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Byline: M. Strupp (1), T. Brandt (1), A. Muller (2) Keywords: Key words Post-lumbar puncture syndrome; Post-lumbar puncture headache; 'Sprotte's atraumatic; needle'; Stylet Abstract: The post-lumbar puncture syndrome (PLPS) can best be explained by prolonged spinal fluid leakage owing to delayed closure of a dural defect. Its incidence after spinal anaesthesia is much lower than after diagnostic lumbar puncture (LP). This difference could be caused by a strand of arachnoid, which might enter the needle with the outflowing cerebrospinal fluid (CSF) during diagnostic LP and upon removal of the needle be threaded back through the dura to produce prolonged CSF leakage. To find a technique that further reduces the incidence of PLPS, this hypothesis was tested by evaluating the effect that reinserting the stylet before removing the needle had on the incidence of PLPS. By reinserting the stylet to the tip of the needle, the hypothesized strand would be pushed out, thereby reducing the frequency of PLPS. Sprotte's 'atraumatic needle' (21 gauge) was used for LP. A total of 600 patients participated in the prospective study. They were randomized into two groups and questioned about their complaints every day for up to 7 days after the LP. All LPs were performed by two experienced neurologists (T.B., M.S.). In 300 patients, the stylet was reinserted to the tip of the needle in the other 300 it was not reinserted. Whereas 49 of the 300 patients without reinsertion developed PLPS, only 15 of the 300 patients with reinsertion did. This significant difference (16.3 vs 5.0%, P &lt 0.005, chi square test) supports our hypothesis. On the basis of our results, we recommend reinserting the stylet before removing the needle in order to reduce the incidence of PLPS. Author Affiliation: (1) Department of Neurology, Ludwig-Maximilians University of Munich, Klinikum Grosshadern, Marchioninistrasse 15, D-81366 Munich, Germany e-mail: mstrupp@nefo.med.uni-muenchen.de Tel.: +49-89-7095-2571 Fax: +49-89-7095-8883, DE (2) Department of Neurosurgery, University of Munich, Klinikum Grosshadern, Munich, Germany, DE Article note: Received: 30 September 1997 Received in revised form: 9 March 1998 Accepted: 20 March 1998

The aim of this consensus paper is to discuss the roles of the cerebellum in human gait, as well as its assessment and therapy. Cerebellar vermis is critical for postural control. The cerebellum ensures the mapping of sensory information into temporally relevant motor commands. Mental imagery of gait involves intrinsically connected fronto-parietal networks comprising the cerebellum. Muscular activities in cerebellar patients show impaired timing of discharges, affecting the patterning of the synergies subserving locomotion. Ataxia of stance/gait is amongst the first cerebellar deficits in cerebellar disorders such as degenerative ataxias and is a disabling symptom with a high risk of falls. Prolonged discharges and increased muscle coactivation may be related to compensatory mechanisms and enhanced body sway, respectively. Essential tremor is frequently associated with mild gait ataxia. There is growing evidence for an important role of the cerebellar cortex in the pathogenesis of essential tremor. In multiple sclerosis, balance and gait are affected due to cerebellar and spinal cord involvement, as a result of disseminated demyelination and neurodegeneration impairing proprioception. In orthostatic tremor, patients often show mild-to-moderate limb and gait ataxia. The tremor generator is likely located in the posterior fossa. Tandem gait is impaired in the early stages of cerebellar disorders and may be particularly useful in the evaluation of pre-ataxic stages of progressive ataxias. Impaired inter-joint coordination and enhanced variability of gait temporal and kinetic parameters can be grasped by wearable devices such as accelerometers. Kinect is a promising low cost technology to obtain reliable measurements and remote assessments of gait. Deep learning methods are being developed in order to help clinicians in the diagnosis and decision-making process. Locomotor adaptation is impaired in cerebellar patients. Coordinative training aims to improve the coordinative strategy and foot placements across strides, cerebellar patients benefiting from intense rehabilitation therapies. Robotic training is a promising approach to complement conventional rehabilitation and neuromodulation of the cerebellum. Wearable dynamic orthoses represent a potential aid to assist gait. The panel of experts agree that the understanding of the cerebellar contribution to gait control will lead to a better management of cerebellar ataxias in general and will likely contribute to use gait parameters as robust biomarkers of future clinical trials., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Spinocerebellar ataxias (SCAs) represent a large group of hereditary degenerative diseases of the nervous system, in particular the cerebellum, and other systems that manifest with a variety of progressive motor, cognitive, and behavioral deficits with the leading symptom of cerebellar ataxia. SCAs often lead to severe impairments of the patient's functioning, quality of life, and life expectancy. For SCAs, there are no proven effective pharmacotherapies that improve the symptoms or substantially delay disease progress, i.e., disease-modifying therapies. To study SCA pathogenesis and potential therapies, animal models have been widely used and are an essential part of pre-clinical research. They mainly include mice, but also other vertebrates and invertebrates. Each animal model has its strengths and weaknesses arising from model animal species, type of genetic manipulation, and similarity to human diseases. The types of murine and non-murine models of SCAs, their contribution to the investigation of SCA pathogenesis, pathological phenotype, and therapeutic approaches including their advantages and disadvantages are reviewed in this paper. There is a consensus among the panel of experts that (1) animal models represent valuable tools to improve our understanding of SCAs and discover and assess novel therapies for this group of neurological disorders characterized by diverse mechanisms and differential degenerative progressions, (2) thorough phenotypic assessment of individual animal models is required for studies addressing therapeutic approaches, (3) comparative studies are needed to bring pre-clinical research closer to clinical trials, and (4) mouse models complement cellular and invertebrate models which remain limited in terms of clinical translation for complex neurological disorders such as SCAs., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The virtual practice has made major advances in the way that we care for patients in the modern era. The culture of virtual practice, consulting, and telemedicine, which had started several years ago, took an accelerated leap as humankind was challenged by the novel coronavirus pandemic (COVID19). The social distancing measures and lockdowns imposed in many countries left medical care providers with limited options in evaluating ambulatory patients, pushing the rapid transition to assessments via virtual platforms. In this novel arena of medical practice, which may form new norms beyond the current pandemic crisis, we found it critical to define guidelines on the recommended practice in neurotology, including remote methods in examining the vestibular and eye movement function. The proposed remote examination methods aim to reliably diagnose acute and subacute diseases of the inner-ear, brainstem, and the cerebellum. A key aim was to triage patients into those requiring urgent emergency room assessment versus non-urgent but expedited outpatient management. Physicians who had expertise in managing patients with vestibular disorders were invited to participate in the taskforce. The focus was on two topics: (1) an adequate eye movement and vestibular examination strategy using virtual platforms and (2) a decision pathway providing guidance about which patient should seek urgent medical care and which patient should have non-urgent but expedited outpatient management.

The current worldwide severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic that causes coronavirus disease 2019 (COVID-19) has brought some medical systems to the brink of collapse. This crisis is also negatively impacting the care of patients with non-COVID-19 conditions, including those with cerebellar ataxia (CA). Older patients with CA and those with immune-mediated ataxias on immunosuppressive medication are potentially at high risk of developing serious complications of the infection, although it is also possible that immunosuppressive agents may provide a defense against cytokine storm. This has implications for even greater attention to preventing contracting the disease through physical distancing and/or isolation. The CA patient population is also at higher risk because of the neurological complexities of their underlying disorder and the comorbid medical illnesses that often accompany the genetic ataxias. As the disruption of social patterns and healthcare delivery in response to the crisis continues, interruption of rehabilitation, speech and language therapy, and face-to-face consultations threatens to have a negative impact on the course and well-being of CA patients. Mental and physical health is also potentially at greater risk because the prevailing uncertainty and anxiety may be superimposed upon cerebellum-specific neuropsychological challenges. We identify and review some of the short- and long-term consequences of this global pandemic for the community of ataxia patients and their families and for the clinical and academic neurologists/ataxiologists caring for these patients. This includes the recognition that telemedicine has emerged as a principle means of caregiver-patient contact and that neurological manifestations of COVID-19 including those specific to cerebellar neurobiology are increasingly recognized and will require close surveillance and monitoring. This COVID-19 Cerebellum Task Force consensus provides some guidance on how we may approach this uncertain time and consider preparing for the new realities we face in CA patient care once this acute crisis has passed.

Downbeat nystagmus (DBN) is a frequent form of acquired persisting central fixation nystagmus, often associated with other cerebellar ocular signs, such as saccadic smooth pursuit or gaze-holding deficits. Despite its distinct clinical features, the underlying etiology of DBN often remains unclear. Therefore, a genome-wide association study (GWAS) was conducted in 106 patients and 2609 healthy controls of European ancestry to identify genetic variants associated with DBN. A genome-wide significant association (p < 5 × 10 -8 ) with DBN was found for a variation on chromosome 13 located within the fibroblast growth factor 14 gene (FGF14). FGF14 is expressed in Purkinje cells (PCs) and a reduction leads to a decreased spontaneous firing rate and excitability of PCs, compatible with the pathophysiology of DBN. In addition, mutations in the FGF14 gene cause spinocerebellar ataxia type 27. Suggestive associations (p < 1 × 10 -05 ) could be detected for 15 additional LD-independent loci, one of which is also located in the FGF14 gene. An association of a region containing the dihydrofolate reductase (DHFR) and MutS Homolog 3 (MSH3) genes on chromosome 5 was slightly below the genome-wide significance threshold. DHFR is relevant for neuronal regulation, and a dysfunction is known to induce cerebellar damage. Among the remaining twelve suggestive associations, four genes (MAST4, TPPP, FTMT, and IDS) seem to be involved in cerebral pathological processes. Thus, this GWAS analysis has identified a potential genetic contribution to idiopathic DBN, including suggestive associations to several genes involved in postulated pathological mechanisms of DBN (i.e., impaired function of cerebellar PCs).

The differential diagnosis of vertigo or dizziness as a result of cerebellar disorders can be difficult as many patients with a cerebellar pathology do not present with the full spectrum of cerebellar signs. The main goal of this study was to describe the typical clinical features of these patients with vertigo or dizziness of a cerebellar origin. We reviewed the medical records of 5400 patients with vertigo and dizziness from our tertiary outpatient clinic for vertigo and balance disorders. In 459 the diagnosis of "cerebellar vertigo or dizziness" was made; 90 patients were excluded from further analysis due to evident structural changes in MRI. Of the remaining 369 patients (67.0 ± 15.1, 54% female, symptom duration until diagnosis 5.5 ± 6.9 years), 81% suffered from persistent vertigo or dizziness, 31% from attacks of vertigo and dizziness and 21% from both. Neuro-ophthalmologically, 95% had saccadic smooth pursuit, 80% gaze-holding deficits, 64% a pathological fixation suppression of the VOR, 24% central fixation nystagmus (in 64% of these cases downbeat nystagmus (DBN)), 23% rebound nystagmus, and an ocular misalignment in 84% in near view and 50% in distance view. Eleven percent had isolated mild to moderate cerebellar ocular motor disturbances without any other typical cerebellar signs. The most common diagnoses were sporadic adult-onset degenerative ataxia in 26%; idiopathic DBN syndrome in 20%; cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in 10%; episodic ataxia type 2 in 7%; and multiple system atrophy cerebellar type in 6%. In posturography, a typical cerebellar 3-Hz sway was found in 16%. The diagnostic key to patients with cerebellar vertigo or dizziness is a careful examination of eye movements since practically all of them have cerebellar ocular disturbances.

The world's population is ageing due to increased hygiene and improved medical care. Dizziness and imbalance frequently affect the elderly and is most common among individuals over the age of 60. In this age group approximately 30% of the population experience these debilitating symptoms at some point. They contribute to falls and frailty, which often result in hospitalization causing tremendous cost for the health care systems, and increased mortality. To make the matters worse balance disorders are often complex. Physicians face the difficulty of diagnosing the patient with the exact disorder especially since each disorder may manifest differently in each patient. In addition, several treatment options exist, however, with a low level of evidence. This chapter summarizes the underlying degenerative processes of the peripheral as well as the central vestibular system, diagnostic tools, the most common balance disorders in the elderly, and possible treatment options of these disorders.

The cerebellum is involved in sensorimotor operations, cognitive tasks and affective processes. Here, we revisit the concept of the cerebellar syndrome in the light of recent advances in our understanding of cerebellar operations. The key symptoms and signs of cerebellar dysfunction, often grouped under the generic term of ataxia, are discussed. Vertigo, dizziness, and imbalance are associated with lesions of the vestibulo-cerebellar, vestibulo-spinal, or cerebellar ocular motor systems. The cerebellum plays a major role in the online to long-term control of eye movements (control of calibration, reduction of eye instability, maintenance of ocular alignment). Ocular instability, nystagmus, saccadic intrusions, impaired smooth pursuit, impaired vestibulo-ocular reflex (VOR), and ocular misalignment are at the core of oculomotor cerebellar deficits. As a motor speech disorder, ataxic dysarthria is highly suggestive of cerebellar pathology. Regarding motor control of limbs, hypotonia, a- or dysdiadochokinesia, dysmetria, grasping deficits and various tremor phenomenologies are observed in cerebellar disorders to varying degrees. There is clear evidence that the cerebellum participates in force perception and proprioceptive sense during active movements. Gait is staggering with a wide base, and tandem gait is very often impaired in cerebellar disorders. In terms of cognitive and affective operations, impairments are found in executive functions, visual-spatial processing, linguistic function, and affective regulation (Schmahmann's syndrome). Nonmotor linguistic deficits including disruption of articulatory and graphomotor planning, language dynamics, verbal fluency, phonological, and semantic word retrieval, expressive and receptive syntax, and various aspects of reading and writing may be impaired after cerebellar damage. The cerebellum is organized into (a) a primary sensorimotor region in the anterior lobe and adjacent part of lobule VI, (b) a second sensorimotor region in lobule VIII, and (c) cognitive and limbic regions located in the posterior lobe (lobule VI, lobule VIIA which includes crus I and crus II, and lobule VIIB). The limbic cerebellum is mainly represented in the posterior vermis. The cortico-ponto-cerebellar and cerebello-thalamo-cortical loops establish close functional connections between the cerebellum and the supratentorial motor, paralimbic and association cortices, and cerebellar symptoms are associated with a disruption of these loops.

Pharmacological treatment of cerebellar ataxias and cerebellar nystagmus still remains difficult. The efficacy of most of the agents recommended in the past for symptomatic or even causative therapy could not be proven in larger state-of-the art clinical trials. Exceptions are (a) 4-aminopyridine (4-AP) for episodic ataxia type 2 (EA2): one observational and one randomized controlled trial showed a significant effect on the number of attacks of ataxia and quality of life; (b) aminopyridines in cerebellar downbeat nystagmus (DBN): two randomized controlled trials and several observational studies demonstrate a significant improvement of the intensity of DBN, visual acuity, and postural imbalance. In both diseases the sustained-release form is evidently also efficient; (c) 4-AP in cerebellar gait ataxia: evidence comes from two observational studies. (d) chlorzoxazone in DBN which, however, was so far demonstrated in only one observational study; (e) the modified amino acid acetyl-DL-leucine: evidently effective in cerebellar ataxias, shown in three observational studies, one on patients with Niemann-Pick type C; its mode of action has to be evaluated in animal models and on a cellular/electrophysiological level. There are ongoing randomized placebo-controlled trials on EA2 with 4-AP versus acetazolamide (EAT-2-TREAT), cerebellar gait ataxia with 4-AP (FACEG), and a multinational trial on cerebellar ataxia with acetyl-DL-leucine (ALCAT).

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.

Varicella-zoster virus (VZV) causes chickenpox, establishes latency in trigeminal (TG) and dorsal root ganglia (DRG), and can lead to herpes zoster upon reactivation. The VZV proteome expressed during latency remains ill-defined, and previous studies have shown discordant data on the spectrum and expression pattern of VZV proteins and transcripts in latently infected human ganglia. Recently, Zerboni and colleagues have provided new insight into this discrepancy (Zerboni et al. in J Virol 86:578-583, 2012). They showed that VZV-specific ascites-derived monoclonal antibody (mAb) preparations contain endogenous antibodies directed against blood group A1 proteins, resulting in false-positive intra-neuronal VZV staining in formalin-fixed human DRG. The aim of the present study was to confirm and extend this phenomenon to snap-frozen TG (n=30) and DRG (n=9) specimens of blood group genotyped donors (n=30). The number of immunohistochemically stained neurons was higher with mAb directed to immediate early protein 62 (IE62) compared with IE63. The IE63 mAb-positive neurons always co-stained for IE62 but not vice versa. The mAb staining was confined to distinct large intra-neuronal vacuoles and restricted to A1(POS) donors. Anti-VZV mAb staining in neurons, but not in VZV-infected cell monolayers, was obliterated after mAb adsorption against blood group A1 erythrocytes. The data presented demonstrate that neuronal VZV protein expression detected by ascites-derived mAb in snap-frozen TG and DRG of blood group A1(POS) donors can be misinterpreted due to the presence of endogenous antibodies directed against blood group A1-associated antigens present in ascites-derived VZV-specific mAb preparations.

Human herpesvirus 6 (HHV-6) persists in the central nervous system, but its prevalence in the peripheral nervous system, a preferred latency site for herpesviruses, has not been studied. Using nested polymerase chain reaction (PCR), the authors determined the distribution of HHV-6 in human sensory ganglia. HHV-6 was present in 30% of trigeminal, 40% of geniculate, 25% of vestibular, and 55% of dorsal root ganglia. It co-occurred with alpha-herpesviruses (herpes simplex virus type 1 or varicella-zoster virus) in 91% of the ganglia. As HHV-6 positivity did not depend on the presence of inflammatory cells, known to harbor the virus, HHV-6 probably resides in the ganglia themselves.

Episodic ataxia type 2 (EA 2) is a rare neurological disorder of autosomal dominant inheritance resulting from dysfunction of a voltage-gated calcium channel. It manifests with recurrent disabling attacks of imbalance, vertigo, and ataxia, and can be provoked by physical exertion or emotional stress. In the spell-free interval, patients present with central ocular motor dysfunction, mainly downbeat nystagmus. A slow progression of cerebellar signs accompanied by a slight atrophy of midline cerebellar structures is commonly observed during the course of the disease. EA 2 is caused most often by the loss of function mutations of the calcium channel gene CACNA1A, which encodes the Ca(v)2.1 subunit of the P/Q-type calcium channel and is primarily expressed in Purkinje cells. To date, more than 30 mutations have been described. Two effective treatment options have been established for EA 2: acetazolamide (ACTZ), which probably changes the intracellular pH and thereby the transmembraneous potential, and 4-aminopyridine (4-AP), a potassium channel blocker. Approximately 70% of all patients respond to treatment with ACTZ, but the effect is often only transient. In an open trial, 4-AP prevented attacks in five of six patients with EA 2, most likely by increasing the resting activity and excitability of the Purkinje cells. These findings were confirmed by experiments in animal models of EA 2. Many aspects of the pathophysiology (e.g., induction of the attacks) and treatment of EA 2 (e.g., mode of action of ACTZ and 4-AP) still remain unclear and need to be addressed in further animal and clinical studies.

Vertigo follows headache as the second most common key symptom--not only in neurology and ENT medicine. Careful history-taking and a physical examination are sufficient for a correct diagnostic classification of most vertigo syndromes. In most cases, the etiology is benign, the course favorable, and treatment successful. In this brief overview, the clinical presentation and treatment of the most common peripheral and central vertigo syndromes are described, and the characteristics and treatment of the--to date too rarely diagnosed--subjective vertigo are described.

In isolated rat hearts perfused according to the Langendorff technique lactate and glucose concentrations were determined in the interstitial transudate and the venous effluent before, during and after periods of 15 or 30 min anoxia. The interstitial transudate emerged at the surface of the heart as a result of albumin-free perfusion. During normoxic perfusion the interstitial lactate concentration was 0.144 +/- 0.025 mmol/l (n = 6); the venous lactate concentration was 0.033 +/- 0.005 mmol/l. From the interstitial and the mean vascular concentration, together with the lactate release and the glucose uptake, the apparent permeability surface area products (P.S product) were calculated using Fick's law. The apparent P.S products for lactate and glucose were 4.6 and 3.9 ml/(min x g), respectively. During anoxia we measured a four- to sixfold increase of the interstitial lactate concentration. At the end of the anoxic periods the apparent P.S product was two- to threefold higher than during normoxia; the apparent glucose P.S product increased about fourfold. After 15 min anoxia the increases of permeability were completely reversed in the reoxygenation period. However, after a period of 30 min anoxia the apparent P.S products for lactate and glucose remained raised, which means that there was a prolonged or even irreversible increase of capillary permeability. Besides the marked transcapillary concentration difference for lactate, these data show prolonged functional alteration of the capillary wall after 30 min anoxia.

The effects of glutathione were studied on the gating behaviour of sodium channels in membrane patches of rat axons. Depolarizing pulses from -120 to -40 mV elicited sodium currents of up to 500 pA, indicating the simultaneous activation of up to 250 sodium channels. Inactivation of these channels in the excised, inside-out configuration was fitted by two time constants (tau h1 = 0.81 ms; tau h2 = 5.03 ms) and open time histograms at 0 mV revealed a biexponential distribution of channel openings (tau short = 0.28 ms; tau long = 3.68 ms). Both, the slow time constant of inactivation and the long lasting single channel openings disappeared after addition of the reducing agent glutathione (2-5 mM) to the bathing solution. Sodium channels of excised patches with glutathione present on the cytoplasmatic face of the membrane had inactivation kinetics similar to channels recorded in the cell-attached configuration. These observations indicate that redox processes may contribute to the gating of axonal sodium channels.