Optimal timing of needle electromyography to diagnose lesion severity in traumatic radial nerve injury.

INTRODUCTION/AIMS: In patients with traumatic radial nerve injury (RNI), the chance of spontaneous recovery must be balanced against the benefits of early surgical reconstruction. We aimed to explore the time-specific value of needle electromyography (NEMG) to diagnose nerve lesion severity. METHODS: In this retrospective diagnostic accuracy study at Leiden Nerve Center, patients at least 12 years of age with RNI caused by fractures or fracture treatment were included. The sensitivity and specificity of the patients' first NEMG examination were assessed, stratified by the timing after the nerve injury. The absence of motor unit potentials (MUPs) in muscles distal to the nerve lesion was considered a positive test result. Lesion severity was dichotomized to moderate injury (spontaneous Medical Research Council grade ≥3 recovery) or severe injury (poor spontaneous recovery or surgical confirmation of a mainly neurotmetic lesion). RESULTS: Ninety-five patients were included in our study. The sensitivity of NEMG to detect severe RNI was 75.0% (3 of 4) in the fourth, 66.7% (2 of 3) in the fifth, and 66.7% (2 of 3) in the sixth month after the nerve injury. The specificity in the first to the sixth month was 0.0% (0 of 1), 50.0% (2 of 4), 77.3% (17 of 22), 95.5% (21 of 22), 95.8% (23 of 24), and 100.0% (12 of 12), respectively. DISCUSSION: The specificity of NEMG is higher than 95% and therefore clinically relevant from the fourth month after the nerve injury onward. Absence of MUPs at this time can be considered an indication to plan nerve exploration. Moreover, the presence of MUPs on NEMG does not completely exclude the necessity for surgical reconstruction.

Evidence in peroneal nerve entrapment: A scoping review.

BACKGROUND AND PURPOSE: Daily management of patients with foot drop due to peroneal nerve entrapment varies between a purely conservative treatment and early surgery, with no high-quality evidence to guide current practice. Electrodiagnostic (EDX) prognostic features and the value of imaging in establishing and supplementing the diagnosis have not been clearly established. METHODS: We performed a literature search in the online databases MEDLINE, Embase, and the Cochrane Library. Of the 42 unique articles meeting the eligibility criteria, 10 discussed diagnostic performance of imaging, 11 reported EDX limits for abnormal values and/or the value of EDX in prognostication, and 26 focused on treatment outcome. RESULTS: Studies report high sensitivity and specificity of both ultrasound (varying respectively from 47.1% to 91% and from 53% to 100%) and magnetic resonance imaging (MRI; varying respectively from 31% to 100% and from 73% to 100%). One comparative trial favoured ultrasound over MRI. Variable criteria for a conduction block (>20%-≥50) were reported. A motor conduction block and any baseline compound motor action potential response were identified as predictors of good outcome. Based predominantly on case series, the percentage of patients with good outcome ranged 0%-100% after conservative treatment and 40%-100% after neurolysis. No study compared both treatments. CONCLUSIONS: Ultrasound and MRI have good accuracy, and introducing imaging in the standard diagnostic workup should be considered. Further research should focus on the role of EDX in prognostication. No recommendation on the optimal treatment strategy of peroneal nerve entrapment can be made, warranting future randomized controlled trials.

Fusion rates support wired allograft combined with instrumented craniocervical fixation in the paediatric population.

BACKGROUND: Occipitocervical and atlantoaxial instability in the pediatric population is a rare and challenging condition to treat. Variable surgical techniques have been employed to achieve fusion. The study aimed to assess bony fusion with rigid craniocervical fixation using an allograft bone block to serve as scaffold for bony fusion. METHODS: This is a single center case series from a tertiary referral neurosurgical center. The series includes 12 consecutive pediatric patients with rigid craniocervical fusion between 2006 and 2014. The primary outcome was bony fusion as assessed by computed tomography and flexion-extension radiographs. The authors did not receive external funding for this study. RESULTS: Twelve patients (age 1-15 years) were operated with a median imaging follow-up time of 22 months (range 6-69 m). A modified Gallie fusion technique with a tightly wired allograft bone block was used in 10 of 13 procedures. One patient underwent re-fixation due to screw breakage. Eleven out of 13 procedures resulted in a stable construct with bony fusion. All 10 patients operated with the modified Gallie fusion technique with sublaminar wiring of allograft bone block had bony fusion. No post-operative complications of the posterior fixation procedure were noted. CONCLUSIONS: The modified Gallie fusion technique with allograft bone block without post-operative immobilization achieved excellent fusion. We conclude there is no need to use autograft or BMPs in craniocervical fusion in the pediatric population, which avoids related donor-site morbidity. LEVEL OF EVIDENCE: Level IV-case series; therapeutic.

CACNA1B mutation is linked to unique myoclonus-dystonia syndrome.

Using exome sequencing and linkage analysis in a three-generation family with a unique dominant myoclonus-dystonia-like syndrome with cardiac arrhythmias, we identified a mutation in the CACNA1B gene, coding for neuronal voltage-gated calcium channels CaV2.2. This mutation (c.4166G>A;p.Arg1389His) is a disruptive missense mutation in the outer region of the ion pore. The functional consequences of the identified mutation were studied using whole-cell and single-channel patch recordings. High-resolution analyses at the single-channel level showed that, when open, R1389H CaV2.2 channels carried less current compared with WT channels. Other biophysical channel properties were unaltered in R1389H channels including ion selectivity, voltage-dependent activation or voltage-dependent inactivation. CaV2.2 channels regulate transmitter release at inhibitory and excitatory synapses. Functional changes could be consistent with a gain-of-function causing the observed hyperexcitability characteristic of this unique myoclonus-dystonia-like syndrome associated with cardiac arrhythmias.

Anterior subcutaneous transposition for persistent ulnar neuropathy after neurolysis.

OBJECTIVE Little is known about optimal treatment if neurolysis for ulnar nerve entrapment at the elbow fails. The authors evaluated the clinical outcome of patients who underwent anterior subcutaneous transposition after failure of neurolysis of ulnar nerve entrapment (ASTAFNUE). METHODS A consecutive series of patients who underwent ASTAFNUE performed by a single surgeon between 2009 and 2014 was analyzed retrospectively. Preoperative and postoperative complaints in the following 3 clinical modalities were compared: pain and/or tingling, weakness, and numbness. Six-point satisfaction scores were determined on the basis of data from systematic telephonic surveys. RESULTS Twenty-six patients were included. The median age was 56 years (range 22-79 years). The median duration of complaints before ASTAFNUE was 23 months (range 8-78 months). The median interval between neurolysis and ASTAFNUE was 11 months (range 5-34 months). At presentation, 88% of the patients were experiencing pain and/or tingling, 46% had weakness, and 50% had numbness of the fourth and fifth fingers. Pain and/or tingling improved in 35%, motor function in 23%, and sensory disturbances in 19% of all the patients. Improvement in at least 1 of the 3 clinical modalities was found in 58%. However, a deterioration in 1 of the 3 modalities was noted in 46% of the patients. On the patient-satisfaction scale, 62% reported a good or excellent outcome. Patients with a good/excellent outcome were a median of 11 years younger than patients with a fair/poor outcome. No other factor was significantly related to satisfaction score. CONCLUSIONS A majority of the patients were satisfied after ASTAFNUE, even though their symptoms only partly resolved or even deteriorated. Older age is a risk factor for a poor outcome. Other factors that affect outcome might play a role, but they remain unidentified. One of these factors might be earlier surgical intervention. The modest results of ASTAFNUE should be mentioned when counseling patients after failure of neurolysis of ulnar nerve entrapment to manage their expectations. Patients, especially those who are elderly, might even consider not undergoing a secondary procedure. A randomized trial that includes a conservative treatment group and groups undergoing one of the several possible surgical procedures is needed to find the definitive answer for this clinical problem.

RELN rare variants in myoclonus-dystonia.

BACKGROUND: Myoclonus-dystonia (M-D) is a hyperkinetic movement disorder with predominant myoclonic symptoms combined with dystonia of the upper part of the body. A proportion of M-D cases are caused by mutations in the epsilon-sarcoglycan gene. In remaining M-D patients, no genetic factor has been established, indicating genetic heterogeneity. METHODS: Patients were included in a prospective clinical database and recruited from referral centers and general neurology clinics in The Netherlands. To investigate new genetic causal factors in M-D syndrome, we performed homozygosity mapping combined with exome sequencing in a three-generation M-D family and genetically screened 24 additional patients with M-D. RESULTS: We found co-segregation of the rare missense variant Thr1904Met in the RELN gene. By additional screening of an M-D cohort, we identified co-segregation of RELN variants in two families (Thr1904Met, Ile1217Met) and identified two sporadic RELN mutation carriers (Pro1703Arg, Leu411Ile). Taken together, five of 25 SGCE-negative M-D patients carried RELN rare missense variants. CONCLUSION: We propose that RELN mutations contribute to the genetic heterogeneity of M-D. Reelin is a large secreted glycoprotein that plays essential roles in the cytoarchitecture of laminated brain structures and modulation of synaptic transmission and plasticity.

Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene.

OBJECTIVE: A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family. METHODS: Genome-wide linkage analysis was carried out in 14 family members followed by genome sequencing in 2 individuals. The index patient underwent a detailed neurological follow-up examination, including electrophysiological studies and magnetic resonance imaging scanning. Biopsies of the skin and olfactory mucosa were obtained, and expression levels of TUBB4 mRNA were determined by quantitative real-time polymerase chain reaction in 3 different cell types. All exons of TUBB4 were screened for mutations in 394 unrelated dystonia patients. RESULTS: The disease-causing gene was mapped to a 23cM region on chromosome 19p13.3-p13.2 with a maximum multipoint LOD score of 5.338 at markers D9S427 and D9S1034. Genome sequencing revealed a missense variant in the TUBB4 (tubulin beta-4; Arg2Gly) gene as the likely cause of disease. Sequencing of TUBB4 in 394 unrelated dystonia patients revealed another missense variant (Ala271Thr) in a familial case of segmental dystonia with spasmodic dysphonia. mRNA expression studies demonstrated significantly reduced levels of mutant TUBB4 mRNA in different cell types from a heterozygous Arg2Gly mutation carrier compared to controls. INTERPRETATION: A mutation in TUBB4 causes DYT4 dystonia in this Australian family with so-called whispering dysphonia, and other mutations in TUBB4 may contribute to spasmodic dysphonia. Given that TUBB4 is a neuronally expressed tubulin, our results imply abnormal microtubule function as a novel mechanism in the pathophysiology of dystonia.

Genome-wide association study in musician's dystonia: a risk variant at the arylsulfatase G locus?

Musician's dystonia (MD) affects 1% to 2% of professional musicians and frequently terminates performance careers. It is characterized by loss of voluntary motor control when playing the instrument. Little is known about genetic risk factors, although MD or writer's dystonia (WD) occurs in relatives of 20% of MD patients. We conducted a 2-stage genome-wide association study in whites. Genotypes at 557,620 single-nucleotide polymorphisms (SNPs) passed stringent quality control for 127 patients and 984 controls. Ten SNPs revealed P < 10(-5) and entered the replication phase including 116 MD patients and 125 healthy musicians. A genome-wide significant SNP (P < 5 × 10(-8) ) was also genotyped in 208 German or Dutch WD patients, 1,969 Caucasian, Spanish, and Japanese patients with other forms of focal or segmental dystonia as well as in 2,233 ethnically matched controls. Genome-wide significance with MD was observed for an intronic variant in the arylsulfatase G (ARSG) gene (rs11655081; P = 3.95 × 10(-9) ; odds ratio [OR], 4.33; 95% confidence interval [CI], 2.66-7.05). rs11655081 was also associated with WD (P = 2.78 × 10(-2) ) but not with any other focal or segmental dystonia. The allele frequency of rs11655081 varies substantially between different populations. The population stratification in our sample was modest (λ = 1.07), but the effect size may be overestimated. Using a small but homogenous patient sample, we provide data for a possible association of ARSG with MD. The variant may also contribute to the risk of WD, a form of dystonia that is often found in relatives of MD patients.

Is TOR1A a risk factor in adult-onset primary torsion dystonia?

BACKGROUND: Studies of genetic association between TOR1A and adult-onset primary torsion dystonia have contradictory results. METHODS: The authors genotyped TOR1A single nucleotide polymorphisms rs1801968, rs2296793, rs1182 and rs3842225 in a cohort of clinically well characterized cervical dystonia patients (n=367) and constructed haplotypes. The authors systematically reviewed the published case-control TOR1A association studies in adult-onset primary torsion dystonia. RESULTS: In this Dutch cervical dystonia cohort, no significant association was found with TOR1A variants. In the meta-analysis (eight studies, 1332 adult-onset primary dystonia patients) no variant reached overall significance. However, in a selection of familial cases the functional variant p.Asp216His (rs1801968) was associated with increased dystonia risk (odds ratio 1.43; 95%CI 1.01-2.02). CONCLUSIONS: Meta-analysis does not show association with common variants in TOR1A in adult-onset primary dystonia, except for the functional variant rs1801968 in familial focal dystonia cases.

Early grafting in severe adult traumatic brachial plexus injury.

Nerve surgical treatment for severe adult traumatic brachial plexus injury is traditionally delayed for months to await spontaneous recovery. Since 2009, the authors have strived to operate on patients with severe brachial plexus lesions within 2 weeks after trauma. This video shows the workup, surgical strategy, and benefits of early supraclavicular nerve grafting, including intraoperative nerve stimulation. The video can be found here: https://stream.cadmore.media/r10.3171/2022.10.FOCVID2288.

A randomized controlled trial comparing conservative versus surgical treatment in patients with foot drop due to peroneal nerve entrapment: results of an internal feasibility pilot study.

BACKGROUND: Based on the lack of literature to support any treatment strategy in patients with foot drop due to peroneal nerve entrapment, a prospective study randomizing patients between surgery and conservative treatment is warranted. Since studies comparing surgery to no surgery are often challenging, we first examined the feasibility of such a randomized controlled trial. METHODS/DESIGN: An internal feasibility pilot study was conducted to assess several aspects of process, resource, management, and scientific feasibility. The main objective was the assessment of the recruitment rate. The criterion to embark on a full study was the recruitment of at least 14 patients in 6 participating centers within 6 months. Cross-over rate, blinding measures, training strategies, and trial assessments were evaluated. The trial was entirely funded by the KCE Trials public funding program of the Belgian Health Care Knowledge Centre (ID KCE19-1232). RESULTS: The initial duration was prolonged due to the COVID-19 pandemic. Between April 2021 and October 2022, we included 19 patients of which 15 were randomized. Fourteen patients were treated as randomized. One drop-out occurred after randomization, prior to surgery. We did not document any cross-over or accidental unblinding. Training strategies were successful. Patients perceived the quality of life questionnaire as the least relevant assessment. Assessment of ankle dorsiflexion range of motion was prone to interobserver variability. All other trial assessments were adequate. DISCUSSION: Recruitment of the anticipated 14 patients was feasible although slower than expected. The Short-Form Health Survey (SF-36) and assessment of ankle dorsiflexion range of motion will no longer be included in the full-scale FOOTDROP trial. CONCLUSION: The FOOTDROP study is feasible. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT04695834 . Registered 4 January 2021.

Cognition and psychopathology in myoclonus-dystonia.

OBJECTIVE: (1) To study the neuropsychological and psychopathological profile in myoclonus-dystonia (M-D) patients with and without a mutation in the DYT11 gene. (2) To explore whether cognitive and psychiatric impairments are related to severity and duration of motor symptoms. Herewith, this study may help to clarify whether neuropsychological and psychiatric symptoms are associated with the DYT11 mutation or are secondary to the burden of motor impairments that originated in early childhood. METHODS: Extensive batteries of neuropsychological tests and psychiatric questionnaires were administered to DYT11 gene mutation-carrying (MC) M-D patients (n=31), non-mutation-carrying (NMC) M-D patients (n=20) and a healthy control group (n=36). RESULTS: MC M-D patients demonstrated mild impairments in executive functions. On the contrary, with the exception of one type of verbal fluency, no evident cognitive impairments were found in NMC M-D patients. Further, increased rates of anxiety disorders were found only in MC M-D patients, whereas increased rates of depressive symptoms were observed in both M-D groups. Correlation analyses yielded modest associations between severity of myoclonus and executive functions. No relationships were found between neuropsychological test performance and scores on the psychiatric assessments. CONCLUSIONS: The findings of this study suggest that anxiety disorders and executive dysfunctions may be part of the phenotype of M-D patients with a DYT11 mutation, whereas depressive symptoms and semantic fluency impairments may be secondary to suffering from a chronic movement disorder, regardless of DYT11 gene mutation.

Phenotypes and genetic architecture of focal primary torsion dystonia.

BACKGROUND: The focal primary torsion dystonias (FPTDs) form a group of clinical heterogeneous syndromes and can be considered a genetic complex disease; it is thought to be primed by genetic variants with variable impact and triggered by non-genetic factors. Thorough clinical description of FPTDs cohorts is sparse but essential for further progress in genetic research. OBJECTIVE: To establish suggested relations between age at onset (AaO), site and family history in a large focal dystonias cohort and gain more insight into familial clustering for genetic research. PATIENTS AND METHODS: A prospective cohort study between March 2008 and March 2011, including 676 FPTD patients attending the botulinum toxin outpatient clinics of six Dutch movement disorder centres. RESULTS AND CONCLUSIONS: Of all of the FPTD patients, 25% had a familial predisposition; in 2.4% a Mendelian inheritance pattern was noted. With a stronger family history, a significantly lower AaO was seen in all focal dystonias. In both the sporadic and familial focal dystonia groups, AaO had an effect on the distribution of dystonia, with a caudal to cranial tendency. In all focal dystonia forms, women were more frequently affected, except for writer's cramp. Careful clinical characterisation will allow the formation of phenotype subgroups. We suggest that genetic research into FPTDs will benefit from this approach and discuss genetic research strategies to decipher the complex background of focal dystonias.

A new familial syndrome with dystonia and lower limb action myoclonus.

BACKGROUND: Myoclonus-dystonia (M-D) is genetic and clinically heterogeneous. Identification and description of rare M-D syndromes may contribute to gene identification. RESULTS: Here, we describe a new, autosomal dominant M-D syndrome in a 3-generation pedigree showing anticipation. Patients have progressive action-induced multifocal dystonia and generalized myoclonus. A remarkable feature of the syndrome is action myoclonus in the lower extremities triggered by upright posture, causing instability. Electrophysiological characterization shows a 12-Hz peak in the EMG autospectrum and corticomuscular and intermuscular coherences. CONCLUSIONS: A new familial M-D syndrome with progressive action myoclonus and dystonia is described.

Rare functional missense variants in CACNA1H: What can we learn from Writer's cramp?

Writer's cramp (WC) is a task-specific focal dystonia that occurs selectively in the hand and arm during writing. Previous studies have shown a role for genetics in the pathology of task-specific focal dystonia. However, to date, no causal gene has been reported for task-specific focal dystonia, including WC. In this study, we investigated the genetic background of a large Dutch family with autosomal dominant‒inherited WC that was negative for mutations in known dystonia genes. Whole exome sequencing identified 4 rare variants of unknown significance that segregated in the family. One candidate gene was selected for follow-up, Calcium Voltage-Gated Channel Subunit Alpha1 H, CACNA1H, due to its links with the known dystonia gene Potassium Channel Tetramerization Domain Containing 17, KCTD17, and with paroxysmal movement disorders. Targeted resequencing of CACNA1H in 82 WC cases identified another rare, putative damaging variant in a familial WC case that did not segregate. Using structural modelling and functional studies in vitro, we show that both the segregating p.Arg481Cys variant and the non-segregating p.Glu1881Lys variant very likely cause structural changes to the Cav3.2 protein and lead to similar gains of function, as seen in an accelerated recovery from inactivation. Both mutant channels are thus available for re-activation earlier, which may lead to an increase in intracellular calcium and increased neuronal excitability. Overall, we conclude that rare functional variants in CACNA1H need to be interpreted very carefully, and additional studies are needed to prove that the p.Arg481Cys variant is the cause of WC in the large Dutch family.

Late-onset Huntington disease with intermediate CAG repeats: true or false?

Huntington disease (HD) is a neurodegenerative disorder associated with an expanded CAG trinucleotide repeat length in the huntingtin gene. 'Intermediate alleles' with 27 to 35 CAG repeats generally do not cause HD but are unstable upon germ-line transmission. Insights in CAG repeat mosaicism and enhanced trinucleotide expansion in postmitotic neurons indicate that in the intermediate range, other factors than the CAG repeat length in diagnostic tests have to be considered. Here, we report two patients with mild, late onset HD and an intermediate repeat allele. The authors anticipate that intermediate repeats can cause late-onset HD due to disease modifiers and may be more common than previously stated.

DYT6 dystonia: mutation screening, phenotype, and response to deep brain stimulation.

Mutations in THAP1, a gene encoding a nuclear pro-apoptotic protein, have been associated with DYT6 dystonia. First reports on the phenotype of DYT6 dystonia show an early onset dystonia with predominant cranio-cervical and laryngeal involvement. Here we assessed the frequency and phenotype of THAP1 mutation carriers in a large Dutch cohort of adult-onset (≥26 years) dystonia (n = 388) and early-onset dystonia (n = 67) patients. We describe the phenotype of DYT6 dystonia patients and their response on GPi DBS. Overall, 3 nonsynonymous heterozygous mutations were detected in the early-onset group (4.5%). Two DYT6 families were identified, showing a heterozygous phenotype. All patients had segmental or generalized dystonia, often associated with profound oromandibular and laryngeal involvement. No nonsynonymous mutations were found in patients with adult-onset focal dystonia. Rare synonymous variants were identified in conserved regions of THAP1, two in the adult-onset cervical dystonia group and one in the control group. Four DYT6 dystonia patients were treated with GPi DBS with moderate to good response on motor function but marginal benefit on speech.

Surgical Interventions for Cervical Radiculopathy Caused by a Vertebral Artery Loop: A Case Report and Review of the Literature.

BACKGROUND: Aberrant vertebral artery loops are a rare clinical condition, with sparse data regarding the optimal treatment guidelines for individual patients. The heterogeneity of treatment options in the literature creates a problem when tailoring treatments to individual patients. In this review of the literature, multiple surgical treatments for cervical vertebral artery loops were analyzed and compared. In addition, this article provides a clinical case of a patient with a vertebral artery loop. METHODS: A literature review was conducted to identify studies investigating surgical treatments for a vertebral artery loop. Different surgical techniques were examined and the involved techniques and approaches described. The outcomes were assessed for each study and the effectiveness of the treatment determined. RESULTS: Twelve articles met the inclusion criteria for this review. Six types of surgical interventions were found in the literature. Each intervention had similar postoperative results, leading to either a significant improvement or a complete resolution of symptoms. CONCLUSIONS: Multiple successful surgical interventions have been described in the medical literature. However, because of the lack of evidence-based studies, no surgical intervention protocol could be determined. Treatment should therefore be tailored to individual patients' characteristics. Because not every radiologically detected vertebral artery loop is the main reason for a patient's symptoms, a thorough multidisciplinary approach is justified and advocated in patients with an atypical presentation, before a neurosurgical intervention takes place. More deliberate clinical decisions can be made once the understanding of the pathogenesis of this rare disease entity has been established and treatment protocols formulated.