Two New Families and a Literature Review of ELOVL4-Associated Spinocerebellar Ataxia Type 34.

Autosomal dominant variants in ELOVL4 cause spinocerebellar ataxia type 34 (SCA34; ATX-ELOVL4), classically associated with a skin condition known as erythrokeratoderma. Here, we report a large Italian-Maltese-Australian family with spinocerebellar ataxia. Notably, while there were dermatological manifestations (eczema), erythrokeratoderma was not present. Using a next-generation sequencing panel, we identified a previously reported ELOVL4 variant, NM_022726.4: c.698C > T p.(Thr233Met). The variant was initially classified as a variant of uncertain significance; however, through segregation studies, we reclassified the variant as likely pathogenic. We next identified an individual from another family (Algerian-Maltese-Australian) with the same ELOVL4 variant with spinocerebellar ataxia but without dermatological manifestations. We subsequently performed the first dedicated literature review of ELOVL4-associated ataxia to gain further insights into genotype-phenotype relationships. We identified a total of 60 reported cases of SCA34 to date. The majority had gait ataxia (88.3%), limb ataxia (76.7%), dysarthria (63.3%), and nystagmus (58.3%). Of note, skin lesions related to erythrokeratoderma were seen in a minority of cases (33.3%). Other extracerebellar manifestations included pyramidal tract signs, autonomic disturbances, retinitis pigmentosa, and cognitive impairment. For brain MRI data, cerebellar atrophy was seen in all cases (100%), whereas the hot cross bun sign (typically associated with multiple system atrophy type C) was seen in 32.4% of cases. Our family study and literature review highlight the variable phenotypic spectrum of SCA34. Importantly, it shows that erythrokeratoderma is not found in most cases and that, while a dermatological assessment may be helpful in these patients, SCA34 diagnosis should be considered irrespective of dermatological manifestations.

Video head impulse and suppression head impulse test in vestibular migraine.

BACKGROUND: Vestibular Migraine (VM) is a frequent cause of recurrent spontaneous vertigo. While some report a normal Video Head Impulse Test (vHIT) in VM, others observed abnormal results on this test. Whether or not methodological discrepancies could be the cause of these differences is not known. There are 2 vHIT methods: subjects fixating an earth-fixed target (HIMP paradigm) or a head-fixed target, the suppression head impulse test (SHIMP paradigm). OBJECTIVES: The present study aimed to compare VM patients against healthy controls on both HIMP and SHIMP in order to unravel any differences between them. METHODS: Forty-eight VM patients and 27 healthy controls tested with both the HIMP and SHIMP paradigm. Results: Our 48 VM patients showed mean VOR normal range gains in both the HIMP and SHIMP paradigms, although there were some VOR impairments in individual semicircular SCCs. VM patients with motion sickness had lower horizontal VOR gain than those without motion sickness, with the HIMP, but not the SHIMP paradigm. CONCLUSION: VM patients have normal VOR gain with either vHIT paradigm. SIGNIFICANCE: The clinical significance of this observation is that a definitely abnormal vHIT with either method is unlikely to be due to vestibular migraine and an alternative diagnosis should be sought.

Wilson Disease: A Case Report of Psychosis Preceding Parkinsonism.

BACKGROUND A first psychotic episode requires the exclusion of toxic-metabolic, inflammatory, infective, and neoplastic causes. Wilson disease is a rare, autosomal recessive disorder of copper metabolism and can present with neuropsychiatric symptoms secondary to copper accumulation in the brain. CASE REPORT We describe the case of a 48-year-old man with parkinsonism on a background of longstanding schizophrenia and psychotic depression in the setting of previously undiagnosed Wilson disease. The common history of neuropsychiatric disturbance and neuroleptic use complicated the assessment of parkinsonism. However, close attention to the temporal appearance of symptoms and signs differentiated his case from drug-induced parkinsonism, which commonly develops hours to weeks after commencement or uptitration of antipsychotic medication. The early features of sialorrhea and dysarthria were also atypical for idiopathic Parkinson disease. The diagnosis was confirmed by serum copper testing and supported by Kayser-Fleischer rings on bedside ophthalmological examination. Magnetic resonance imaging (MRI) of the brain demonstrated copper accumulation in the basal ganglia and pons, contributing to the characteristic neurological manifestations of an akinetic-rigid syndrome with dysarthria. CONCLUSIONS Serum copper testing is easily obtained and should be considered as part of the first-line investigations for new neuropsychiatric disturbances. Although rare, Wilson disease, if diagnosed early, is a potentially treatable and reversible cause of psychosis. With advanced disease, extrapyramidal findings on examination correlate with MRI brain changes, aiding the clinical assessment in differentiating the disease from drug-induced parkinsonism.

Neurological update: neuro-otology 2023.

Much has changed since our last review of recent advances in neuro-otology 7 years ago. Unfortunately there are still not many practising neuro-otologists, so that most patients with vestibular problems need, in the first instance, to be evaluated and treated by neurologists whose special expertise is not neuro-otology. The areas we consider here are mostly those that almost any neurologist should be able to start managing: acute spontaneous vertigo in the Emergency Room-is it vestibular neuritis or posterior circulation stroke; recurrent spontaneous vertigo in the office-is it vestibular migraine or Meniere's disease and the most common vestibular problem of all-benign positional vertigo. Finally we consider the future: long-term vestibular monitoring and the impact of machine learning on vestibular diagnosis.

Mitochondrial DNA 13513G>A Mutation Causing Leber Hereditary Optic Neuropathy Associated With Adult-Onset Renal Failure.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is one of the more common mitochondrial diseases and is rarely associated with mitochondrial renal disease. We report 3 unrelated patients with a background of adult-onset renal failure who presented to us with LHON and were shown to have a heteroplasmic mitochondrial DNA mutation (m.13513G>A). METHODS: Retrospective chart review. RESULTS: All 3 patients had a background of chronic renal failure and presented to us with bilateral optic neuropathy (sequential in 2) and were found to have heteroplasmic m.13513G>A mutations in the MT-ND5 gene. Two of the patients were females (aged 30 and 45 years) with chronic kidney disease from their 20s, attributed to pre-eclampsia, one of whom also had diabetes and sudden bilateral hearing loss. One patient was a male (aged 54 years) with chronic kidney disease from his 20s attributed to IgA nephropathy. His mother had diabetes and apparently sudden bilateral blindness in her 70s. Renal biopsy findings were variable and included interstitial fibrosis, acute tubular necrosis, focal segmental glomerulosclerosis, and IgA/C3 tubular casts on immunofluorescence. Mild improvements in vision followed treatment with either idebenone or a combination supplement including coenzyme Q10, alpha-lipoic acid, and B vitamins. CONCLUSIONS: Our cases expand the clinical syndromes associated with m.13513G>A to include bilateral optic neuropathy and adult-onset renal disease. This highlights that in patients with bilateral, especially sequential, optic neuropathy a broad approach to mitochondrial testing is more useful than a limited LHON panel. Mitochondrial diseases present a diagnostic challenge because of their clinical and genetic variability.

Subjective visual horizontal correlates better with ocular than with cervical vestibular evoked myogenic potentials.

OBJECTIVE: To examine the relationship between widely used otolith function tests: the Subjective Visual Horizontal (SVH) and Vestibular Evoked Myogenic Potentials (VEMP). METHODS: A retrospective analysis was performed on 301 patients who underwent SVH, ocular and cervical VEMP (oVEMP and cVEMP) tests on the same day. Correlations between the mean SVH tilt and amplitude asymmetry ratios for bone-conducted (BC) oVEMP and air-conducted (AC) cVEMP were examined. Diagnoses included vestibular neuritis, stroke, vestibular migraine, Meniere's disease, sudden sensorineural hearing loss (SSNHL) and vestibular schwannoma. RESULTS: SVH results were concordant with the oVEMP in 64% of cases and the cVEMP in 51%. Across all patients, SVH demonstrated a significant moderate correlation with BC oVEMP amplitude asymmetry ratios (r = 0.55, p < 0.001) and a weak correlation with AC cVEMP amplitude asymmetry ratios (r = 0.35, p < 0.001). A stronger correlation between SVH and oVEMPs was observed in patients with vestibular neuritis (r = 0.67, p < 0.001) and SSNHL (r = 0.76, p = 0.001). CONCLUSIONS: SVH correlates better with oVEMP than cVEMP symmetry. SIGNIFICANCE: This finding reinforces the hypothesis of a common utricular origin for both SVH and oVEMPs which is distinct from the saccular origin of cVEMPs.

A review of the geometrical basis and the principles underlying the use and interpretation of the video head impulse test (vHIT) in clinical vestibular testing.

This paper is concerned mainly with the assumptions underpinning the actual testing procedure, measurement, and interpretation of the video head impulse test-vHIT. Other papers have reported in detail the artifacts which can interfere with obtaining accurate eye movement results, but here we focus not on artifacts, but on the basic questions about the assumptions and geometrical considerations by which vHIT works. These matters are crucial in understanding and appropriately interpreting the results obtained, especially as vHIT is now being applied to central disorders. The interpretation of the eye velocity responses relies on thorough knowledge of the factors which can affect the response-for example the orientation of the goggles on the head, the head pitch, and the contribution of vertical canals to the horizontal canal response. We highlight some of these issues and point to future developments and improvements. The paper assumes knowledge of how vHIT testing is conducted.

Optic nerve sheath fenestration for treating papilloedema in the era of cerebral venous sinus stenting.

BACKGROUND: Pseudotumour cerebri (PTC) is the syndrome of intracranial hypertension without intracranial mass or hydrocephalus and is the commonest cause of papilloedema seen in many eye clinics. In the last 10 years, we have increasingly used TSS in patients whose papilloedema was not well controlled with medical treatment and have done fewer ONSFs. Here, we review our experience at Royal Prince Alfred Hospital Sydney with ONSF in 35 patients over the period 2002-2021. METHODS: Retrospective case series of 35 patients, 30 of whom had primary PTC [i.e., idiopathic intracranial hypertension (IIH)] and 5 with secondary PTC. RESULTS: Eighteen patients had bilateral ONSF and 17 patients unilateral ONSF, in each case of the worse eye. Thirteen patients then underwent transverse sinus stenting (TSS), in each case following ONSF. The primary outcome measures were visual acuity (VA) and mean deviation (MD) on visual field (VF) testing. MD improved by 5 dB or more in 34 of 70 total eyes (48.6%); VA improved by 0.2 logMAR (two lines on Snellen chart) or more in 21 eyes (30%), and by both in 15 eyes (21.4%). Final MD was -10 dB or better in 38 eyes (54.3%); final VA was 0.3 (6/12) or better in 54 eyes (77.1%), and both in 39 eyes (55.7%). CONCLUSIONS: The results confirm that ONSF can relieve papilloedoema in both eyes and improve both VF and VA, even in cases of fulminant PTC with severe acute visual impairment.

Truncal sensory polyneuropathy in light-chain amyloidosis.

We describe a case of truncal sensory polyneuropathy in a patient with light-chain amyloidosis. We highlight the clinical signs and differential diagnoses related to the presentation.

Vestibular contributions to the Romberg test: Testing semicircular canal and otolith function.

Normal stance relies on three sensory inputs: vision, proprioception and vestibular function. The Romberg test, trying to stand with feet together and eyes closed, is familiar to every medical student as a test of distal proprioceptive impairment. It remains the best known of Romberg's many remarkable contributions to clinical neurology. In Romberg's time almost nothing was known about the function of the vestibular system. We now know that standing with the eyes closed on a compliant rather than a firm surface is more a test of vestibular than proprioceptive function. Peripheral vestibular function tests in clinical use today all rely on measurements of oligosynaptic brainstem reflexes. Short-latency eye rotations in response to rapid, brief head rotations (head impulses) give an accurate, robust and reproducible measure of the function of any and each of the six semicircular canals. Short-latency evoked potentials from sternomastoid and inferior oblique muscles in response to loud clicks or skull taps (vestibular evoked myogenic potentials) give an accurate and reproducible measure of the function of each and any of the four otolith organs. In the present paper, we briefly review what is now known about the anatomy and physiology of the peripheral receptors and brainstem pathways mediating these reflexes and examine how this knowledge can help interpret the Romberg test.

Head impulse gain and saccade analysis in pontine-cerebellar stroke and vestibular neuritis.

OBJECTIVE: We sought to quantify and compare angular vestibulo-ocular reflex (aVOR) gain and compensatory saccade properties elicited by the head impulse test (HIT) in pontine-cerebellar stroke (PCS) and vestibular neuritis (VN). METHODS: Horizontal HIT was recorded ≤7 days from vertigo onset with dual-search coils in 33 PCS involving the anterior inferior, posterior inferior, and superior cerebellar arteries (13 AICA, 17 PICA, 3 SCA) confirmed by MRI and 20 VN. We determined the aVOR gain and asymmetry, and compensatory overt saccade properties including amplitude asymmetry and cumulative amplitude (ipsilesional trials [I]; contralesional trials [C]). RESULTS: The aVOR gain (normal: 0.96; asymmetry = 2%) was bilaterally reduced, greater in AICA (I = 0.39, C = 0.57; asymmetry = 20%) than in PICA/SCA strokes (I = 0.75, C = 0.74; asymmetry = 7%), in contrast to the unilateral deficit in VN (I = 0.22, C = 0.76; asymmetry = 54%). Cumulative amplitude (normal: 1.1°) was smaller in AICA (I = 4.2°, C = 3.0°) and PICA/SCA strokes (I = 2.1°, C = 3.0°) compared with VN (I = 8.5°, C = 1.3°). Amplitude asymmetry in AICA and PICA/SCA strokes was comparable, but favored the contralesional side in PICA/SCA strokes and the ipsilesional side in VN. Saccade asymmetry <61% was found in 97% of PCS and none of VN. Gain asymmetry <40% was found in 94% of PCS and 10% of VN. CONCLUSION: HIT gains and compensatory saccades differ between PCS and VN. VN was characterized by unilateral gain deficits with asymmetric large saccades, AICA stroke by more symmetric bilateral gain reduction with smaller saccades, and PICA stroke by contralesional gain bias with the smallest saccades. Saccade and gain asymmetry should be investigated further in future diagnostic accuracy studies. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that aVOR testing accurately distinguishes patients with PCS from VN (sensitivity 94%-97%, specificity 90%-100%).

A new model for neurology care in the emergency department.

OBJECTIVE: To assess the feasibility of using a rapid access neurology clinic to assess and manage patients considered safe to discharge home from the emergency department (ED), yet requiring specialist neurology review. DESIGN, SETTING AND PARTICIPANTS: The ED Rapid Access Neurology (ED RAN) clinic was trialled at Royal Prince Alfred Hospital, a major tertiary teaching hospital in Sydney, over a 12-month period (23 March 2008 - 22 March 2009). The service uses a new clinic and referral system to offer suitable patients specialist neurology outpatient review within 5 working days of their discharge from the ED. MAIN OUTCOME MEASURES: Quality of patient care, patient satisfaction, estimated service impact on the hospital system. RESULTS: During the 12-month trial period, 311 patients were referred to the ED RAN clinic. Of these referrals, 222 patients (71%) attended the clinic, where a number of serious neurological diagnoses were made, and eight patients required admission after specialist review. All patients attending the clinic found the visit helpful. Consultant ED physicians believed that the clinic prevented 83 unnecessary admissions and 188 out-of-hours neurology registrar consultations, and saved an estimated 809 hours of ED bed time. CONCLUSIONS: The ED RAN clinic provides a viable model for improving the quality of patient care, with high levels of patient satisfaction. This model of care may allow significant cost savings and help to relieve the major access block in Australian EDs.