Distance to first symptoms measured by the 6-min walking test differentiates between treatment success and failure in patients with degenerative lumbar disorders

PURPOSE The smartphone-based 6-min walking test (6WT) is an established digital outcome measure in patients undergoing surgery for degenerative lumbar disorders (DLD). In addition to the 6WTs primary outcome measure, the 6-min walking distance (6WD), the patient's distance to first symptoms (DTFS) and time to first symptoms (TTFS) can be recorded. This is the first study to analyse the psychometric properties of the DTFS and TTFS. METHODS Forty-nine consecutive patients (55 ± 15.8 years) completed the 6WT pre- and 6 weeks (W6) postoperative. DTFS and TTFS were assessed for reliability and content validity using disease-specific patient-reported outcome measures. The Zurich Claudication Questionnaire patient satisfaction subscale was used as external criterion for treatment success. Internal and external responsiveness for both measures at W6 was evaluated. RESULTS There was a significant improvement in DTFS and TTFS from baseline to W6 (p < 0.001). Both measures demonstrated a good test-retest reliability (β = 0.86, 95% CI 0.81-0.90 and β = 0.83, 95% CI 0.76-0.87, both p < 0.001). The DTFS exceeded the 6WD capability to differentiate between satisfied (82%) and unsatisfied patients (18%) with an AUC of 0.75 (95% CI 0.53-0.98) vs. 0.70 (95% CI 0.52-0.90). The TTFS did not demonstrate meaningful discriminative abilities. CONCLUSION Change in DTFS can differentiate between satisfied and unsatisfied patients after spine surgery. Digital outcome measures on the 6WT metric provide spine surgeons and researchers with a mean to assess their patient's functional disability and response to surgical treatment in DLD

The association of patient age with postoperative morbidity and mortality following resection of intracranial tumors

INTRODUCTION The postoperative functional status of patients with intracranial tumors is influenced by patient-specific factors, including age. RESEARCH QUESTION This study aimed to elucidate the association between age and postoperative morbidity or mortality following the resection of brain tumors. MATERIAL AND METHODS A multicenter database was retrospectively reviewed. Functional status was assessed before and 3-6 months after tumor resection by the Karnofsky Performance Scale (KPS). Uni- and multivariable linear regression were used to estimate the association of age with postoperative change in KPS. Logistic regression models for a ≥10-point decline in KPS or mortality were built for patients ≥75 years. RESULTS The total sample of 4864 patients had a mean age of 56.4 ​± ​14.4 years. The mean change in pre-to postoperative KPS was -1.43. For each 1-year increase in patient age, the adjusted change in postoperative KPS was -0.11 (95% CI -0.14 - - 0.07). In multivariable analysis, patients ≥75 years had an odds ratio of 1.51 to experience postoperative functional decline (95%CI 1.21-1.88) and an odds ratio of 2.04 to die (95%CI 1.33-3.13), compared to younger patients. DISCUSSION Patients with intracranial tumors treated surgically showed a minor decline in their postoperative functional status. Age was associated with this decline in function, but only to a small extent. CONCLUSION Patients ≥75 years were more likely to experience a clinically meaningful decline in function and about two times as likely to die within the first 6 months after surgery, compared to younger patients

Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia

Background: Friedreich’s ataxia (FRDA) is the most common autosomal recessive ataxia. Disease-modifying treatments are not available yet; however, several compounds are currently under investigation. As a result, there is a growing need for the identification of robust and easily accessible biomarkers for the monitoring of disease activity and therapeutic efficacy. The simultaneous measurement of multiple brain-derived proteins could represent a time- and cost-efficient approach for biomarker investigation in pathologically complex neurodegenerative diseases like FRDA.Objectives: To investigate the role of plasma neurofilament-light chain (NfL), glial fibrillary acidic protein (GFAP), total tau (t-tau) and ubiquitin C-terminal hydrolase L1(UCHL1) as biomarkers in FRDA. Additionally, NfL measurements derived from the novel multiplex assay were compared to those from an established NfL singleplex assay.Methods: In this study, an ultrasensitive Single molecule array (Simoa) 4-plex assay was used for the measurement of plasma NfL, GFAP, t-tau, and UCHL1 in 33 FRDA patients and 13 age-matched controls. Differences in biomarker concentrations between these groups were computed and associations with genetic and disease related parameters investigated. Additionally, the agreement between NfL measurements derived from the 4-Plex and an established Simoa NfL singleplex assay was assessed.Results: Mean plasma NfL, GFAP and UCHL1 levels were significantly higher in FRDA patients than in controls (NfL: p &lt; 0.001; GFAP: p = 0.006, and UCHL1: p = 0.020). Conversely, there was no significant difference in concentrations of t-tau in the patient and control group (p = 0.236). None of the proteins correlated with the GAA repeat length or the employed measures of disease severity. The individual NfL values derived from the two assays showed a strong concordance (rc = 0.93). Although the mean difference of 1.29 pg/mL differed significantly from 0 (p = 0.006), regression analysis did not indicate the presence of a proportional bias.Conclusion: This is the first study demonstrating that NfL, GFAP, and UCHL1 levels are raised in FRDA, potentially reflecting ongoing neuronal degeneration and glial activation. Further studies are required to determine their role as marker for disease activity and progression. Furthermore, the novel 4-plex assay appears to be a valid tool to simultaneously measure brain-derived proteins at extremely low concentrations in the peripheral circulation

Association of pre- and postoperative αKlotho levels with long-term remission after pituitary surgery for acromegaly

Soluble αKlotho (sKl) is a disease-specific biomarker that is elevated in patients with acromegaly and declines after surgery for pituitary adenoma. Approximately 25% of patients do not achieve remission after surgery, therefore a risk stratification for patients early in the course of their disease may allow for the identification of patients requiring adjuvant treatment. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) have been assessed as biomarker for disease activity, however the value of sKl as a predictive biomarker of surgical success has not been evaluated yet. In this study, we measured serum biomarkers before and after transsphenoidal pituitary surgery in 55 treatment-naïve patients. Based on biochemical findings at follow-up (7-16 years), we divided patients into three groups: (A) long-term cure (defined by normal IGF-1 and random low GH (< 1 μg/l) or a suppressed GH nadir (< 0.4/μg/l) on oral glucose testing); (B) initial remission with later disease activity; (C) persistent clinical and/or biochemical disease activity. sKl levels positively related to GH, IGF-1 levels and tumor volume. Interestingly, there was a statistically significant difference in pre- and postoperative levels of sKl between the long-term cure group and the group with persistent disease activity. This study provides first evidence that sKl may serve as an additional marker for surgical success, decreasing substantially in all patients with initial clinical remission while remaining high after surgery in patients with persistent disease activity

A T-cell antigen atlas for meningioma: novel options for immunotherapy

Meningiomas are the most common primary intracranial tumors. Although most symptomatic cases can be managed by surgery and/or radiotherapy, a relevant number of patients experience an unfavorable clinical course and additional treatment options are needed. As meningiomas are often perfused by dural branches of the external carotid artery, which is located outside the blood-brain barrier, they might be an accessible target for immunotherapy. However, the landscape of naturally presented tumor antigens in meningioma is unknown. We here provide a T-cell antigen atlas for meningioma by in-depth profiling of the naturally presented immunopeptidome using LC-MS/MS. Candidate target antigens were selected based on a comparative approach using an extensive immunopeptidome data set of normal tissues. Meningioma-exclusive antigens for HLA class I and II are described here for the first time. Top-ranking targets were further functionally characterized by showing their immunogenicity through in vitro T-cell priming assays. Thus, we provide an atlas of meningioma T-cell antigens which will be publicly available for further research. In addition, we have identified novel actionable targets that warrant further investigation as an immunotherapy option for meningioma

Complexity of the Genetics and Clinical Presentation of Spinocerebellar Ataxia 17

Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the TATA-box binding protein gene (TBP). The disease has a varied age at onset and clinical presentation. It is distinct from other SCAs for its association with dementia, psychiatric symptoms, and some patients presenting with chorea. For this reason, it is also called Huntington’s disease-like 4 (HDL-4). Here we examine the distribution of SCA17 allele repeat sizes in a United Kingdom-based cohort with ataxia and find that fully penetrant pathogenic alleles are very rare (5 in 1,316 chromosomes; 0.38%). Phenotype-genotype correlation was performed on 30 individuals and the repeat structure of their TBP genes was examined. We found a negative linear correlation between total CAG repeat length and age at disease onset and, unlike SCA1, there was no correlation between the longest contiguous CAG tract and age at disease onset. We were unable to identify any particular phenotypic trait that segregated with particular CAG/CAA repeat tract structures or repeat lengths. One individual within the cohort was homozygous for variable penetrance range SCA17 alleles. This patient had a similar age at onset to heterozygotes with the same repeat sizes, but also presented with a rapidly progressive dementia. A pair of monozygotic twins within the cohort presented 3 years apart with the sibling with the earlier onset having a more severe phenotype with dementia and chorea in addition to the ataxia observed in their twin. This appears to be a case of variable expressivity, possibly influenced by other environmental or epigenetic factors. Finally, there was an asymptomatic father with a severely affected child with an age at onset in their twenties. Despite this, they share the same expanded allele repeat sizes and sequences, which would suggest that there is marked difference in the penetrance of this 51-repeat allele. We therefore propose that the variable penetrance range extend from 48 repeats to incorporate this allele. This study shows that there is variability in the presentation and penetrance of the SCA17 phenotype and highlights the complexity of this disorder

Complexity of the Genetics and Clinical Presentation of Spinocerebellar Ataxia 17

Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the TATA-box binding protein gene (TBP). The disease has a varied age at onset and clinical presentation. It is distinct from other SCAs for its association with dementia, psychiatric symptoms, and some patients presenting with chorea. For this reason, it is also called Huntington’s disease-like 4 (HDL-4). Here we examine the distribution of SCA17 allele repeat sizes in a United Kingdom-based cohort with ataxia and find that fully penetrant pathogenic alleles are very rare (5 in 1,316 chromosomes; 0.38%). Phenotype-genotype correlation was performed on 30 individuals and the repeat structure of their TBP genes was examined. We found a negative linear correlation between total CAG repeat length and age at disease onset and, unlike SCA1, there was no correlation between the longest contiguous CAG tract and age at disease onset. We were unable to identify any particular phenotypic trait that segregated with particular CAG/CAA repeat tract structures or repeat lengths. One individual within the cohort was homozygous for variable penetrance range SCA17 alleles. This patient had a similar age at onset to heterozygotes with the same repeat sizes, but also presented with a rapidly progressive dementia. A pair of monozygotic twins within the cohort presented 3 years apart with the sibling with the earlier onset having a more severe phenotype with dementia and chorea in addition to the ataxia observed in their twin. This appears to be a case of variable expressivity, possibly influenced by other environmental or epigenetic factors. Finally, there was an asymptomatic father with a severely affected child with an age at onset in their twenties. Despite this, they share the same expanded allele repeat sizes and sequences, which would suggest that there is marked difference in the penetrance of this 51-repeat allele. We therefore propose that the variable penetrance range extend from 48 repeats to incorporate this allele. This study shows that there is variability in the presentation and penetrance of the SCA17 phenotype and highlights the complexity of this disorder

Smartphone-Based Self-Assessment of Objective Functional Impairment (6-Minute Walking Test) in Patients Undergoing Epidural Steroid Injection

Epidural steroid injection (ESI) represents a popular treatment option in patients with lumbar degenerative disc disease (DDD). The main objective of the article was to determine whether the 6-minute walking test (6WT) could assist in the discrimination between ESI responders and nonresponders. We used a validated 6WT smartphone application to assess self-measured objective functional impairment (OFI) in 3 patients with DDD undergoing ESI. Patient-reported outcome measures (PROMs), including the Core Outcome Measures Index and the Oswestry Disability Index, were obtained at baseline and at the 3-, 7-, and 28-day follow-up. Descriptive analyses were used to compare PROMs with OFI over time. Two patients responded well to the ESI, illustrated by clinically meaningful improvements in PROMs. This improvement was accompanied by a substantial increase in the 6WT distance (case I: 358 m vs. 517 m and case II: 296 m vs. 625 m). One patient reported only moderate improvement in leg pain and conflicting results in the other PROMs. The 6WT demonstrated a persistent OFI (487 m vs. 488 m). This patient was considered a nonresponder and underwent surgical treatment. This case series illustrates the feasibility of the smartphone-based 6WT as a tool to assess OFI in patients undergoing ESI for lumbar DDD

Longitudinal smartphone-based self-assessment of objective functional impairment in patients undergoing surgery for lumbar degenerative disc disease: initial experience

BACKGROUND: The worldwide spread of smartphone usage enables new possibilities for longitudinal monitoring of objective functional impairment (OFI) in patients undergoing surgery for lumbar degenerative disc disease (DDD). METHODS: Three patients, undergoing elective surgery for lumbar DDD, self-assessed OFI using a recently validated 6-min walking test (6WT) smartphone application. Results are presented as raw 6-min walking distance (6WD) as well as in reference to age- and sex-specific healthy population reference values using standardized z-scores (number of standard deviations). In parallel, patient-reported outcome measures (PROMs), including numeric rating scale (NRS) leg-pain and Core Outcome Measures Index (COMI) were obtained before (pre) and 6 weeks (6 W) as well as 3 months (3 M) after surgery. Descriptive analyses were used to compare PROMs with repeated 6WT measurements over time. The feasibility and benefits of the longitudinal OFI measurements using the 6WT app are discussed. RESULTS: One patient presented a favorable outcome, reflected by a clinically meaningful improvement in PROMs. Correspondingly, the 6WT distance gradually improved above the normal population values ((pre 399 m (z-score - 1.96) vs. 6 W 494 m (- 0.85) vs. 3 M 557 m (- 0.1)). One patient experienced initial improvement at 6 W, followed by a decline in 6WD at 3 M which promoted further interventions with subsequent recovery ((358 m (z-score - 3.29) vs 440 m (- 2.2) vs 431 m (- 2.32) vs 471 m (- 1.78)). The last patient showed a lack of improvement in PROMs as well as in OFI (360 m (z-score 0.0) vs 401 m (0.30) vs 345 m (- 0.11)) resulting in secondary surgery. CONCLUSION: The longitudinal assessment of OFI using the 6WT app was feasible and provided the physician with a detailed history of patients' postoperative walking capacity complementing commonly used PROMs

Assessment of the Minimum Clinically Important Difference in the Smartphone-Based 6-Minute Walking Test after Surgery for Lumbar Degenerative Disc Disease

STUDY DESIGN Prospective cohort study. OBJECTIVE The aim of this study was to determine the minimum clinically important difference (MCID) of the 6-minute walking test (6WT) after surgery for lumbar degenerative disc disease (DDD). SUMMARY OF BACKGROUND DATA The smartphone-based 6WT is a valid and reliable tool to quantify objective functional impairment in patients with lumbar DDD. To date, the MCID of the 6WT has not been described in patients with DDD. METHODS We assessed patients pre- and 6-weeks postoperatively, analyzing both raw 6-minute walking distances (6WD; in meters) and standardized 6WT z scores. Three methods were applied to compute MCID values using established patient-reported outcomes measures (PROMs) as anchors (VAS back/leg pain, Zurich Claudication Questionnaire [ZCQ], Core Outcome Measures Index [COMI]): average change, minimum detectable change, and the change difference approach. RESULT We studied 49 patients (59% male) with a mean age of 55.5 ± 15.8 years. The computation methods revealed MCID values ranging from 81 m (z score of 0.9) based on the VAS back pain to 99 m (z score of 1.0) based on the ZCQ physical function scale. The average MCID of the 6WT was 92 m (z score of 1.0). Based on the average MCID of raw 6WD values or standardized z scores, 53% or 49% of patients classified as 6-week responders to surgery for lumbar DDD, respectively. CONCLUSION The MCID for the 6WT in lumbar DDD patients is variable, depending on the calculation technique. We propose a MCID of 92m (z score of 1.0), based on the average of all three methods. Using a z score as MCID allows for the standardization of clinically meaningful change and attenuates age- and sex-related differences.Level of Evidence: 3