GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort.

BACKGROUND: GAA-FGF14 disease/spinocerebellar ataxia 27B is a recently described neurodegenerative disease caused by (GAA)≥250 expansions in the fibroblast growth factor 14 (FGF14) gene, but its phenotypic spectrum, pathogenic threshold, and evidence-based treatability remain to be established. We report on the frequency of FGF14 (GAA)≥250 and (GAA)200-249 expansions in a large cohort of patients with idiopathic downbeat nystagmus (DBN) and their response to 4-aminopyridine. METHODS: Retrospective cohort study of 170 patients with idiopathic DBN, comprising in-depth phenotyping and assessment of 4-aminopyridine treatment response, including re-analysis of placebo-controlled video-oculography treatment response data from a previous randomised double-blind 4-aminopyridine trial. FINDINGS: Frequency of FGF14 (GAA)≥250 expansions was 48% (82/170) in patients with idiopathic DBN. Additional cerebellar ocular motor signs were observed in 100% (82/82) and cerebellar ataxia in 43% (35/82) of patients carrying an FGF14 (GAA)≥250 expansion. FGF14 (GAA)200-249 alleles were enriched in patients with DBN (12%; 20/170) compared to controls (0.87%; 19/2191; OR, 15.20; 95% CI, 7.52-30.80; p < 0.0001). The phenotype of patients carrying a (GAA)200-249 allele closely mirrored that of patients carrying a (GAA)≥250 allele. Patients carrying a (GAA)≥250 or a (GAA)200-249 allele had a significantly greater clinician-reported (80%, 33/41 vs 31%, 5/16; RR, 2.58; 95% CI, 1.23-5.41; Fisher's exact test, p = 0.0011) and self-reported (59%, 32/54 vs 11%, 2/19; RR, 5.63; 95% CI, 1.49-21.27; Fisher's exact test, p = 0.00033) response to 4-aminopyridine treatment compared to patients carrying a (GAA)<200 allele. Placebo-controlled video-oculography data, available for four patients carrying an FGF14 (GAA)≥250 expansion, showed a significant decrease in slow phase velocity of DBN with 4-aminopyridine, but not placebo. INTERPRETATION: This study confirms that FGF14 GAA expansions are a frequent cause of DBN syndromes. It provides preliminary evidence that (GAA)200-249 alleles might be pathogenic. Finally, it provides large real-world and preliminary piloting placebo-controlled evidence for the efficacy of 4-aminopyridine in GAA-FGF14 disease. FUNDING: This work was supported by the Clinician Scientist program "PRECISE.net" funded by the Else Kröner-Fresenius-Stiftung (to CW, AT, and MSy), the grant 779257 "Solve-RD" from the European's Union Horizon 2020 research and innovation program (to MSy), and the grant 01EO 1401 by the German Federal Ministry of Education and Research (BMBF) (to MSt). This work was also supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) N° 441409627, as part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP N° 825575 (to MSy, BB and-as associated partner-SZ), the NIH National Institute of Neurological Disorders and Stroke (grant 2R01NS072248-11A1 to SZ), the Fondation Groupe Monaco (to BB), and the Montreal General Hospital Foundation (grant PT79418 to BB). The Care4Rare Canada Consortium is funded in part by Genome Canada and the Ontario Genomics Institute (OGI-147 to KMB), the Canadian Institutes of Health Research (CIHR GP1-155867 to KMB), Ontario Research Foundation, Genome Quebec, and the Children's Hospital of Eastern Ontario Foundation. The funders had no role in the conduct of this study.

Skull-vibration-induced nystagmus test in patients who are candidates for intratympanic gentamicin injection.

Objective: This study aims to evaluate the utility of the skull-vibration-induced nystagmus test (SVINT) in the selection of patients with Ménière's disease (MD) for intratympanic injection of gentamicin. To date the indications for this treatment have been based only on subjective elements. Methods: A retrospective study was performed in 20 patients diagnosed with unilateral MD. SVINT were performed monthly and the evoked responses were evaluated. After 6 months, the results from patients who were candidates for gentamicin treatment (G group) were compared with those who did not need it (nG group). Correlation with Dizziness Handicap Inventory (DHI) score was evaluated. Results: 120 tests were performed. Positive SVINTs were identified in 52 cases (43.3%) and included excitatory nystagmus in 18 (34.7%), inhibitory nystagmus in 28 (53.8%), and atypical pattern in 6 cases (11.5%). A significant increase excitatory nystagmus was recorded in group G (p = 0.00001). Moreover, there was a significant increase in the DHI score in group G compared with the nG group (p < 0.0001) and in patients with evoked excitatory nystagmus. Conclusions: The finding of excitatory nystagmus during SVINTs performed on several occasions in the follow-up prior to intratympanic injection of gentamicin strengthens this therapeutic choice.

Downbeat Nystagmus and Bilateral Sudden Hearing Loss by Suicidal Aspirin Intoxication.

Ototoxic side effects such as sensorineural hearing loss and tinnitus can be caused by acute salicylate intoxication. Bilateral symmetric sensori- neural hearing loss involving all tested frequencies is a typical pattern of hearing loss in acute salicylate intoxication, which usually resolves within 2 or 3 days without any specific treatment for ototoxicity. Herein, we report a case of suicidal aspirin intoxication resulting in sudden bilateral hearing loss and vertigo. The patient exhibited spontaneous downbeat nystagmus, and the mechanism underlying this characteristic nystagmus is discussed.

Lessons of the month 2: A case of inappropriate drug-drug interaction in kidney transplant.

Carbamazepine remains a first-line antiepileptic medication for the treatment of partial seizures. Despite its widespread use, carbamazepine has significant neurotoxicity and hypersensitivity reactions. We report a case of a patient post-kidney transplant who was on regular carbamazepine for childhood epilepsy and developed nystagmus, diplopia and a broad-base gait after receiving diltiazem. Understanding of the interaction between diltiazem and carbamazepine is necessary to prevent the neurotoxic effects.

Vestibular Disorders after Kidney Transplantation: Focus on the Pathophysiological Mechanisms Underlying the Vertical Nystagmus Associated with Tacrolimus-Related Hypomagnesamia.

The purpose of this paper is to present the case of a patient undergoing kidney transplantation who developed limb tremor dizziness and vertical nystagmus (ny) during Tacrolimus (TAC) therapy and to investigate the pathophysiological mechanisms underlying the balance disorder. This case study regards a 51-year old kidney transplant male patient with hand tremors and lower limbs asthenia associated with dizziness and nausea. The symptoms started two months after the beginning of intravenous TAC for renal transplantation. The pure-tone audiometry showed a mild symmetrical high-frequencies down-sloping sensorineural hearing loss. Acoustic emittance measures showed a normal tympanogram; stapedial reflexes were normally elicited. The Auditory Brainstem Responses (ABR) and Cervical Vestibular Evoked Myogenic Potentials (c-VEMPs) were bilaterally normally evoked. The bedside vestibular examination showed spontaneous down-beating stationary persistent, omni-positional nystagmus, not inhibited by fixation. The Head-Shaking Test accentuates the spontaneous ny. The horizontal clinical head impulse test was negative, bilaterally. A biochemical blood test revealed a decrease in Magnesium (Mg) levels (0.8 mg/dL; normal range 1.58-2.55). The integration of Mg induced both a plasma levels normalization and an improvement of clinical symptoms. This case suggests that TAC treatment can induce a Mg depletion that caused the transient cerebellar lesion. Therefore, the monitoring of serum electrolytes during immunosuppressive treatment appears to be a useful tool in order to reduce the central system symptomatology.

Central nystagmus and alterations in vestibular tests due to an inadvertent gentamicin administration into spinal space: A CARE case report.

INTRODUCTION: Gentamicin has a well-known potential for damaging the peripheral vestibular organs. However, it is considered to be innocuous to the CNS as it crosses the blood-brain barrier poorly. Here, we describe central neuro-otological abnormalities developed by a patient after deployment of gentamicin into his spinal space. CASE SUMMARY: A 61-year-old male unintentionally received gentamicin during spinal locoregional anesthesia for a urological procedure. During the first 48 hours the patient presented upper extremity dysmetria, dysarthria, and bilateral abducens nerve paralysis from which he recovered completely. He remained asymptomatic from day 3 to 10 after the incident. On day 11 he presented an acute vestibular syndrome. Severe bilateral vestibulopathy was confirmed by means of video head impulse testing. From day 14 onwards, he presented a persistent horizontal left-beating nystagmus, showing no variation or signs of compensation after 14 months, not responding to intensive vestibular rehabilitation or vestibular suppressant drugs. During follow-up, intercurrent gaze-evoked/direction-changing nystagmus has been recorded in various opportunities. DISCUSSION: We interpreted these findings as signs of both severe peripheral bilateral vestibulopathy and cerebellar and/or midbrain late-onset neurotoxicity, which can be explained by the intrinsic neurotoxic capability of high doses of gentamicin in the CNS.

Vigabatrin add-on therapy for drug-resistant focal epilepsy.

BACKGROUND: This is an updated version of the original Cochrane Review published in 2008 and updated in 2013. Epilepsy is a common neurological condition which affects up to 1% of the population. Approximately 30% of people with epilepsy do not respond to treatment with currently available drugs. The majority of these people have focal epilepsy. Vigabatrin is an antiepileptic drug licensed for use in drug-resistant epilepsy. OBJECTIVES: To assess the efficacy and tolerability of vigabatrin as an add-on therapy for people with drug-resistant focal epilepsy. SEARCH METHODS: For the latest update of this review, we searched the following databases on 1 November 2018: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid 1946 to 31 October 2018), ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. The Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL) are both included in the Cochrane Register of Studies (CRS Web). We checked reference lists of retrieved studies for additional reports of relevant studies and contacted Hoechst Marion Roussel (manufacturers of vigabatrin) in 2000. SELECTION CRITERIA: We included randomised, double-blind, placebo-controlled, fully published trials of vigabatrin in people of any age with drug-resistant focal epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors assessed trials for inclusion and extracted data using the standard methodological procedures expected by Cochrane. Primary analysis was by intention-to-treat (ITT). We evaluated: 50% or greater reduction in seizure frequency, treatment withdrawal, adverse effects, dose-response analysis, cognitive outcomes and quality of life. We presented results as risk ratios (RR) with 95% or 99% confidence intervals (CI). MAIN RESULTS: We identified 11 trials that included 756 participants (age range: 10 to 64 years). The trials tested vigabatrin doses between 1 g/day and 6 g/day. All 11 trials displayed a risk of bias across at least three risk of bias domains. Predominantly, the risk of bias was associated with: allocation concealment (selection bias), blinding of outcome assessment (detection bias) and incomplete outcome data (attrition bias). Participants treated with vigabatrin may be two to three times more likely to obtain a 50% or greater reduction in seizure frequency compared with those treated with placebo (RR 2.60, 95% CI 1.87 to 3.63; 4 studies; low-certainty evidence). Those treated with vigabatrin may also be three times more likely to have treatment withdrawn although we are uncertain (RR 2.86, 95% CI 1.25 to 6.55; 4 studies; very low-certainty evidence). Compared to placebo, participants given vigabatrin were more likely to experience adverse effects: dizziness/light-headedness (RR 1.74, 95% CI 1.05 to 2.87; 9 studies; low-certainty evidence), fatigue (RR 1.65, 95% CI 1.08 to 2.51; 9 studies; low-certainty evidence), drowsiness (RR 1.70, 95% CI 1.18 to 2.44; 8 studies) and depression (RR 3.28, 95% CI 1.30 to 8.27; 6 studies). Although the incidence rates were higher among participants receiving vigabatrin compared to those receiving placebo, the effect was not significant for the following adverse effects: ataxia (RR 2.76, 95% CI 0.96 to 7.94; 7 studies; very low-certainty evidence), nausea (RR 3.57, 95% CI 0.63 to 20.30; 4 studies), abnormal vision (RR 1.64, 95% CI 0.67 to 4.02; 5 studies; very low-certainty evidence), headache (RR 1.23, 95% CI 0.79 to 1.92; 9 studies), diplopia (RR 1.76, 99% CI 0.94 to 3.30) and nystagmus (RR 1.53, 99% CI 0.62 to 3.76; 2 studies; low-certainty evidence). Vigabatrin had little to no effect on cognitive outcomes or quality of life. AUTHORS' CONCLUSIONS: Vigabatrin may significantly reduce seizure frequency in people with drug-resistant focal epilepsy. The results largely apply to adults and should not be extrapolated to children under 10 years old. Short-term follow-up of participants showed that some adverse effects were associated with its use. Analysis of longer-term observational studies elsewhere, however, has demonstrated that vigabatrin use can lead to the development of visual field defects.

Early recognition of thiamine deficiency: ocular motor deficits in a patient with nutritional deprivation due to persistent antibiotic-related nausea.

CASE DESCRIPTION: A 73-year-old male presented with new onset dizziness and a 22-kg weight loss due to antibiotic-induced nausea/vomiting. Due to gaze-evoked nystagmus (GEN), thiamine deficiency was suspected. Within 12 h after replacement, his GEN decreased. CONCLUSION: In patients with nutritional deprivation, new onset GEN should prompt further diagnostics and immediate thiamine supplementation to avoid disease progression.

A case of skew deviation and downbeat Nystagmus induced by Lithium.

BACKGROUND: Lithium salts have been commonly used for prophylaxis and treatment of bipolar disorder and have numerous side effects. However, there has been no report of skew deviation and downbeat nystagmus associated with lithium. Herein, we report the first case of lithium-induced skew deviation and downbeat nystagmus. CASE PRESENTATION: A 39 years-old woman presented with intermittent vertical diplopia and dizziness within 1-2 months. Ophthalmologic examination revealed downbeat nystagmus and 6 prism diopters of right hypertropia. Funduscopic examination showed mild incyclotorsion on right eye. However, ductions and versions were within normal range. Other neurological examinations were also normal. She had a history of bipolar disorder treated with daily 600-900 mg of lithium for past 6 years, and 2 months before the first visit, daily dose of lithium was increased to 1200 mg. We referred the patients to psychiatrist. Although the serum level of lithium was within the normal therapeutic range, her daily dose of lithium was reduced to 600 mg and then stopped. 6 days after cessation of lithium, down beat nystagmus and right hypertropia were completely resolved and symptoms did not recur over a year. CONCLUSION: Even within a normal therapeutic range, downbeat nystagmus and skew deviation can occur as side effect of lithium. Dehydration may contribute to the neurotoxicity of lithium.

Rat Model of Ménière's Attack: Intratympanic Injection of Potassium Chloride Produces Direction-Changing Spontaneous Nystagmus and Hearing Fluctuations.

The major symptoms of Ménière's disease are episodic vertigo, fluctuating hearing loss, and tinnitus. Direction-changing spontaneous nystagmus is a characteristic vestibular finding in Ménière's disease. In the acute stage, spontaneous nystagmus beating to the affected side (irritative nystagmus) is often observed, while paralytic nystagmus beating to the healthy side is found in the chronic stage. This direction-changing nystagmus can be reproduced in guinea pigs by increasing the potassium ion concentration in the perilymph. The objectives of the present study were to examine the effects of increasing the potassium ion concentration of the rat perilymph on hearing and nystagmus. Under isoflurane anesthesia, 22 rats received intratympanic injection of different concentrations of potassium chloride (KCl) solution or distilled water: groups 1, 2, 3, and 4 received saturated (3.4 M) KCl solution, 2 M KCl, 1 M KCl, and distilled water, respectively. The nystagmus direction and number per 15 s were monitored for 150 min. In the other 8 rats, hearing was monitored 30 min and 20 h after intratympanic injection of 2 M KCl (group 5) or distilled water (group 6) using the auditory brainstem responses. Rats in groups 1 and 2 showed spontaneous irritative nystagmus beating to the affected ear followed by paralytic nystagmus beating to the contralateral side. In group 3, irritative nystagmus occurred but paralytic nystagmus was rarely observed. Rats in group 4 showed no nystagmus. Rats in group 5 showed significant hearing impairment 30 min after KCl injection that recovered 20 h later. Control animals in group 6 showed no significant changes in hearing. The reversible hearing impairment with direction-changing spontaneous nystagmus induced by potassium injection into the tympanic cavity in rats was quite similar to that observed in acute Ménière's attacks. This rat model could be used for basic research investigating the pathophysiological mechanisms underlying Ménière's attacks.

Visual and oculomotor outcomes in children with prenatal opioid exposure.

PURPOSE OF REVIEW: To summarize the visual and oculomotor outcomes in children with prenatal opioid exposure and review the effects of opioids on the developing central nervous system. RECENT FINDINGS: Animal models and imaging studies in children suggest that prenatal opioid exposure may affect neuronal survival and result in delayed maturation of white matter tracts and decreased volumes in certain brain areas. Visual evoked potential testing in children demonstrates delayed maturation of the afferent visual system in opioid-exposed groups compared with controls, though 'catch-up' development is seen with longitudinal follow-up. Strabismus and nystagmus are also more common in exposed children, and these findings appear to persist. SUMMARY: As rates of opioid dependence and prenatal opioid exposure continue to increase, it is important to evaluate the short-term and long-term effects of opioids on the developing visual system. An understanding of these risks is important when counseling the parents or guardians of opioid-exposed children, though larger studies with more long-term follow-up will improve our prognostic abilities.

Acute Cerebellar Ataxia Induced by Nivolumab.

A 54-year-old woman with adenocarcinoma of the lung and lymph node metastasis experienced nystagmus and cerebellar ataxia 2 weeks after initiating nivolumab therapy. An evaluation for several autoimmune-related antibodies and paraneoplastic syndrome yielded negative results. We eventually diagnosed the patient with nivolumab-induced acute cerebellar ataxia, after excluding other potential conditions. Her ataxic gait and nystagmus resolved shortly after intravenous steroid pulse therapy followed by the administration of decreasing doses of oral steroids. Nivolumab, an immune checkpoint inhibitor, is known to induce various neurological adverse events. However, this is the first report of acute cerebellar ataxia associated with nivolumab treatment.

Downbeat nystagmus due to ranitidine in a pediatric patient.

BACKGROUND: Ranitidine has not been considered as a potential cause of ocular movement conditions. However, it is known that the vestibular nucleus complex, that has a key role in gaze control and vestibule-ocular reflexes, receives hypothalamic histaminergic innervations. Some studies reported the effect of ranitidine blocking the excitatory responses of vestibular nuclei neurons to histamine. CASE REPORT: We report the first case of a downbeat nystagmus secondary to ranitidine in an infant. A 3-month-old female developed a downbeat gaze after starting treatment with ranitidine for a pediatric gastroesophageal reflux disease. Microbiological test were negative and neuroblastoma evaluation was normal. CONCLUSION: As ranitidine is widely prescribed in the pediatric population, clinicians should be aware of its potential to cause ocular movements disorders.

[Accidental amphetamine poisoning in an 11-month-old boy]. / Intoxication involontaire aux amphétamines chez un nourrisson de 11 mois.

INTRODUCTION: In France, the use of illicit drugs is increasing and therefore accidental poisoning may occur in infants and children. We report on a case of ecstasy poisoning in an infant who presented with atypical neurological symptoms. CASE REPORT: An 11-month-old infant suddenly developed agitation with eye rolling and unreactive bilateral mydriasis. All neurologic causes were excluded. The search for toxicants revealed an intoxication with an amphetamine and MDMA. Progression was favorable in 24h. CONCLUSION: Although rare, pediatric intoxications by ecstasy have become more common in recent years, due to its consumption within households, exposing young children and infants to accidental ingestion of a tablet of ecstasy.