Genome sequencing reanalysis increases the diagnostic yield in dystonia.

PURPOSE: We investigated the contribution of genomic data reanalysis to the diagnostic yield of dystonia patients who remained undiagnosed after prior genome sequencing. METHODS: Probands with heterogeneous dystonia phenotypes who underwent initial genome sequencing (GS) analysis in 2019 were included in the reanalysis, which was performed through gene-specific discovery collaborations and systematic genomic data reanalysis. RESULTS: Initial GS analysis in 2019 (n = 111) identified a molecular diagnosis in 11.7 % (13/111) of cases. Reanalysis between 2020 and 2023 increased the diagnostic yield by 7.2 % (8/111); 3.6 % (4/111) through focused gene-specific clinical correlation collaborative efforts [VPS16 (two probands), AOPEP and POLG], and 3.6 % (4/111) by systematic reanalysis completed in 2023 [NUS1 (two probands) and DDX3X variants, and a microdeletion encompassing VPS16]. Seven of these patients had a high phenotype-based dystonia score ≥3. Notable unverified findings in four additional cases included suspicious variants of uncertain significance in FBXL4 and EIF2AK2, and potential phenotypic expansion associated with SLC2A1 and TREX1 variants. CONCLUSION: GS data reanalysis increased the diagnostic yield from 11.7 % to 18.9 %, with potential extension up to 22.5 %. While optimal timing for diagnostic reanalysis remains to be determined, this study demonstrates that periodic re-interrogation of dystonia GS datasets can provide additional genetic diagnoses, which may have significant implications for patients and their families.

An Update on the Adult-Onset Hereditary Cerebellar Ataxias: Novel Genetic Causes and New Diagnostic Approaches.

The hereditary cerebellar ataxias (HCAs) are rare, progressive neurologic disorders caused by variants in many different genes. Inheritance may follow autosomal dominant, autosomal recessive, X-linked or mitochondrial patterns. The list of genes associated with adult-onset cerebellar ataxia is continuously growing, with several new genes discovered in the last few years. This includes short-tandem repeat (STR) expansions in RFC1, causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), FGF14-GAA causing spinocerebellar ataxia type 27B (SCA27B), and THAP11. In addition, the genetic basis for SCA4, has recently been identified as a STR expansion in ZFHX3. Given the large and growing number of genes, and different gene variant types, the approach to diagnostic testing for adult-onset HCA can be complex. Testing methods include targeted evaluation of STR expansions (e.g. SCAs, Friedreich ataxia, fragile X-associated tremor/ataxia syndrome, dentatorubral-pallidoluysian atrophy), next generation sequencing for conventional variants, which may include targeted gene panels, whole exome, or whole genome sequencing, followed by various potential additional tests. This review proposes a diagnostic approach for clinical testing, highlights the challenges with current testing technologies, and discusses future advances which may overcome these limitations. Implementing long-read sequencing has the potential to transform the diagnostic approach in HCA, with the overall aim to improve the diagnostic yield.

Imbalance and lower limb tremor in chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND AND AIMS: Imbalance is a prominent symptom of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Although upper limb tremor in CIDP is described, lower limb tremor has not been assessed. The aim of this study was to determine whether lower limb tremor was present in CIDP and assess potential relationships with imbalance. METHODS: This was a cross-sectional observational study of prospectively recruited consecutive patients with typical CIDP (N = 25). Clinical phenotyping, lower limb nerve conduction and tremor studies, and posturography analyses were performed. The Berg Balance Scale (BBS) divided CIDP patients into those with "good" and "poor" balance. RESULTS: Lower limb tremor was evident in 32% of CIDP patients and associated with poor balance (BBSTremor 35 [23-46], BBSNo Tremor 52 [44-55], p = .035). Tremor frequency was 10.2-12.5 Hz with legs outstretched and on standing, apart from four patients with a lower frequency tremor (3.8-4.6 Hz) while standing. Posturography analysis revealed a high-frequency spectral peak in the vertical axis in 44% of CIDP patients (16.0 ± 0.4 Hz). This was more likely in those with "good" balance (40% vs. 4%, p = .013). INTERPRETATION: Lower limb tremor is present in one third of CIDP patients and is associated with poor balance. A high-frequency peak on posturography is associated with better balance in CIDP. Lower limb tremor and posturography assessments could serve as important biomarkers of balance in a clinical setting.

A Prospective Study of Electromyographic Amplitude Changes During Intraoperative Neural Monitoring for Open Thyroidectomy.

BACKGROUND: Intraoperative nerve monitoring (IONM) of the vagus and recurrent laryngeal nerve (RLN) enables prediction of postoperative nerve function. The underlying mechanism for loss of signal (LOS) in a visually intact nerve is poorly understood. The correlation of intraoperative electromyographic amplitude changes (EMG) with surgical manoeuvres could help identify mechanisms of LOS during conventional thyroidectomy. METHODS: A prospective study of consecutive patients undergoing thyroidectomy was performed with intermittent IONM using the NIM Vital nerve monitoring system. The ipsilateral vagus and RLN was stimulated, and vagus nerve signal amplitude recorded at five time points during thyroidectomy (baseline, after mobilisation of superior pole, medialisation of the thyroid lobe, before release at Ligament of Berry, end of case). RLN signal amplitude was recorded at two time points; after medialisation of the thyroid lobe (R1), and end of case (R2). RESULTS: A total of 100 consecutive patients undergoing thyroidectomy were studied with 126 RLN at risk. The overall rate of LOS was 4.0%. Cases without LOS demonstrated a highly significant vagus nerve median percentage amplitude drop at medialisation of the thyroid lobe (- 17.9 ± 53.1%, P < 0.001), and end of case (- 16.0 ± 47.2%, P < 0.001) compared to baseline. RLN had no significant amplitude drop at R2 compared to R1 (P = 0.207). CONCLUSIONS: A significant reduction in vagus nerve EMG amplitude at medialisation of the thyroid and the end of case compared to baseline indicates that stretch injury or traction forces during thyroid mobilisation are the most likely mechanism of RLN impairment during conventional thyroidectomy.

Hypertrophic olivary degeneration associated with bilateral vocal cord adductor dystonia.

BACKGROUND: Hypertrophic olivary degeneration (HOD) is a rare condition caused by lesions within the dentato-rubro-olivary pathway, resulting in ocular nystagmus and palatal myoclonus (oculopalatal tremor) but not usually dystonia. Dystonia is an uncommon association, and we present the first reported association of hypertrophic olivary degeneration with bilateral vocal cord dystonia. CASE PRESENTATION: A 33 year old male presented initially with acute hydrocephalus on the background of previous ventriculoperitoneal (VP) shunting for previously treated medulloblastoma. After revision of the VP shunt, the patient developed progressive hiccups and stridor leading to respiratory failure requiring intubation. Ocular pendular nystagmus and palatal myoclonus at 3 Hz was observed. Flexible nasendoscopy (FNE) demonstrated bilateral tonic adduction of the vocal folds with 3 Hz coarse supraglottic, pharyngeal and palatal rhythmic myoclonus. MRI imaging demonstrated T2 hyperintensity within the bilateral inferior olivary nuclei consistent with stage 3 radiological HOD. CONCLUSIONS: Dystonia is a rarely reported phenomenon in HOD but is not unexpected with the inferior olivary nucleus implicated in dystonic disorders. We report the association of HOD with bilateral vocal cord adductor dystonia, a potentially life threatening condition.

Chronic inflammatory demyelinating polyradiculoneuropathy-associated tremor: Phenotype and pathogenesis.

BACKGROUND AND PURPOSE: Tremor in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is underrecognized, and the pathophysiology remains incompletely understood. This study evaluated tremor in CIDP and tested the hypothesis, established in other demyelinating neuropathies, that tremor occurs due to mistimed peripheral inputs affecting central motor processing. Additionally, the tremor stability index (TSI) was calculated with the hypothesis that CIDP-related tremor is more variable than other tremor disorders. METHODS: Consecutive patients with typical CIDP were prospectively recruited from neuromuscular clinics. Alternative causes of neuropathy and tremor were excluded. Cross-sectional clinical assessment and extensive tremor study recordings were undertaken. Pearson correlation coefficient was used to compare nerve conduction studies and tremor characteristics, and t-test was used for comparisons between groups. RESULTS: Twenty-four patients with CIDP were included. Upper limb postural and action tremor was present in 66% and was mild according to the Essential Tremor Rating Assessment Scale. Tremor did not significantly impact disability. Surface electromyography (EMG) found high-frequency spectral peaks in deltoid (13.73 ± 0.66 Hz), biceps brachii (11.82 ± 0.91 Hz), and extensor carpi radialis (11.87 ± 0.91 Hz) muscles, with lower peaks in abductor pollicis brevis EMG (6.07 ± 0.45 Hz) and index finger accelerometry (6.53 ± 0.42 Hz). Tremor was unchanged by weight loading but correlated with ulnar nerve F-wave latency and median nerve sensory amplitude. TSI (2.3 ± 0.1) was significantly higher than essential tremor. CONCLUSIONS: Postural tremor is a common feature in CIDP. Tremor was unaffected by weight loading, typical of centrally generated tremors, although there was a correlation with peripheral nerve abnormalities. The high beat-to-beat variability on TSI and gradation of peak frequencies further suggest a complex pathophysiology. These findings may assist clinicians with the diagnosis of neuropathic tremor.

Outcomes of Cerebral Venous Thrombosis due to Vaccine-Induced Immune Thrombotic Thrombocytopenia After the Acute Phase.

BACKGROUND: Cerebral venous thrombosis (CVT) due to vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe condition, with high in-hospital mortality rates. Here, we report clinical outcomes of patients with CVT-VITT after SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) vaccination who survived initial hospitalization. METHODS: We used data from an international registry of patients who developed CVT within 28 days of SARS-CoV-2 vaccination, collected until February 10, 2022. VITT diagnosis was classified based on the Pavord criteria. Outcomes were mortality, functional independence (modified Rankin Scale score 0-2), VITT relapse, new thrombosis, and bleeding events (all after discharge from initial hospitalization). RESULTS: Of 107 CVT-VITT cases, 43 (40%) died during initial hospitalization. Of the remaining 64 patients, follow-up data were available for 60 (94%) patients (37 definite VITT, 9 probable VITT, and 14 possible VITT). Median age was 40 years and 45/60 (75%) patients were women. Median follow-up time was 150 days (interquartile range, 94-194). Two patients died during follow-up (3% [95% CI, 1%-11%). Functional independence was achieved by 53/60 (88% [95% CI, 78%-94%]) patients. No new venous or arterial thrombotic events were reported. One patient developed a major bleeding during follow-up (fatal intracerebral bleed). CONCLUSIONS: In contrast to the high mortality of CVT-VITT in the acute phase, mortality among patients who survived the initial hospitalization was low, new thrombotic events did not occur, and bleeding events were rare. Approximately 9 out of 10 CVT-VITT patients who survived the acute phase were functionally independent at follow-up.

Eculizumab for acute relapse of neuromyelitis optica spectrum disorder: Case report.

Introduction: Eculizumab has been shown to be an effective and typically well-tolerated medication in the treatment of neuromyelitis optica spectrum disorder (NMOSD) in maintaining disease remission in patients who are aquaporin-4 water channel autoantibody (AQP4-IgG) seropositive. The efficacy of eculizumab in an acute relapse of NMOSD however is still under review. Case: We describe a 46 year-old female who presented with acute left monocular vision loss on a background of bilateral optic neuritis treated 15 years prior as suspected NMOSD. She had very poor vision from the right eye (6/60). On presentation she was not on any long-term immunosuppressive agents. Her serum was positive for AQP4-IgG and MRI brain and spine demonstrated areas of demyelination in the corpus callosum and thoracic spine. She was treated with high dose intravenous methylprednisolone and underwent plasmapheresis for five consecutive days, but continued to clinically deteriorate with ongoing blindness in her left eye (light perception only). She was subsequently administered eculizumab with weaning oral corticosteroids. Clinically her vision improved to counting fingers and she remains on maintenance eculizumab infusions in the community. At 3 months, there is a steady improvement but still significant loss of central vision from that eye. Conclusion: The utility of eculizumab in NMOSD may assist with treating acute episodes. This theoretically accords with the mode of action in inhibiting conversion of C5-C5a/b, perhaps arresting the acute inflammatory process in this disease. Given that disease burden and mortality in NMOSD is almost entirely related to relapses, increased use of eculizumab acutely could potentially aid recovery from an attack in very severe attacks, and therefore minimize immediate stepwise accrual of disability.

Unusual presentations of central nervous system myeloid sarcoma.

Myeloid sarcoma (MS), also termed 'chloroma' or 'granulocytic sarcoma', is a tumour mass consisting of myeloid blasts occurring at an anatomical site other than the bone marrow. MS occurs in up to 8% of patients with acute myeloid leukaemia. While MS typically involves the skin or lymph nodes, almost any tissue can be affected, and symptoms largely depend on the organ involved and subsequent mass effect. We present a case series of patients that presented to a tertiary hospital with MS affecting the central nervous system over a 4-month period. These three cases demonstrate the vast spectrum of clinical presentations of MS and, furthermore, show rare examples of intramedullary spinal cord involvement and disseminated intraparenchymal brain disease.

Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing.

More than 50 neurological and neuromuscular diseases are caused by short tandem repeat (STR) expansions, with 37 different genes implicated to date. We describe the use of programmable targeted long-read sequencing with Oxford Nanopore's ReadUntil function for parallel genotyping of all known neuropathogenic STRs in a single assay. Our approach enables accurate, haplotype-resolved assembly and DNA methylation profiling of STR sites, from a list of predetermined candidates. This correctly diagnoses all individuals in a small cohort (n = 37) including patients with various neurogenetic diseases (n = 25). Targeted long-read sequencing solves large and complex STR expansions that confound established molecular tests and short-read sequencing and identifies noncanonical STR motif conformations and internal sequence interruptions. We observe a diversity of STR alleles of known and unknown pathogenicity, suggesting that long-read sequencing will redefine the genetic landscape of repeat disorders. Last, we show how the inclusion of pharmacogenomic genes as secondary ReadUntil targets can further inform patient care.

Serum electrolyte concentrations and skeletal muscle excitability in vivo.

OBJECTIVE: Multi-fibre muscle velocity recovery cycle (MVRC) assessment is a well-tolerated method of evaluating sarcolemmal excitability in vivo that shows promise as a research tool and biomarker. MVRC parameters correlate with venous electrolyte concentrations in myopathies. We sought to determine the nature of any such relationships in individuals without muscle disease. METHODS: Tibialis anterior MVRCs were recorded and electrolyte concentrations measured from two groups of healthy volunteers. After studying a single measure cohort (n = 65, one recording/person), we studied a repeated measures cohort (n = 4, eight recordings/person) to better study intra-individual relationships using repeated measures correlation (rmcorr). RESULTS: In the single measure cohort, no significant correlations were present between MVRC parameters and electrolyte levels after accounting for age. In the repeated measures cohort, the relative refractory period (P < 0.01) and stimulus frequency measures (P < 0.01) correlated positively with potassium levels. Multiple late supernormality group measures correlated negatively with bicarbonate levels (P < 0.01). CONCLUSIONS: MVRC measures that vary with the resting muscle membrane potential correlate with venous potassium concentrations, as in myopathies. Late supernormality measures correlate with bicarbonate levels. SIGNIFICANCE: Determination of serum electrolyte levels may inform the interpretation of MVRC study results if variation in concentrations is anticipated to be significant.

Posturography as a biomarker of intravenous immunoglobulin efficacy in chronic inflammatory demyelinating polyradiculoneuropathy.

INTRODUCTION/AIMS: Imbalance is a common feature of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Intravenous immunoglobulin (IVIg) exerts clinical benefit in CIDP, including improving balance, although objective markers of efficacy are lacking. Posturography is an established objective marker of balance; therefore, this study aimed to determine the utility of posturography as an objective marker of treatment efficacy in CIDP. METHODS: Posturography was performed on 18 CIDP patients, established on IVIg infusions, and results were compared to age-matched healthy controls. CIDP patients were assessed just prior to IVIg infusion and at the mid-point of the cycle. Center of pressure (CoP) was measured and the total path traveled by CoP (Sway Path, SP) was calculated for five different conditions: feet placed in parallel 16 cm apart at the medial border with eyes open (16cmEO) and eyes closed (16cmEC); medial borders of the feet touching with eyes open (0cmEO) and eyes closed (0cmEC); and tandem stance. RESULTS: The sway path (SP) was significantly increased in CIDP patients (mean SP 1191 ± 104 mm) when compared to healthy controls (mean SP 724 ± 26 mm, P < .001). The increase was most prominent during eyes closed and tandem stance conditions. Treatment with IVIg significantly reduced SP when assessing 0cmEC (1759 ± 324 mm vs. 1081 ± 134 mm, P = .019) and tandem stance (1775 ± 290 mm vs. 1152 ± 113 mm, P = .027). DISCUSSION: Posturography detected significant improvements in balance following IVIg in CIDP patients established on maintenance therapy. As such, posturography may be considered an objective marker of treatment response in clinical management and therapeutic trials.

Increase in ACC GABA+ levels correlate with decrease in migraine frequency, intensity and disability over time.

BACKGROUND: An imbalance between inhibitory and excitatory neurometabolites has been implicated in chronic pain. Prior work identified elevated levels of Gamma-aminobutyric acid + macromolecules ("GABA+") using magnetic resonance spectroscopy (MRS) in people with migraine. What is not understood is whether this increase in GABA+ is a cause, or consequence of living with, chronic migraine. Therefore, to further elucidate the nature of the elevated GABA+ levels reported in migraine, this study aimed to observe how GABA+ levels change in response to changes in the clinical characteristics of migraine over time. METHODS: We observed people with chronic migraine (ICHD-3) over 3-months as their treatment was escalated in line with the Australian Pharmaceutical Benefits Scheme (PBS). Participants underwent an MRS scan and completed questionnaires regarding migraine frequency, intensity (HIT-6) and disability (WHODAS) at baseline and following the routine 3 months treatment escalation to provide the potential for some participants to recover. We were therefore able to monitor changes in brain neurochemistry as clinical characteristics potentially changed over time. RESULTS: The results, from 18 participants who completed both baseline and follow-up measures, demonstrated that improvements in migraine frequency, intensity and disability were associated with an increase in GABA+ levels in the anterior cingulate cortex (ACC); migraine frequency (r = - 0.51, p = 0.03), intensity (r = - 0.51, p = 0.03) and disability (r = - 0.53, p = 0.02). However, this was not seen in the posterior cingulate gyrus (PCG). An incidental observation found those who happened to have their treatment escalated with CGRP-monoclonal antibodies (CGRP-mAbs) (n = 10) had a greater increase in ACC GABA+ levels (mean difference 0.54 IU IQR [0.02 to 1.05], p = 0.05) and reduction in migraine frequency (mean difference 10.3 IQR [2.52 to 18.07], p = 0.01) compared to those who did not (n = 8). CONCLUSION: The correlation between an increase in ACC GABA+ levels with improvement in clinical characteristics of migraine, suggest previously reported elevated GABA+ levels may not be a cause of migraine, but a protective mechanism attempting to suppress further migraine attacks.

Increased GABA+ in People With Migraine, Headache, and Pain Conditions- A Potential Marker of Pain.

Treatment outcomes for migraine and other chronic headache and pain conditions typically demonstrate modest results. A greater understanding of underlying pain mechanisms may better inform treatments and improve outcomes. Increased GABA+ has been identified in recent studies of migraine, however, it is unclear if this is present in other headache, and pain conditions. We primarily investigated GABA+ levels in the posterior cingulate gyrus (PCG) of people with migraine, whiplash-headache and low back pain compared to age- and sex-matched controls, GABA+ levels in the anterior cingulate cortex (ACC) and thalamus formed secondary aims. Using a cross-sectional design, we studied people with migraine, whiplash-headache or low back pain (n = 56) and compared them with a pool of age- and sex-matched controls (n = 22). We used spectral-edited magnetic resonance spectroscopy at 3T (MEGA-PRESS) to determine levels of GABA+ in the PCG, ACC and thalamus. PCG GABA+ levels were significantly higher in people with migraine and low back pain compared with controls (eg, migraine 4.89 IU ± 0.62 vs controls 4.62 IU ± 0.38; P = .02). Higher GABA+ levels in the PCG were not unique to migraine and could reflect a mechanism of chronic pain in general. A better understanding of pain at a neurochemical level informs the development of treatments that target aberrant brain neurochemistry to improve patient outcomes. PERSPECTIVE: This study provides insights into the underlying mechanisms of chronic pain. Higher levels of GABA+ in the PCG may reflect an underlying mechanism of chronic headache and pain conditions. This knowledge may help improve patient outcomes through developing treatments that specifically address this aberrant brain neurochemistry.