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).

Addressing a real-life problem: treatment with intravenous thrombolysis and mechanical thrombectomy in acute stroke patients with an extended time window beyond 4.5 h based on computed tomography perfusion imaging.

BACKGROUND AND PURPOSE: Acute ischemic stroke treatment with intravenous thrombolysis (IVT) is restricted to a time window of 4.5 h after known or presumed onset. Recently, magnetic resonance imaging-guided treatment decision-making in wake-up stroke (WUS) was shown to be effective. The aim of this study was to determine the safety and outcome of IVT in patients with a time window beyond 4.5 h selected by computed tomography perfusion (CTP) imaging. METHODS: We analyzed all consecutive patients last seen well beyond 4.5 h after stroke onset treated with IVT based on CTP between January 2015 and October 2018. CTP was visually assessed to estimate the mismatch between cerebral blood flow and cerebral blood volume maps. Early infarct signs were documented according to Alberta Stroke Program Early CT Score (ASPECTS). Safety data were obtained for mortality and symptomatic intracerebral hemorrhage (sICH). Follow-up was assessed with the modified Rankin Scale (mRS). RESULTS: A total of 70 patients fulfilled the inclusion criteria (mean age ± SD 77.6 ± 11.5 years, 50.0% female). Median National Institutes of Health Stroke Scale score on admission was 8.0 [interquartile range (IQR), 4-14]. The most frequent reasons for an extended time window were WUS (60.0%) and delayed hospital admission (27.1%). Median time from last seen well to IVT was 11.4 h. Median ASPECTS was 10 (IQR, 9-10) and CTP mismatch 90% (IQR, 80%-100%). A total of 24 patients (34.3%) underwent additional mechanical thrombectomy. sICH occurred in four patients (5.7%). At follow-up, 49.3% had an mRS score of 0-2 and 22.4% had an mRS score of 0-1. CONCLUSIONS: In patients presenting in an extended time window beyond 4.5 h, IVT treatment with decision-making based on CTP might be a safe procedure. Further evaluation in clinical trials is needed.

[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).

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.

[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.

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.

[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.

Saccadic disinhibition in patients with acute and remitted schizophrenia and their first-degree biological relatives.

OBJECTIVE: Performance on measures of saccadic inhibition and control was investigated in a large family study of schizophrenia to evaluate the utility of using antisaccade task performance as an endophenotypic marker of genetic liability for schizophrenia. METHOD: Ninety-five patients with acute schizophrenia and 116 of their first-degree biological relatives, 13 schizophrenia patients whose illness was in full remission, 35 patients with acute psychotic affective disorder, and 109 nonpsychiatric comparison subjects were administered antisaccade and prosaccade tasks. RESULTS: Both schizophrenia patient groups had a greater number of errors on the antisaccade task than did the first-degree relatives and the affective disorder group, which both had more errors than the comparison subjects. Among the first-degree relatives of the probands with acute schizophrenia, relatives of poor-performing patients performed worse on the antisaccade task than relatives of patients with good performance. Reflexive errors were not likely the result of interfering psychotic symptoms, medication, or medication side effects. Although the schizophrenia patients demonstrated other signs of saccadic abnormalities, these problems, which were not observed in their relatives even though they had high antisaccade error rates, seem unlikely to account for the higher antisaccade error rate of the schizophrenia patients. CONCLUSIONS: These findings suggest that saccadic disinhibition is strongly associated with the genetic liability for schizophrenia.

Spinal afferents to functionally distinct periaqueductal gray columns in the rat: an anterograde and retrograde tracing study.

The segmental and laminar organization of spinal projections to the functionally distinct ventrolateral (vlPAG) and lateral periaqueductal gray (lPAG) columns was examined by using retrograde and anterograde tracing techniques. It was found 1) that spinal input to both vlPAG and lPAG columns arose predominantly from neurons in the upper cervical (C1-4) and sacral spinal cord; 2) that there was a topographical separation of vl-PAG projecting and lPAG-projecting neurons within the upper cervical spinal cord; but 3) that below spinal segment C4, vlPAG-projecting and lPAG-projecting spinal neurons were similarly distributed, predominantly within contralateral lamina I, the nucleus of the dorsolateral fasciculus (the lateral spinal nucleus) and the lateral (reticular) part of lamina V. Consistent with the retrograde results, the greatest density of anterograde label, within both the vlPAG and lPAG, was found after tracer injections made either in the superficial or deep dorsal horn of the upper cervical spinal cord. Tracer injections made within the thoraco-lumbar spinal cord revealed that the vlPAG column received a convergent input from both the superficial and deep dorsal horn. However, thoraco-lumbar input to the lPAG was found to arise uniquely from the superficial dorsal horn; whereas the deep dorsal horn was found to innervate the "juxta-aqueductal" PAG region rather than projecting to the lPAG. These findings suggest that similar to spino-parabrachial projections, spinal projections to the lPAG (and juxta-aqueductal PAG) are topographically organised, with distinct subgroups of spinal neurons projecting to specific lPAG or juxta-aqueductal PAG subregions. In contrast, the vlPAG receives a convergent spinal input which arises from the superficial and deep dorsal horn of cervical, thoracic, lumbar, and sacral spinal segments.

Topographic organization of spinal and trigeminal somatosensory pathways to the rat parabrachial and Kölliker-Fuse nuclei.

We examined the organization of somatosensory projections to the parabrachial (PB) and Kölliker-Fuse (KF) nuclei by employing the retrograde and anterograde axonal transport of Fluorogold and Phaseolus vulgaris-leucoagglutinin (PHA-L), respectively. Small PHA-L injections were made into different parts of the spinal trigeminal complex, including the paratrigeminal nucleus, and into different segments and laminae of the spinal dorsal horn. The subnuclear distribution of axonal labeling in the PB and KF was mapped with a camera lucida. Our results show that the somatosensory input to the PB and KF is highly organized. Neurons in the spinal trigeminal nuclei project predominantly to the KF and to the ventral portion of the external lateral PB. Neurons in the paratrigeminal nucleus project to the ventral lateral PB, the external medial PB, and to caudal aspects of the medial PB. These findings were supported by retrograde tracing experiments with Fluorogold. Spinal cord neurons located in the superficial dorsal horn (laminae I-II) of upper cervical segments project specifically to the ventral portion of the external lateral PB and, although more sparsely, to various other lateral PB nuclei. In contrast, neurons in the superficial dorsal horn of thoracic and lumbar spinal segments project mainly to the dorsal lateral and the central lateral PB. Finally, neurons in the lateral reticulated area and the lateral spinal nucleus of all spinal segments project almost exclusively to the internal lateral PB, whereas neurons in the respective nuclei of upper cervical segments also project to the KF. From our data we conclude that the somatosensory projections to the PB and KF are topographically organized. It is assumed that these pathways, which run from trigeminal and spinal neurons through the PB and KF to various forebrain, medullary, and spinal nuclei, form functionally different neural circuits that are involved in somatoautonomic processing.