the population respectively. Both are related to migraine and show a familial trend. Bilateral vestibular hypofunction is a rare condition, and some of patients also present cerebellar ataxia and neuropathy. We present recent advances in the genetics of vestibular disorders with familial aggregation. The clinical heterogeneity observed in different relatives of the same families suggests a variable penetrance and the interaction of several genes in each family. Some Mendelian sensorineural hearing loss also exhibits vestibular dysfunction, including DFNA9, DFNA11, DFNA15 and DFNA28. However, the most relevant finding during the past years is the familial clustering observed in Meniere’s disease. By using whole exome sequencing and combining bioinformatics tools, novel variants in DTNA and FAM136A genes have been identified in familial Meniere’s disease, and this genomic strategy will facilitate the discovery of the genetic basis of familial vestibular disorders.
doi:10.1007/s00415-015-7988-9
PMCID: PMC4833787  PMID: 27083884
Vestibular disorders; Whole exome sequencing; Vestibular migraine; Motion sickness; Meniere disease
6.  Current concepts and future approaches to vestibular rehabilitation 
Journal of Neurology  2016;263:65-70.
Over the last decades methods of vestibular rehabilitation to enhance adaptation to vestibular loss, habituation to changing sensory conditions, and sensory reweighting in the compensation process have been developed. However, the use of these techniques still depends to a large part on the educational background of the therapist. Individualized assessment of deficits and specific therapeutic programs for different disorders are sparse. Currently, vestibular rehabilitation is often used in an unspecific way in dizzy patients irrespective of the clinical findings. When predicting the future of vestibular rehabilitation, it is tempting to foretell advances in technology for assessment and treatment only, but the current intense exchange between clinicians and basic scientists also predicts advances in truly understanding the complex interactions between the peripheral senses and central adaptation mechanisms. More research is needed to develop reliable techniques to measure sensory dependence and to learn how this knowledge can be best used—by playing off the patient’s sensory strength or working on the weakness. To be able using the emerging concepts, the neuro-otological community must strive to educate physicians, physiotherapists and nurses to perform the correct examinations for assessment of individual deficits and to look for factors that might impede rehabilitation.
doi:10.1007/s00415-015-7914-1
PMCID: PMC4833789  PMID: 27083886
Adaptation; Habituation; Sensory reweighting; Vestibular rehabilitation
7.  What is Menière’s disease? A contemporary re-evaluation of endolymphatic hydrops 
Journal of Neurology  2016;263:71-81.
Menière’s disease is a chronic condition with a prevalence of 200–500 per 100,000 and characterized by episodic attacks of vertigo, fluctuating hearing loss, tinnitus, aural pressure and a progressive loss of audiovestibular functions. Over 150 years ago, Prosper Menière was the first to recognize the inner ear as the site of lesion for this clinical syndrome. Over 75 years ago, endolymphatic hydrops was discovered as the pathologic correlate of Menière’s disease. However, this pathologic finding could be ascertained only in post-mortem histologic studies. Due to this diagnostic dilemma and the variable manifestation of the various audiovestibular symptoms, diagnostic classification systems based on clinical findings have been repeatedly modified and have not been uniformly used in scientific publications on Menière’s disease. Furthermore, the higher level measures of impact on quality of life such as vitality and social participation have been neglected hitherto. Recent developments of high-resolution MR imaging of the inner ear have now enabled us to visualize in vivo endolymphatic hydrops in patients with suspected Menière’s disease. In this review, we summarize the existing knowledge from temporal bone histologic studies and from the emerging evidence on imaging-based evaluation of patients with suspected Menière’s disease. These indicate that endolymphatic hydrops is responsible not only for the full-blown clinical triad of simultaneous attacks of auditory and vestibular dysfunction, but also for other clinical presentations such as “vestibular” and “cochlear Menière’s disease”. As a consequence, we propose a new terminology which is based on symptomatic and imaging characteristics of these clinical entities to clarify and simplify their diagnostic classification.
doi:10.1007/s00415-015-7930-1
PMCID: PMC4833790  PMID: 27083887
Menière’s disease; Endolymphatic hydrops; Magnetic resonance imaging; Diagnosis; Classification
8.  DIZZYNET—a European network initiative for vertigo and balance research: visions and aims 
Journal of Neurology  2016;263:2-9.
Vertigo is one of the most common complaints in medicine. Despite its high prevalence, patients with vertigo often receive either inappropriate or inadequate treatment. The most important reasons for this deplorable situation are insufficient interdisciplinary cooperation, nonexistent standards in diagnostics and therapy, the relatively rare translations of basic science findings to clinical applications, and the scarcity of prospective controlled multicenter clinical trials. To overcome these problems, the German Center for Vertigo and Balance Disorders (DSGZ) started an initiative to establish a European Network for Vertigo and Balance Research called DIZZYNET. The central aim is to create a platform for collaboration and exchange among scientists, physicians, technicians, and physiotherapists in the fields of basic and translational research, clinical management, clinical trials, rehabilitation, and epidemiology. The network will also promote public awareness and help establish educational standards in the field. The DIZZYNET has the following objectives as regards structure and content: to focus on multidisciplinary translational research in vertigo and balance disorders,to develop interdisciplinary longitudinal and transversal networks for patient care by standardizing and personalizing the management of patients,to increase methodological competence by implementing common standards of practice and quality management,to internationalize the infrastructure for prospective multicenter clinical trials,to increase recruitment capacity for clinical trials,to create a common data base for patients with vertigo and balance disorders,to offer and promote attractive educational and career paths in a network of cooperating institutions.In the long term, the DIZZYNET should serve as an internationally visible network for interdisciplinary and multiprofessional research on vertigo and balance disorders. It ideally should equally attract the afflicted patients and those managing their disorders. DIZZYNET will not compete with the traditional national or international societies active in the field, but will function as an additional structure that addresses some of the above problems.
doi:10.1007/s00415-015-7912-3
PMCID: PMC4833796  PMID: 27083879
European Dizzynet; Vertigo; Dizziness; Balance disorders; Vestibular
9.  Vestibular animal models: contributions to understanding physiology and disease 
Journal of Neurology  2016;263:10-23.
Our knowledge of the vestibular sensory system, its functional significance for gaze and posture stabilization, and its capability to ensure accurate spatial orientation perception and spatial navigation has greatly benefitted from experimental approaches using a variety of vertebrate species. This review summarizes the attempts to establish the roles of semicircular canal and otolith endorgans in these functions followed by an overview of the most relevant fields of vestibular research including major findings that have advanced our understanding of how this system exerts its influence on reflexive and cognitive challenges encountered during daily life. In particular, we highlight the contributions of different animal models and the advantage of using a comparative research approach. Cross-species comparisons have established that the morpho-physiological properties underlying vestibular signal processing are evolutionarily inherent, thereby disclosing general principles. Based on the documented success of this approach, we suggest that future research employing a balanced spectrum of standard animal models such as fish/frog, mouse and primate will optimize our progress in understanding vestibular processing in health and disease. Moreover, we propose that this should be further supplemented by research employing more “exotic” species that offer unique experimental access and/or have specific vestibular adaptations due to unusual locomotor capabilities or lifestyles. Taken together this strategy will expedite our understanding of the basic principles underlying vestibular computations to reveal relevant translational aspects. Accordingly, studies employing animal models are indispensible and even mandatory for the development of new treatments, medication and technical aids (implants) for patients with vestibular pathologies.
doi:10.1007/s00415-015-7909-y
PMCID: PMC4833800  PMID: 27083880
Otolith organ; Semicircular canal; Sensory–motor processing; Motion perception; Gaze stabilization; Vestibulo-ocular reflex
10.  Vestibular compensation: the neuro-otologist’s best friend 
Journal of Neurology  2016;263:54-64.
Why vestibular compensation (VC) after an acute unilateral vestibular loss is the neuro-otologist’s best friend is the question at the heart of this paper. The different plasticity mechanisms underlying VC are first reviewed, and the authors present thereafter the dual concept of vestibulo-centric versus distributed learning processes to explain the compensation of deficits resulting from the static versus dynamic vestibular imbalance. The main challenges for the plastic events occurring in the vestibular nuclei (VN) during a post-lesion critical period are neural protection, structural reorganization and rebalance of VN activity on both sides. Data from animal models show that modulation of the ipsilesional VN activity by the contralateral drive substitutes for the normal push–pull mechanism. On the other hand, sensory and behavioural substitutions are the main mechanisms implicated in the recovery of the dynamic functions. These newly elaborated sensorimotor reorganizations are vicarious idiosyncratic strategies implicating the VN and multisensory brain regions. Imaging studies in unilateral vestibular loss patients show the implication of a large neuronal network (VN, commissural pathways, vestibulo-cerebellum, thalamus, temporoparietal cortex, hippocampus, somatosensory and visual cortical areas). Changes in gray matter volume in these multisensory brain regions are structural changes supporting the sensory substitution mechanisms of VC. Finally, the authors summarize the two ways to improve VC in humans (neuropharmacology and vestibular rehabilitation therapy), and they conclude that VC would follow a “top-down” strategy in patients with acute vestibular lesions. Future challenges to understand VC are proposed.
doi:10.1007/s00415-015-7903-4
PMCID: PMC4833803  PMID: 27083885
Unilateral vestibular loss; Vestibular compensation; Static deficits recovery; Dynamic deficits recovery; Animal models; Human brain imaging
11.  Health care utilization, prognosis and outcomes of vestibular disease in primary care settings: systematic review 
Journal of Neurology  2016;263:36-44.
Vertigo and dizziness are frequent complaints in primary care that lead to extensive health care utilization. The objective of this systematic review was to examine health care of patients with vertigo and dizziness in primary care settings. Specifically, we wanted to characterize health care utilization, therapeutic and referral behaviour and to examine the outcomes associated with this. A search of the MEDLINE and EMBASE databases was carried out in May 2015 using the search terms ‘vertigo’ or ‘dizziness’ or ‘vestibular and primary care’ to identify suitable studies. We included all studies that were published in the last 10 years in English with the primary diagnoses of vertigo, dizziness and/or vestibular disease. We excluded drug evaluation studies and reports of adverse drug reactions. Data were extracted and appraised by two independent reviewers; 16 studies with a total of 2828 patients were included. Mean age of patients ranged from 45 to 79 with five studies in older adults aged 65 or older. There were considerable variations in diagnostic criteria, referral and therapy while the included studies failed to show significant improvement of patient-reported outcomes. Studies are needed to investigate current practice of care across countries and health systems in a systematic way and to test primary care-based education and training interventions that improve outcomes.
doi:10.1007/s00415-015-7913-2
PMCID: PMC4833809  PMID: 27083883
Vertigo; Dizziness; Primary care; Epidemiology; Systematic review
12.  Update on the pharmacotherapy of cerebellar and central vestibular disorders 
Journal of Neurology  2016;263:24-29.
An overview of the current pharmacotherapy of central vestibular syndromes and the most common forms of central nystagmus as well as cerebellar disorders is given. 4-aminopyridine (4-AP) is recommended for the treatment of downbeat nystagmus, a frequent form of acquired persisting fixation nystagmus, and upbeat nystagmus. Animal studies showed that this non-selective blocker of voltage-gated potassium channels increases Purkinje cell excitability and normalizes the irregular firing rate, so that the inhibitory influence of the cerebellar cortex on vestibular and deep cerebellar nuclei is restored. The efficacy of 4-AP in episodic ataxia type 2, which is most often caused by mutations of the PQ-calcium channel, was demonstrated in a randomized controlled trial. It was also shown in an animal model (the tottering mouse) of episodic ataxia type 2. In a case series, chlorzoxazone, a non-selective activator of small-conductance calcium-activated potassium channels, was shown to reduce the DBN. The efficacy of acetyl-DL-leucine as a potential new symptomatic treatment for cerebellar diseases has been demonstrated in three case series. The ongoing randomized controlled trials on episodic ataxia type 2 (sustained-release form of 4-aminopyridine vs. acetazolamide vs. placebo; EAT2TREAT), vestibular migraine with metoprolol (PROVEMIG-trial), cerebellar gait disorders (sustained-release form of 4-aminopyridine vs. placebo; FACEG) and cerebellar ataxia (acetyl-DL-leucine vs. placebo; ALCAT) will provide new insights into the pharmacotherapy of cerebellar and central vestibular disorders.
doi:10.1007/s00415-015-7987-x
PMCID: PMC4833819  PMID: 27083881
Cerebellar ataxia; Central vestibular disorders; Vestibular migraine; Aminopyridines; Episodic ataxia type 2; Downbeat nystagmus
13.  [No title available] 
PMCID: PMC4826655  PMID: 27037802
14.  Status of diagnostic approaches to AQP4-IgG seronegative NMO and NMO/MS overlap syndromes 
Journal of neurology  2015;263(1):140-149.
Distinguishing aquaporin-4 IgG(AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD) from opticospinal predominant multiple sclerosis (MS) is a clinical challenge with important treatment implications. The objective of the study was to examine whether expert clinicians diagnose and treat NMO/MS overlapping patients in a similar way. 12 AQP4-IgG-negative patients were selected to cover the range of clinical scenarios encountered in an NMO clinic. 27 NMO and MS experts reviewed their clinical vignettes, including relevant imaging and laboratory tests. Diagnoses were categorized into four groups (NMO, MS, indeterminate, other) and management into three groups (MS drugs, immunosuppression, no treatment). The mean proportion of agreement for the diagnosis was low (po = 0.51) and ranged from 0.25 to 0.73 for individual patients. The majority opinion was divided between NMOSD versus: MS (nine cases), monophasic longitudinally extensive transverse myelitis (LETM) (1), acute disseminated encephalomyelitis (ADEM) (1) and recurrent isolated optic neuritis (RION) (1). Typical NMO features (e.g., LETM) influenced the diagnosis more than features more consistent with MS (e.g., short TM). Agreement on the treatment of patients was higher (po = 0.64) than that on the diagnosis with immunosuppression being the most common choice not only in patients with the diagnosis of NMO (98 %) but also in those indeterminate between NMO and MS (74 %). The diagnosis in AQP4-IgG-negative NMO/MS overlap syndromes is challenging and diverse. The classification of such patients currently requires new diagnostic categories, which incorporate lesser degrees of diagnostic confidence. Long-term follow-up may identify early features or biomarkers, which can more accurately distinguish the underlying disorder.
doi:10.1007/s00415-015-7952-8
PMCID: PMC4816597  PMID: 26530512
All demyelinating disease (CNS); Multiple sclerosis; Devic’s syndrome; Optic neuritis; Transverse myelitis
15.  [No title available] 
PMCID: PMC4826653  PMID: 26946499
16.  Key emerging issues in progressive supranuclear palsy and corticobasal degeneration 
Journal of neurology  2015;262(3):783-788.
It has been approximately 50 years since neurologists were introduced to the entities progressive supranuclear palsy and corticobasal degeneration. Since the two seminal publications, there have been significant advancements in our understanding of these two neurodegenerative diseases, particularly the fact that both are associated with tau. Recent advances over the past 3 years that are notable to the field are discussed in this review that covers clinical diagnosis, pathological features, neuroimaging and CSF biomarkers, genetic associations and clinical trials related to progressive supranuclear palsy and corticobasal degeneration.
doi:10.1007/s00415-015-7682-y
PMCID: PMC4372246  PMID: 25701010
PSP; corticobasal; tau; update; MRI; GWAS; Davunetide; longitudinal; Tideglusib; CSF
17.  Advances in biomarker research in multiple sclerosis 
Journal of Neurology  2016;263:621-623.
doi:10.1007/s00415-016-8062-y
PMCID: PMC4785207  PMID: 26914928
18.  [No title available] 
PMCID: PMC4826665  PMID: 26914922
19.  [No title available] 
PMCID: PMC4826660  PMID: 26886201
20.  New ways of looking at an old disease: the reimagination of epilepsy 
Journal of Neurology  2016;263:414-416.
doi:10.1007/s00415-016-8025-3
PMCID: PMC4751183  PMID: 26846914
21.  [No title available] 
PMCID: PMC4826658  PMID: 26810721
23.  An MRI-defined measure of cerebral lesion severity to assess therapeutic effects in multiple sclerosis 
Journal of Neurology  2016;263:531-538.
Assess the sensitivity of the Magnetic Resonance Disease Severity Scale (MRDSS), based on cerebral lesions and atrophy, for treatment monitoring of glatiramer acetate (GA) in relapsing-remitting multiple sclerosis (MS). This retrospective non-randomized pilot study included patients who started daily GA [n = 23, age (median, range) 41 (26.2, 53.1) years, Expanded Disability Status Scale (EDSS) score 1.0 (0, 3.5)], or received no disease-modifying therapy (noDMT) [n = 21, age 44.8 (28.2, 55.4), EDSS 0 (0, 2.5)] for 2 years. MRDSS was the sum of z-scores (normalized to a reference sample) of T2 hyperintense lesion volume (T2LV), the ratio of T1 hypointense LV to T2LV (T1/T2), and brain parenchymal fraction (BPF) multiplied by negative 1. The two groups were compared by Wilcoxon rank sum tests; within group change was assessed by Wilcoxon signed rank tests. Glatiramer acetate subjects had less progression than noDMT on T1/T2 [(median z-score change (range), 0 (−1.07, 1.20) vs. 0.41 (−0.30, 2.51), p = 0.003)] and MRDSS [0.01 (−1.33, 1.28) vs. 0.46 (−1.57, 2.46), p = 0.01]; however, not on BPF [0.12 (−0.18, 0.58) vs. 0.10 (−1.47,0.50), p = 0.59] and T2LV [−0.03 (−0.90, 0.57) vs. 0.01 (−1.69, 0.34), p = 0.40]. While GA subjects worsened only on BPF [0.12 (−0.18, 0.58), p = 0.001], noDMT worsened on BPF [0.10 (−1.47, 0.50), p = 0.002], T1/T2 [0.41 (−0.30, 2.51), p = 0.0002], and MRDSS [0.46 (−1.57, 2.46), p = 0.0006]. These preliminary findings show the potential of two new cerebral MRI metrics to track MS therapeutic response. The T1/T2, an index of the destructive potential of lesions, may provide particular sensitivity to treatment effects.
doi:10.1007/s00415-015-8009-8
PMCID: PMC4785194  PMID: 26754005
MRI; Multiple sclerosis; Glatiramer acetate; Brain atrophy; Composite scale
24.  CGRP and migraine 
Journal of Neurology  2016;263:192-194.
doi:10.1007/s00415-015-8000-4
PMCID: PMC4723620  PMID: 26747058
25.  Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p 
Journal of neurology  2010;258(4):647-655.
Families with autosomal dominant frontotemporal dementia and amyotrophic lateral sclerosis (FTD/ALS) have previously been linked to a locus on chromosome 9p21. We describe the clinical phenotype and pathology of a large family with autosomal dominant FTD/ALS with nine affected members originating from Gwent in South Wales, UK. We also further refine the locus on chromosome 9p21 using a haplotype sharing approach and assess heterogeneity in 9p21 linked families. Within this family, affected individuals present with either FTD or ALS or both diseases simultaneously. In addition there was marked phenotypic variation including ataxia, Parkinsonism, psychosis and visuo-spatial cognitive deficits. The pathological features of the three cases described were consistent with type 2 FTD pathology, as previously reported in similar families. However, we also report distinctive cerebellar and glial pathology and a significant proportion of TDP-43 negative inclusions. No mutations in known genes for FTD or ALS were found. We identified a large 4.8-megabase haplotype on chromosome 9p21, which was shared by all affected family members. This haplotype overlaps and limits the previously reported FTD/ALS linkage region on chromosome 9p21. Sequencing of this region did not identify any evidence of a pathogenic exonic mutation. This suggests that the pathogenic change affects non-coding DNA and that the disease is caused by variation in gene or protein expression.
doi:10.1007/s00415-010-5815-x
PMCID: PMC4696389  PMID: 21072532
Frontotemporal dementia; Amyotrophic lateral sclerosis; Mendelian; Chromosome 9

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