The cerebellar ataxias (CAs) are a heterogeneous group of disorders characterized by progressive incoordination. Seventeen repeat expansion (RE) loci have been identified as the primary genetic cause and account for >80% of genetic diagnoses. Despite this, diagnostic testing is limited and inefficient, often utilizing single gene assays. This study evaluates the effectiveness of long- and short-read sequencing as diagnostic tools for CA. We recruited 110 individuals (48 females, 62 males) with a clinical diagnosis of CA. Short-read genome sequencing (SR-GS) was performed to identify pathogenic RE and also non-RE variants in 356 genes associated with CA. Independently, long-read sequencing with adaptive sampling (LR-AS) was performed to identify pathogenic RE. SR-GS provided a genetic diagnosis for 38% of the cohort (40/110) including seven non-RE pathogenic variants. RE causes disease in 33 individuals, with the most common condition being SCA27B ( n = 24). In comparison, LR-AS identified pathogenic RE in 29 individuals. RE identification for the two methods was concordant apart from four SCA27B cases not detected by LR-AS due to low read depth. For both technologies manual review of the RE alignment enhances diagnostic outcomes. Orthogonal testing for SCA27B revealed a 15% and 0% false positive rate for SR-GS and LR-AS, respectively. In conclusion, both technologies are powerful screening tools for CA. SR-GS is a mature technology currently used by diagnostic providers, requiring only minor changes in bioinformatic workflows to enable CA diagnostics. LR-AS offers considerable advantages in the context of RE detection and characterization but requires optimization before clinical implementation.

Vestibular neuritis and more recently acute unilateral peripheral vestibulopathy describe an inflammatory disorder that affects the inner ear or the connecting neural pathways destined for the brainstem. The condition is characterized by acute, severe and prolonged vertigo and postural imbalance accompanied by nausea and vomiting. Spontaneous unidirectional nystagmus and hypofunction of ipsilesional horizontal vestibulo-ocular reflex are typically observed. The acute phase resolves over days and balance recovery occurs gradually in weeks due to a combination of partial inner ear recovery and central compensation. The main differential diagnosis is acute posterior circulation stroke, and this can now be sensitively excluded with quantitative (video) head impulse test.

Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified an intronic (GAA) repeat expansion in fibroblast growth factor 14 (FGF14). Genetic analysis of 95 Australian individuals with adult-onset ataxia identified four (4.2%) with (GAA)>300 and a further nine individuals with (GAA)>250. PCR and long-read sequence analysis revealed these were pure (GAA) repeats. In comparison, no control subjects had (GAA)>300 and only 2/311 control individuals (0.6%) had a pure (GAA)>250. In a German validation cohort, 9/104 (8.7%) of affected individuals had (GAA)>335 and a further six had (GAA)>250, whereas 10/190 (5.3%) control subjects had (GAA)>250 but none were (GAA)>335. The combined data suggest (GAA)>335 are disease causing and fully penetrant (p = 6.0 × 10−8, OR = 72 [95% CI = 4.3–1,227]), while (GAA)>250 is likely pathogenic with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with variable features including vestibular impairment, hyper-reflexia, and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R2 = 0.44, p = 0.00045, slope = −0.12) and identification of a shared haplotype in a minority of individuals suggests that the expansion can be inherited or generated de novo during meiotic division. This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansions via model-free, genome-wide analysis and identifies SCA27B/ATX-FGF14 as a frequent cause of adult-onset ataxia.

Introduction: The head impulse test (HIT) and HIT combined with direction-changing Nystagmus-Test of Skew deviation (HINTS) have been proposed as bedside tests to differentiate between peripheral and central causes of vertigo in the emergency department (ED). We conducted a meta-analysis of the HIT and HINTS tests to diagnose peripheral vertigo (PV) and central vertigo. Methods: Pubmed, Google Scholar, EmBase, and articles references published in English up to July 2021 were searched for keywords "vertigo " or "acute vestibular syndrome " or "dizziness " and "head impulse " and "stroke. " The bivariate method for meta-analysis was used to calculate positive (PLR) and negative likelihood ratios (NLR) and summary receiver operating characteristics area under the curve (AUC). Results: A total of 11 studies were included analysing both HIT (8 studies, N = 417) and HINTS (6 studies, N = 405). HIT and HINTS were performed within 24 h in 4 of 11 studies. PLR and NLR for HIT in PV was 4.85 (95% CI: 2.83-8.08) and 0.19 (95% CI: 0.12-0.29, I-2 63.25%), respectively. The AUC for HIT the diagnosis of PV and stroke was 0.90 and 0.92, respectively. PLR and NLR for a negative HIT in stroke was 5.85 (95% CI: 3.07-10.6) and 0.17 (95% CI: 0.08-0.30), respectively. PLR and NLR for peripheral HINTS pattern for PV was 17.3 (95% CI: 8.38-32.1) and 0.15 (95% CI: 0.07-0.26), respectively. PLR and NLR for central HINTS pattern for stroke: 5.61 (95% CI: 4.19-7.7) and 0.06 (95% CI: 0.03-0.12). In all included studies, HIT and HINTS exams were administered by neurology residents or neurology specialists with additional neuro-otology or neuro-ophthalmology subspeciality experience, and two studies included ED physicians. Raters reported high degree of bias and high concern regarding applicability in most domains of the quality assessment of diagnostic accuracy studies (QUADAS-2) tool. Meta-regression did not demonstrate a statistically significant effect of publication year, time to test, and type of assessor on sensitivity or false positive rate. Conclusion: The HIT and HINTS exams appear to be moderately good discriminators of central and PV. However, in most papers, the tests were administered by neurologists and were evaluated beyond 24 h, which may limit utility in the ED setting.

ABSTRACT Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified a novel intronic GAA repeat expansion in the gene encoding Fibroblast Growth Factor 14 ( FGF14 ). Genetic analysis identified 4/95 previously unresolved Australian affected individuals (4.2%) with (GAA) >335 and a further nine individuals with (GAA) >250 . Notably, PCR and long-read sequence analysis revealed these were pure GAA repeats. In comparison, no controls had (GAA) >300 and only 2/311 control individuals (0.6%) encoded a pure (GAA) >250 . In a German validation cohort 9/104 (8.7%) of affected individuals had (GAA) >335 and a further six had (GAA) >250 . In comparison no controls had (GAA) >335 and 10/190 (5.3%) encoded (GAA) >250 . The combined data suggests (GAA) >335 are disease-causing and fully penetrant [P-value 6.0×10 −8 , OR 72 (95% CI=4.3-1227)], while (GAA) >250 is likely pathogenic, albeit with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with a clinical phenotype that may include vestibular impairment, hyper-reflexia and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R2=0.44 p=0.00045, slope = -0.12). This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansion loci via model free, genome-wide analysis and identifies SCA50/ATX-FGF14 is a frequent cause of adult-onset ataxia.

Objectives We conducted a meta-analysis of the HIT and HINT tests to diagnose peripheral vertigo (PV) and central vertigo in the emergency department (ED). Methods Pubmed, Google Scholar, EmBase and articles references published in English up to July 2021 were searched for keywords 'vertigo' or 'acute vestibular syndrome' or 'dizziness' and 'head impulse' and 'stroke'. Bivariate method for meta-analysis was used. Results 11 studies HIT (8 studies, N = 417) and HINT (6 studies, N = 405). HIT and HINT were performed within 24 hours in 4 of 11 studies. Positive likelihood ratio (PLR) and negative likelihood ratio (NLR) for HIT in PV was 4.85 (95% CI 2.83 – 8.08) and 0.19 (95% CI 0.12 – 0.29, I263.25%) respectively. The (area under the curve) AUC for HIT the diagnosis of PV and stroke was 0.90 and 0.92 respectively. PLR and NLR for a negative HIT in stroke was 5.85 (95% CI 3.07 – 10.6) and 0.17 (95% CI 0.08 – 0.30) respectively. PLR and NLR for peripheral HINT pattern for PV was 17.3 (95% CI 8.38 – 32.1) and 0.15 (95% CI 0.07 – 0.26) respectively. PLR and NLR for central HINT pattern for stroke was 5.61 (95% CI 4.19 – 7.7) and 0.06 (95% CI 0.03 – 0.12) respectively. Conclusion The HIT and HINT exams appear moderately good discriminators of central and peripheral vertigo. However, these results may not apply in the ED setting as most papers evaluated these tests beyond 24 hours.

Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified an intronic (GAA) repeat expansion in the gene encoding Fibroblast Growth Factor 14 (FGF14). Genetic analysis identified 4/95 Australian individuals (4.2%) with (GAA)>300 and a further nine individuals with (GAA)>250. PCR and long-read sequence analysis revealed these were pure (GAA) repeats. In comparison, no controls had (GAA)>300 and only 2/311 control individuals (0.6%) encoded a pure (GAA)>250. In a German validation cohort 9/104 (8.7%) of affected individuals had (GAA)>335 and a further six had (GAA)>250, whereas no controls had (GAA)>335 and 10/190 (5.3%) encoded (GAA)>250. The combined data suggests (GAA)>335 are disease-causing and fully penetrant [P-value 6.0x10-8, OR 72 (95% CI=4.3-1227)], while (GAA)>250 is likely pathogenic with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with variable features including vestibular impairment, hyper-reflexia and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R2=0.44 p=0.00045, slope = -0.12) and identification of a shared haplotype in a minority of individuals suggests that the expansion can be inherited or generated de novo during meiotic division. This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansions via model free, genome-wide analysis and identifies SCA50/ATX-FGF14 as a frequent cause of adult-onset ataxia.

PURPOSE:Superficial siderosis, a progressive, debilitating, neurological disease, often presents with bilateral impairment of auditory and vestibular function. We highlight that superficial siderosis is often due to a repairable spinal dural defect of the type that can also cause spontaneous intracranial hypotension.METHODS:Retrospective chart review of five patients presenting with moderate to severe, progressive bilateral sensorineural hearing loss as well as vestibular loss. All patients had developed superficial siderosis from spinal dural defects: three after trauma, one after spinal surgery and one from a thoracic discogenic microspur.RESULTS:The diagnosis was made late in all five patients; despite surgical repair in four, hearing and vestibular loss failed to improve.CONCLUSIONS:In patients presenting with progressive bilateral sensorineural hearing loss, superficial siderosis should be considered as a possible cause. If these patients also have bilateral vestibular loss, cerebellar impairment and anosmia, then the diagnosis is likely and the inevitable disease progress might be halted by finding and repairing the spinal dural defect.

Transaldolase (TAL) is an enzyme of the non-oxidative part of the pentose phosphate pathway which produces reductive potential in the form of NADPH as well as ribose 5-phosphate for incorporation into nucleotides. Developmental analysis via reverse transcriptase-polymerase chain reaction, immunoblots, enzymatic activity, in situ hybridization and immunocytochemistry demonstrate that TAL is expressed during all developmental stages in Drosophila. The tal locus is unique and contains two small introns. The first two introns in the human gene are situated at the same locations in the coding sequence as in Drosophila. Analysis of TAL protein levels and expression patterns reveals that it is also expressed in all larval tissues examined with particularly high levels in the fat body. Interestingly, we describe specific TAL expression only in non-neuronal cells in the larval brain.

Persistent postural perceptual dizziness (PPPD) is a common chronic vestibular disorder characterized by persistent vestibular symptoms, including postural instability and non-spinning vertigo, which is aggravated by motion, upright posture and moving or complex visual stimuli. In our review of 198 cases seen over a 5 year period, we have confirmed a number of common precipitating conditions for PPPD, including anxiety disorders and vestibular migraine. Vestibular abnormalities, including a unilateral loss of vestibular hypofunction and isolated otolith abnormalities, were found on investigation in just under half the cases. The use of cognitive behavioral therapy (CBT) as a treatment for PPPD resulted in impressive reductions in anxiety and measures of dizziness over follow up periods of up to 6 months.

OBJECTIVE:We characterised the clinical and neuro-otological characteristics of patients with Susac syndrome.METHODS:The medical records of 30 patients with Susac syndrome were reviewed for details of their clinical presentation and course, neuro-otological symptoms, investigation results including audiology and vestibular function tests, treatment and outcomes.RESULTS:Our findings demonstrate that 29 of our 30 patients with Susac syndrome developed neuro-otological symptoms such as hearing loss, disequilibrium, tinnitus or vertigo during their disease course. Hearing loss was the most common neuro-otological symptom occurring in 93% of patients. A rising configuration of low-frequency greater than the high-frequency sensorineural hearing loss was the most characteristic finding on audiological testing (37% of reviewed audiograms). Disproportionately poor speech discrimination was identified in 20% of cases, and one case demonstrated a retrocochlear pattern on electrophysiological testing. Four patients required hearing aids and a further two patients required a cochlear implant due to severe hearing loss. Two out of two treated patients had improvements in hearing after the prompt administration of corticosteroids, indicating the potential for recoverable hearing loss if relapses are treated early. Effects on vestibular function were variable in ten patients who were tested, with most showing preservation of function despite significant hearing loss.CONCLUSIONS:Neuro-otological symptoms in Susac syndrome are almost universal. In the correct clinical context, a rising configuration of low to high-frequency sensorineural hearing loss should prompt consideration of Susac syndrome. Treatment of inner ear symptoms in Susac syndrome requires further research as early immunotherapy may be beneficial.

Over 30 years ago, the head impulse test (HIT) was measured with search coil recordings and it provided robust evidence for a new test of vestibular function that could detect impairment of a single semicircular canal, that is, the lateral canal. Over the next two decades, the diagnostic spectrum of HIT was expanded to the testing of vertical canals, differentiation of central from peripheral vestibulopathy, and incorporation of visual interaction-the suppressed head impulse. However, HIT measurement was limited to very few specialized laboratories that were able to maintain the time-consuming and expensive operation of the scleral search coil system, which is the gold standard in eye movement recording. The video HIT (vHIT) was validated for the first time over 10 years ago, against the search coils, and its introduction into dizzy clinics worldwide has revolutionized the practice of neuro-otology. Here we review the basic physiology, practical aspects, and clinical application of the vHIT.

Bilateral vestibulopathy (BVP), which is due to peripheral lesions, may selectively involve certain semicircular canal (SCC). Recent eye movement recordings with search coil and video head impulse test (HIT) have provided insight in central lesions that can cause bilateral and selective SCC deficit mimicking BVP. Since neurological signs or ocular motor deficits maybe subtle or absent, it is critical to recognize central lesions correctly since there is prognostic and treatment implication. Acute floccular lesions cause bilateral horizontal SCC (HC) impairment while leaving vertical SCC function unaffected. Vestibular nuclear lesions affect bilateral HC and posterior SCC (PC) function, but anterior SCC (AC) function is spared. When both eyes are recorded, medial longitudinal fasciculus lesions cause horizontal dysconjugacy in HC function and catch-up saccades, as well as selective deficiency of PC over AC function. Combined peripheral and central lesions may be difficult to distinguish from BVP. Anterior inferior cerebellar artery stroke causes two types of deficits: 1. ipsilateral pan-SCC deficits and contralateral HC deficit and 2. bilateral HC deficit with vertical SCC sparing. Metabolic disorders such as Wernicke encephalopathy characteristically involve HC but not AC or PC function. Gaucher disease causes uniform loss of all SCC function but with minimal horizontal catch-up saccades. Genetic cerebellar ataxias and cerebellar-ataxia neuropathy vestibular areflexia syndrome typically do not spare AC function. While video HIT does not replace the gold-standard, search coil HIT, clinicians are now able to rapidly and accurately identify specific pattern of SCC deficits, which can aid differentiation of central lesions from BVP.

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The medial longitudinal fasciculus (MLF) is the final common pathway for all conjugate adducting horizontal eye movements, as well as for the vertical–torsional vestibulo-ocular reflex (VOR). MLF lesion causes adduction paresis of ipsilesional (adducting) eye with dissociated nystagmus of contralesional (abducting) eye—the well-known clinical syndrome of internuclear ophthalmoplegia (INO). We measured the VOR stimulation and also any catch-up saccades, from individual semicircular canal (SCC) evoked by the head impulse test (HIT), using head and binocular 3-dimensional scleral search coils in 27 multiple sclerosis (MS) patients, 8 with unilateral, 19 with bilateral INO. In unilateral INO, VOR gain (normal >0.90) from ipsilesional lateral SCC stimulation was 0.48 for the adducting eye and 0.81 for the abducting eye; 0.61 from contralesional anterior SCC stimulation and only 0.29 from contralesional posterior SCC stimulation. In bilateral INO, there were VOR gain deficits from all six SCCs: lateral SCC gains were asymmetrically reduced to 0.45 in the adducting eye and 0.66 in the abducting eye; anterior SCC gain was 0.48 and posterior SCC gain was only 0.19. Horizontal VOR versional dysconjugacy between adducting and abducting eyes at 0.66 was less severe than horizontal catch-up saccade versional dysconjugacy (0.44); normal >0.80. Unexpected partial preservation of horizontal VOR with greater catch-up saccade impairment from the adducting than abducting eye suggests that the ascending tract of Deiters (ATD), an extra-MLF pathway, also mediates the horizontal VOR, but not adducting horizontal saccades. Vertical VOR deficits will produce vertical oscillopsia with any vertical head movement and measurement of the vertical VOR could help with the diagnosis and quantitative evaluation of MLF lesions in suspected MS. Horizontal VOR deficits and catch-up saccade versional dysconjugacy in INO will cause gaze instability and horizontal oscillopsia during active horizontal head movements.

Acute Wernicke's encephalopathy (aWE) is a medical emergency [1]. Delay in treatment can cause permanent cognitive impairment. The classic triad of encephalopathy, ataxia and ophthalmoplegia is not always present: some patients present with an acute vestibular syndrome with selective, symmetrical impairment only of horizontal and not of vertical vestibulo-ocular reflex (VOR) without encephalopathy or ophthalmoplegia [2]. Here we confirm this observation, show that this can be diagnosed and monitored with the video Head-Impulse Test and propose that this unusual pattern of vestibular impairment might be characteristic of aWE.