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.

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.

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.

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.

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.

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.

Early nerve repair in traumatic brachial plexus injuries in adults: treatment algorithm and first experiences.

OBJECTIVE: The object of this study was to assess the advantages and disadvantages of early nerve repair within 2 weeks following adult traumatic brachial plexus injury (ATBPI). METHODS: From 2009 onwards, the authors have strived to repair as early as possible extended C-5 to C-8 or T-1 lesions or complete loss of C-5 to C-6 or C-7 function in patients in whom there was clinical and radiological suspicion of root avulsion. Among a group of 36 patients surgically treated in the period between 2009 and 2011, surgical findings in those who had undergone treatment within 2 weeks after trauma were retrospectively compared with results in those who had undergone delayed treatment. The result of biceps muscle reanimation was the primary outcome measure. RESULTS: Five of the 36 patients were referred within 2 weeks after trauma and were eligible for early surgery. Nerve ruptures and/or avulsions were found in all early cases of surgery. The advantages of early surgery are as follows: no scar formation, easy anatomical identification, and gap length reduction. Disadvantages include less-clear demarcation of vital nerve tissue and unfamiliarity with the interpretation of frozen-section examination findings. All 5 early-treatment patients recovered a biceps force rated Medical Research Council grade 4. CONCLUSIONS: Preliminary results of nerve repair within 2 weeks of ATBPI are encouraging, and the benefits outweigh the drawbacks. The authors propose a decision algorithm to select patients eligible for early surgery. Referral standards for patients with ATBPI must be adapted to enable early surgery.

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.

Impaired health-related quality of life in meningioma patients-a systematic review.

While surgical and radiotherapeutic improvements increased life expectancy of meningioma patients, little is known about these patients' health-related quality of life (HRQoL). Therefore, the objectives of this systematic review were to assess HRQoL in meningioma patients, the methodological quality of the used questionnaires (COSMIN criteria), and the reporting level of patient-reported outcomes (PROs) in the included studies (International Society of Quality of Life Research criteria).Nineteen articles met our inclusion criteria. HRQoL was measured with 13 different questionnaires, 3 validated in meningioma patients. According to our predefined cutoff, HRQoL data were reported sufficiently in 5 out of 19 studies. Both findings hamper interpretation of the PRO results.In general, meningioma patients reported clinically worse HRQoL than healthy controls. Although meningioma patients had better HRQoL than glioma patients, this difference was not clinically relevant. Radiotherapy seemed to improve some domains of HRQoL in the short term, while HRQoL decreased to pre-radiotherapy levels in the long term. Tumor resection increased HRQoL, but long-term follow-up showed persistent reduced HRQoL compared with healthy controls. These results suggest an impaired HRQoL in meningioma patients, even years after anti-tumor treatment. Results of this systematic review warrant high quality prospective studies, better instruments to assess HRQoL, and improved level of reporting for this group of patients.

Reliability and Validity of the Therapy Intensity Level Scale: Analysis of Clinimetric Properties of a Novel Approach to Assess Management of Intracranial Pressure in Traumatic Brain Injury.

We aimed to assess the reliability and validity of the Therapy Intensity Level scale (TIL) for intracranial pressure (ICP) management. We reviewed the medical records of 31 patients with traumatic brain injury (TBI) in two European intensive care units (ICUs). The ICP TIL was derived over a 4-day period for 4-h (TIL4) and 24-h epochs (TIL24). TIL scores were compared with historical schemes for TIL measurement, with each other, and with clinical variables. TIL24 scores in ICU patients with TBI were compared with two control groups: patients with extracranial trauma necessitating intensive care (Trauma_ICU; n = 20) and patients with TBI not needing ICU care (TBI_WARD; n = 19), to further determine the discriminative validity of the TIL for ICP-related ICU interventions. Interrater and intraobserver agreement were excellent for TIL4 and TIL24 (Cohen κ: 0.98-0.99; intraclass correlation coefficient: 0.99-1; p < 0.0005). The mean + standard deviation (SD) TIL24 in the ICU TBI cohort was significantly higher than the Trauma_ICU patients and the TBI_WARD patients (8.2 ± 3.2 vs. 2.2 ± 0.9 and 0.1 ± 0.1, respectively; p < 0.005 for both comparisons). Correlations between the TIL scale scores and historical TIL scores, between TIL24 and the Glasgow Coma Scale, and between a range of TIL metrics and summary measures of ICP over the 4-day period, were all highly significant (p < 0.01). The results were consistent with the expected direction. A linear mixed effect analysis, accounting for within-subjects repeated measures, showed strong correlation between TIL4 and 4-h ICP (p < 0.0000005). The TIL scale is a reliable measurement instrument with a high degree of validity for assessing the therapeutic intensity level of ICP management in patients with TBI.

Accumulation of rare variants in the arylsulfatase G (ARSG) gene in task-specific dystonia.

Musician's dystonia and writer's cramp are examples of task-specific dystonia. Recently, the arylsulfatase G (ARSG) locus was suggested to be associated with musician's dystonia and writer's cramp by a genome-wide association study. To test for the presence of causal variants, the entire coding region and exon-intron boundaries of ARSG were sequenced in DNA samples from 158 musician's dystonia patients which were collected at the University of Music, Drama, and Media (Hanover, Germany), and 72 patients with writer's cramp which were recruited at the Academic Medical Centers in Amsterdam and Groningen, the Netherlands. The frequency of variants within ARSG was compared to publically available data at the exome variant server (EVS) from the NHLBI GO Exome Sequencing Project. We identified 11 single nucleotide variants (SNVs) in the patients including eight non-synonymous substitutions. All variants have previously been reported at EVS including two SNVs with a reported minor allele frequency <1%. One rare missense variant, rs61999318 (p.I493T), was significantly enriched in the group of writer's cramp patients compared to European Americans in EVS database (p = 0.0013). In patients with writer's cramp, there was an overall enrichment for rare, protein-changing variants compared to controls (p < 0.01). In conclusion, we did not detect any conclusive mutation in ARSG. However, we showed an association with rs61999318 in patients with writer's cramp that contributed to an overall enrichment for rare, protein-changing variants in these patients. Thus, our data provide further support for a role of ARSG variants in task-specific dystonia, especially writer's cramp.

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.

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.

DRD1 rare variants associated with tardive-like dystonia: a pilot pathway sequencing study in dystonia.

The dystonias are a clinical heterogeneous group with a complex genetic background. To gain more insight in genetic risk factors in dystonia we used a pathway sequence approach in patients with an extreme dystonia phenotype (n = 26). We assessed all coding and non-coding variants in candidate genes in D1-like subclass of dopamine receptor genes (DRD1, DRD5) and the synaptic vesicle pathway linked to torsinA (TOR1A, STON2, SNAPIN, KLC1 and THAP1), spanning 96 Kb. Two rare missense variants in DRD1 were found: c.68G>A(p.Arg23His) in the screening group and c.776C>A(p.Ser259Tyr) in an additional screen of 15 selected dystonia patients. Genetic burden analysis of DRD1 rare variants in patients (4.8%) versus European American controls from ESP (0.72%) reveals an OR 5.35 (95% CI 1.29-23.1). No rare missense SNVs in the synaptic vesicle pathway were found. Sequencing of TOR1A showed variant enrichment in haplotype 2, possibly accountable for contradictive results in previous association studies. Two new rare SNVs were detected in THAP1, including a nonsense mutation (p.Gln167Ter) and a splice site variant (c.72-1G>A). Screening for rare SNV of candidate pathways in a phenotype extreme population appears to be a promising alternative method to identify genetic risk factors in complex disorders like primary torsion dystonia. These findings indicate a role for rare genetic variation in dopamine processing genes in dystonia pathophysiology.

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.