Successful adaptation of twinning concept for global neurosurgery collaborations-a validation study.

INTRODUCTION: Globally, many regions have an urgent, unmet need of neurosurgical care. A multi-step neurosurgical twinning technique, International Neurosurgical Twinning Modeled for Africa (INTIMA), was proved to be successful during a previous mission to Neurosurgical Unit, Enugu, Nigeria. The Swedish African Neurosurgical Collaboration (SANC) performed a developmental mission together with the local neurosurgical unit in The Gambia, adopting the INTIMA model. METHODS: A multidisciplinary team visited for a 2-week collaborative mission at the Neurosurgical Department of the Edward Francis Small Teaching Hospital in Banjul, The Gambia. The mission followed the data of neurosurgical operations during and after the mission as well as about the operations 3 months prior to and after the mission was collected. RESULTS: During the mission, a total of 22 operations was carried out, the most common being degenerative spinal conditions (n = 9). In the 3 months following the mission, 43 operations were performed compared to 24 during the 3 months leading up to the mission. The complexity of the performed procedures increased after the mission. An operating microscope (Möller-Wedel) was donated and installed and the neurosurgeons on site underwent training in microneurosurgery. The surgical nurses, nurses at the postoperative ward, and the physiotherapists underwent training. A biomedical engineer serviced multiple appliances and devices improving the patient care on site while training local technicians. CONCLUSION: This study validated the use of the INTIMA model previously described in a mission by Swedish African Neurosurgical Collaboration (SANC). The model is sustainable and produces notable results. The core strength of the model is in the multidisciplinary team securing all the aspects and steps of the neurosurgical care. Installation of an operating microscope opened for further microsurgical possibilities, improving the neurosurgical care in The Gambia.

Cerebrospinal fluid glial fibrillary acidic protein, in contrast to amyloid beta protein, is associated with disease symptoms in Huntington's disease.

INTRODUCTION: Huntington's disease (HD) is a hereditary neurodegenerative disease, currently lacking disease-modifying treatments. Biomarkers are needed for objective assessment of disease progression. Evidence supports both complex protein aggregation and astrocyte activation in HD. This study assesses the 42 amino acid long amyloid beta (Aß42) and glial fibrillary acidic protein (GFAP) as potential biomarkers in the cerebrospinal fluid (CSF) of HD mutation carriers. METHODS: CSF from participants was obtained from three sites in Sweden. Clinical symptoms were graded with the composite Unified Huntington's disease rating scale (cUHDRS). Protein concentrations were measured using ELISA. Pearson correlations were calculated to assess disease progression association. Results were adjusted for age and collection site. RESULTS: The study enrolled 28 manifest HD patients (ManHD), 13 premanifest HD gene-expansion carriers (PreHD) and 20 controls. Aß42 levels did not differ between groups and there was no correlation with measures of disease progression. GFAP concentration was higher in ManHD (424 ng/l, SD 253) compared with both PreHD (266 ng/l, SD 92.4) and controls (208 ng/l, SD 83.7). GFAP correlated with both cUHDRS (r = -0.77, p < 0.001), and 5-year risk of disease onset (r = 0.70, p = 0.008). CONCLUSION: We provide evidence that indicates CSF Aß42 has limited potential as a biomarker for HD. GFAP is a potential biomarker of progression in HD. Validation in larger cohorts measuring GFAP in blood and CSF would be of interest.

Inflammatory biomarkers differentiate the stage of maturation in chronic subdural hematomas.

OBJECTIVE: Inflammation is a major pathophysiological driver of the development of chronic subdural hematomas (CSDH), but there is still limited knowledge on the key molecular processes and corresponding biomarkers involved in this disease. In this study, the aim was to study a subset of inflammatory biomarkers and their relation to the clinical status of the patient and the radiological characteristics of the CSDH. METHODS: In this observational study, 58 patients who were operated on with CSDH evacuation, at the Department of Neurosurgery, Uppsala, Sweden, between 2019 and 2021, were prospectively included. The CSDH fluid was collected peri-operatively and was later analyzed with proximity extension assay (PEA) technique (Olink) for a panel of 92 inflammatory biomarkers. Demographic, neurological (Markwalder), radiological (general (Nakaguchi classification) and focal (septa below the burr holes)), and outcome variables were collected. RESULTS: In 84 of the 92 inflammatory biomarkers, the concentration was above the detection limit in >50% of the patients. There was a significant difference in GDNF, NT-3, and IL-8 depending on the Nakaguchi class, with higher values in the trabeculated CSDH subtype. In addition, those with septa at the focal area of CSDH collection, had higher levels of GDNF, MCP-3, NT-3, CXCL1, CXCL5, IL8, and OSM. There was no association between Markwalder grade and the inflammatory biomarkers. CONCLUSIONS: Our findings support the presence of local inflammation in the CSDH, a shift in biomarker pattern as the CSDH matures towards the trabeculated state, potentially differences in biomarker patterns within the CSDH depending on the focal environment with presence of septa, and that the brain might develop protective mechanisms (GDNF and NT-3) in case of mature and long-standing CSDHs.

Effect of Irrigation Fluid Temperature on Recurrence in the Evacuation of Chronic Subdural Hematoma: A Randomized Clinical Trial.

Importance: The effect of a physical property of irrigation fluid (at body vs room temperature) on recurrence rate in the evacuation of chronic subdural hematoma (cSDH) needs further study. Objective: To explore whether irrigation fluid temperature has an influence on cSDH recurrence. Design, Setting, and Participants: This was a multicenter randomized clinical trial performed between March 16, 2016, and May 30, 2020. The follow-up period was 6 months. The study was conducted at 3 neurosurgical departments in Sweden. All patients older than 18 years undergoing cSDH evacuation during the study period were screened for eligibility in the study. Interventions: The study participants were randomly assigned by 1:1 block randomization to the cSDH evacuation procedure with irrigation fluid at room temperature (RT group) or at body temperature (BT group). Main Outcomes and Measures: The primary end point was recurrence requiring reoperation within 6 months. Secondary end points were mortality, health-related quality of life, and complication frequency. Results: At 6 months after surgery, 541 patients (mean [SD] age, 75.8 [9.8] years; 395 men [73%]) had a complete follow-up according to protocol. There were 39 of 277 recurrences (14%) requiring reoperation in the RT group, compared with 16 of 264 recurrences (6%) in the BT group (odds ratio, 2.56; 95% CI, 1.38-4.66; P < .001). There were no significant differences in mortality, health-related quality of life, or complication frequency. Conclusions and Relevance: In this study, irrigation at body temperature was superior to irrigation at room temperature in terms of fewer recurrences. This is a simple, safe, and readily available technique to optimize outcome in patients with cSDH. When irrigation is used in cSDH surgery, irrigation fluid at body temperature should be considered standard of care. Trial Registration: ClincalTrials.gov Identifier: NCT02757235.

Cranioplasty in Brain Tumor Surgery: A Single-Center Retrospective Study Investigating Cranioplasty Failure and Tumor Recurrence.

OBJECTIVE: Cranioplasty with synthetic implant can be performed to restore function and form of the skull after resection of malignancy infiltrating the bone. The aim of this study was to examine the rate of implant failure and tumor recurrence in patients undergoing nonautologous cranioplasty and tumor resection. METHODS: In this retrospective single-center study, 48 patients were identified who had undergone cranioplasty with synthetic implants after tumor resection between 2010 and 2020. The medical records were analyzed to investigate patient demographics, surgery data, cranioplasty failure rates, and rate of tumor recurrence. RESULTS: Cranioplasty failed in 8 patients. The median time to implant failure was 220 days with most failures occurring within 1 year (5 of 8). There was no significant difference in rate or time to failure between the different cranioplasty materials (P = 0.39). Low body mass index (P < 0.05), previous craniectomy/cranioplasty (P < 0.05), previous radiation therapy to the brain/skull (P < 0.05), and skin closure with sutures (P < 0.05) were associated with an increased risk of implant failure. Tumors recurred in 15 patients. CONCLUSIONS: Cranioplasty surgery with synthetic implants carries a relatively high risk of failure, regardless of type of cranioplasty material used. Skin closure with staples may be beneficial in these patients.

Global neurosurgery over a 60-year period: Conceptual foundations, time reference, emerging Co-ordinates and prospects for collaborative interventions in low and middle income countries.

Introduction: We evaluated salient initiatives invested in global neurosurgery over a 60-year period. Research question: What are the Phases, Achievements, Challenges, and Lessons of Global Neurosurgery. Methods: A 60-year retrospective study from 1960 to 2020 analyzing the major phases, lessons, and progress notes. We reviewed the foundational need questions and innovated tools used to answer them. Results: Three phases defining our study period were identified. In the early phase, birthing academic units and the onset of individual volunteerism were dominant concepts. The 2nd phase is summarized by the rise of volunteerism and surgical camps.The third phase is heralded by advocacy and strategies for achieving care equity. The defining moment is the Lancet commission for global surgery summit in 2015. Lessons include the need for evaluation of the resources of recipient and donor locations using novel global surgery tools. Conclusion: Global neurosurgery over the 60-year study period is summarized by indelible touchstones of personal and group efforts as well as triumphs derived from innovations in the face of formidable challenges.

Central nervous system hemangioblastomas in von Hippel-Lindau disease: Total growth rate and risk of developing new lesions not associated with circulating VEGF levels.

BACKGROUND: Hemangioblastomas of the central nervous system are a prominent feature of von Hippel-Lindau-disease (vHL). Hemangioblastomas are known to secrete vascular endothelial growth factor (VEGF), suggesting a potential role of VEGF as a biomarker for tumor growth. METHODS: Plasma VEGF samples from 24 patients with von Hippel-Lindau disease were analyzed by solid-phase proximity ligation assay (PLA). Levels were monitored over time together with numeric and volumetric CNS tumor burden, and compared to plasma VEGF levels in healthy controls. RESULTS: The mean yearly progression in tumor volume was 65.5%. Yearly risk of developing one or several new CNS tumor(s) was 50%. No significant correlation between tumor burden and levels of VEGF was seen. VEGF levels in patients (31.55-92.04; mean 55.83, median 56.41) as measured by immunodetection in a solid-phase PLA did not differ significantly from controls (37.38-104.56; mean 58.89, median 54.12) (p = 0,266). CONCLUSION: The increase in total CNS tumor volume in vHL occurred in a saltatory manner. The risk of developing a new lesion was 50% per year. We found no evidence for VEGF secretion from CNS hemangioblastomas in vHL in circulating blood. Other potential biomarkers should be explored to assess progression of tumor burden in vHL.

Trauma Mechanisms and Surgical Outcomes in the Elderly Patient with Chronic Subdural Hematoma.

Background: Chronic subdural hematoma is the preeminent neurosurgical condition in the older population. This retrospective single-centre study focuses on outcome after surgery of chronic subdural hematoma in patients over 70 years. Methods: Patients treated at a single neurosurgical referral centre between 2010 and 2014 were screened. Included patients were assessed for comorbid conditions, lifestyle factors, and outcomes including recurrence, mortality, and postoperative complications. Results: A total of 511 patients (70-97 yrs) were identified. 50.7% of patients were treated with anticoagulants and/or antiplatelet therapy. A known probable cause for the hematoma was found in 68.1% of patient's histories. Mortality rate was 3.1% and recurrence was seen in 49 patients (9.6%). Postoperative complications were more common in patients with excessive use of alcohol (p value = .02). Neurological function was improved in 78.1% of patients after the initial surgery. A strategy of delayed contralateral surgery in bilateral hematomas showed low rates of recurrence. Conclusion: Fall injuries are the most common underlying trauma mechanism in the elderly with chronic subdural hematoma. Recurrence is not more common in the elderly patient group compared to the general population. Excessive alcohol use is a risk factor for post-operative complications.

Pilot application of Lecture-Panel-Discussion Model (LPDM) in global collaborative neurosurgical education: a novel training paradigm innovated by the Swedish African Neurosurgery Collaboration.

BACKGROUND: Disruptions in global surgery educational routines by the COVID-19 pandemic have elicited demands for alternative formats for rendering qualitative neurosurgical education. This study presents application of a novel model of online neurosurgical course, the Lecture-Panel-Discussion Model (LPDM). METHODS: This is a cross-sectional survey of participants who attended the Swedish African Neurosurgery Collaboration (SANC)-100A course. Participants evaluated the course through an online self-administered questionnaire using a 5-point Likert scale ranging from very poor-1, poor-2, average (fair)-3, good-4, to excellent-5. SANC-100A comprises a tripod of Lectures, Panel review, and interactive case Discussion. This model (LPDM) was innovated by SANC and applied at the Enugu International Neurosurgery course in February 2021. RESULTS: There were 71 attendees, 19 were course faculty, while 52 were participants. Thirty-five attended from Nigeria, 11 from Sweden, 3 from Malawi, 2 from Senegal, and 1 from the UK. Among 44 participants who completed the questionnaire, there were 9 fellows and 35 residents. The overall median course Likert rating was 4.65 ± 0.1. The median overall rating for course events was similar between day 1 (Likert score = 4.45) and day 2 (Likert score = 4.55), U = 55, Z score = 1.10, P = 0.27. The median rating for lectures was 4.50 ± 0.2 and varied from 4.40 on day 1 to 4.55 on day 2. The median rating for panel review was 4.60 ± 0.1 and varied from 4.55 on day 1 to 4.65 on day 2. Interactive case discussions were rated 4.80 on both course days. There was a significant variability in the rating profiles of the course tripod: U = 24.5, P = 0.03. Fifty-one (98%) participants believe LPDM was COVID-19-compliant, while 90% believe the course was beneficial to training and practice. CONCLUSION: Initial application of LPDM is rewarded with both high acceptance and high rating among participants.

Bone formation in custom-made cranioplasty: evidence of early and sustained bone development in bioceramic calcium phosphate implants. Patient series.

BACKGROUND: Implant failure (IF) rates in cranioplasty remain high despite efforts to reduce the incidence. New biomaterials may be part of the solution for this problem. Formation of autologous bone in implants may reduce rates of infection and subsequent failure. OBSERVATIONS: Four patients with calcium phosphate implants supported by titanium mesh and undergoing surgery for reasons unrelated to IF were included in this series. Samples from the implants were microscopically examined. Pathological studies proved the formation of autologous bone in the calcium phosphate implants. LESSONS: Bone and blood vessel formation in the implants and diminished foreign body reaction to autologous bone may reduce the rates of IF.

Proenkephalin Decreases in Cerebrospinal Fluid with Symptom Progression of Huntington's Disease.

OBJECTIVE: Identifying molecular changes that contribute to the onset and progression of Huntington's disease (HD) is of importance for the development and evaluation of potential therapies. METHODS: We conducted an unbiased mass-spectrometry proteomic analysis on the cerebrospinal fluid of 12 manifest HD patients (ManHD), 13 pre-manifest (preHD), and 38 controls. A biologically plausible and significant possible biomarker was validated in samples from a separate cohort of patients and controls consisting of 23 ManHD patients and 23 controls. RESULTS: In ManHD compared to preHD, 10 proteins were downregulated and 43 upregulated. Decreased levels of proenkephalin (PENK) and transthyretin were closely linked to HD symptom severity, whereas levels of 15 upregulated proteins were associated with symptom severity. The decreased PENK levels were replicated in the separate cohort where absolute quantitation was performed. CONCLUSIONS: We hypothesize that declining PENK levels reflect the degeneration of medium spiny neurons (MSNs) that produce PENK and that assays for PENK may serve as a surrogate marker for the state of MSNs in HD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

High frequency of intermediary alleles in the HTT gene in Northern Sweden - The Swedish Huntingtin Alleles and Phenotype (SHAPE) study.

Trinucleotide (CAG) repeat expansions longer than 39 in the huntingtin (HTT) gene cause Huntington's disease (HD). The frequency of intermediate alleles (IA) with a length of 27-35 in the general population is not fully known, but studied in specific materials connected to the incidence of HD. The Swedish Huntingtin Alleles and Phenotype (SHAPE) study aims to assess the frequency of trinucleotide repeat expansions in the HTT gene in north Sweden. 8260 individuals unselected for HD from the counties of Norr- and Västerbotten in the north of Sweden were included. DNA samples were obtained and analysis of the HTT gene was performed, yielding data on HTT gene expansion length in 7379 individuals. A high frequency of intermediate alleles, 6.8%, was seen. Also, individuals with repeat numbers lower than ever previously reported (<5) were found. These results suggest a high frequency of HD in the norther parts of Sweden. Subsequent analyses may elucidate the influence of IA:s on traits other than HD.

Continuous EEG monitoring after brain tumor surgery.

BACKGROUND: Prolonged seizures generate cerebral hypoxia and increased intracranial pressure, resulting in an increased risk of neurological deterioration, increased long-term morbidity, and shorter survival. Seizures should be recognized early and treated promptly. The aim of the study was to investigate the occurrence of postoperative seizures in patients undergoing craniotomy for primary brain tumors and to determine if non-convulsive seizures could explain some of the postoperative neurological deterioration that may occur after surgery. METHODS: A single-center prospective study of 100 patients with suspected glioma. Participants were studied with EEG and video recording for at least 24 h after surgery. RESULTS: Seven patients (7%) displayed seizure activity on EEG recording within 24 h after surgery and another two patients (2%) developed late seizures. One of the patients with early seizures also developed late seizures. In five patients (5%), there were non-convulsive seizures. Four of these patients had a combination of clinically overt and non-convulsive seizures and in one patient, all seizures were non-convulsive. The non-convulsive seizures accounted for the majority of total seizure time in those patients. Non-convulsive seizures could not explain six cases of unexpected postoperative neurological deterioration. Postoperative ischemic lesions were more common in patients with early postoperative seizures. CONCLUSIONS: Early seizures, including non-convulsive, occurred in 7% of our patients. Within this group, non-convulsive seizure activity had longer durations than clinically overt seizures, but only 1% of patients had exclusively non-convulsive seizures. Seizures were not associated with unexpected neurological deterioration.

Gentamicin loading of calcium phosphate implants: implications for cranioplasty.

BACKGROUND: Surgical site infections (SSI) are a significant risk in cranioplasty, with reported rates of around 8-9%. The most common bacteria associated with these nosocomial infections are of the Staphylococcus species, which have the ability to form biofilm. The possibility to deliver antibiotics, such as gentamicin, locally rather than systemically could potentially lower the early postoperative SSI. Various antibiotic dosages are being applied clinically, without any true consensus on the effectiveness. METHODS: Drug release from calcium phosphate (CaP), polyetheretherketone (PEEK), and titanium (Ti) samples was evaluated. Microbiological studies with Staphylococcus aureus (SA) and Staphylococcus epidermidis (SE) including strains from clinical infection were used to establish clinically relevant concentrations. RESULTS: The CaP samples were able to retain and release gentamicin overtime, whereas the Ti and PEEK samples did not show any drug uptake or release. A gentamicin loading concentration of 400 µg/ml was shown to be effective in in vitro microbiological studies with both SA and SE. CONCLUSIONS: Out of the three materials studied, only CaP could be loaded with gentamicin. An initial loading concentration of 400 µg/ml appears to establish an effective gentamicin concentration, possibly translating into a clinical benefit in cranioplasty.

Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington's disease subjects.

Huntington's disease (HD) is a severe neurological disease leading to psychiatric symptoms, motor impairment and cognitive decline. The disease is caused by a CAG expansion in the huntingtin (HTT) gene, but how this translates into the clinical phenotype of HD remains elusive. Using liquid chromatography mass spectrometry, we analyzed the metabolome of cerebrospinal fluid (CSF) from premanifest and manifest HD subjects as well as control subjects. Inter-group differences revealed that the tyrosine metabolism, including tyrosine, thyroxine, L-DOPA and dopamine, was significantly altered in manifest compared with premanifest HD. These metabolites demonstrated moderate to strong associations to measures of disease severity and symptoms. Thyroxine and dopamine also correlated with the five year risk of onset in premanifest HD subjects. The phenylalanine and the purine metabolisms were also significantly altered, but associated less to disease severity. Decreased levels of lumichrome were commonly found in mutated HTT carriers and the levels correlated with the five year risk of disease onset in premanifest carriers. These biochemical findings demonstrates that the CSF metabolome can be used to characterize molecular pathogenesis occurring in HD, which may be essential for future development of novel HD therapies.

Removal of giant intraosseous meningioma followed by cranioplasty using a custom-made bioceramic implant: case report.

Intraosseous meningioma of the chordoid type is a rare clinical entity. Radical surgical removal and subsequent cranioplasty is the treatment of choice. Here, the authors report a severe case involving more than 70% of the calvarial surface area, which was removed and repaired using a prefabricated custom-made, titanium-reinforced, bioceramic implant and bone-cutting guides. Tumor removal and good esthetic outcome were achieved, along with a 17.1% increase of intracranial volume. Bioceramic implants have shown promising initial results and may represent an important new tool in the surgeon's armamentarium.

Cerebrospinal fluid sCD27 levels indicate active T cell-mediated inflammation in premanifest Huntington's disease.

INTRODUCTION: Huntington's disease (HD) is a neurodegenerative disorder, but evidence also suggests neuroinflammation in the pathogenesis. The immune mechanisms involved and the timing of their activation need further clarification. METHODS: A clinically well-characterized HD cohort and gene negative controls were enrolled. YKL-40 reflecting innate immunity and sCD27, a marker of adaptive immunity, were measured across disease stages. Comparisons were made with markers of neurodegeneration: neurofilament light (NFL), total-tau (T-tau), and phospho-tau (P-tau). RESULTS: 52 cross-sectional cerebrospinal fluid samples and 23 follow-up samples were analyzed. sCD27 was elevated in manifest HD and premanifest gene expansion carriers, whereas controls mostly had undetectable levels. YKL-40 showed a trend toward increase in manifest HD. sCD27 correlated with YKL-40 which in turn was closely associated to all included markers of neurodegeneration. YKL-40, NFL, and both forms of tau could all independently predict HD symptoms, but only NFL levels differed between groups after age-adjustment. CONCLUSION: Increased sCD27 in premanifest HD is a sign of T cell-mediated neuroinflammation. This finding is novel since other reports almost exclusively have found early involvement of innate immunity. Validation of sCD27 in a larger HD cohort is needed. The role of adaptive immunity in HD needs further clarification, as it may hasten disease progression.

The Swedish study of Irrigation-fluid temperature in the evacuation of Chronic subdural hematoma (SIC!): study protocol for a multicenter randomized controlled trial.

BACKGROUND: Chronic subdural hematoma (cSDH) is one of the most common conditions encountered in neurosurgical practice. Recurrence, observed in 5-30% of patients, is a major clinical problem. The temperature of the irrigation fluid used during evacuation of the hematoma might theoretically influence recurrence rates since irrigation fluid at body temperature (37 oC) may beneficially influence coagulation and cSDH solubility when compared to irrigation fluid at room temperature. Should no difference in recurrence rates be observed when comparing irrigation-fluid temperatures, there is no need for warmed fluids during surgery. Our main aim is to investigate the effect of irrigation-fluid temperature on recurrence rates and clinical outcomes after cSDH evacuation using a multicenter randomized controlled trial design. METHODS: The study will be conducted in three neurosurgical departments with population-based catchment areas using a similar surgical strategy. In total, 600 patients fulfilling the inclusion criteria will randomly be assigned to either intraoperative irrigation with fluid at body temperature or room temperature. The power calculation is based on a retrospective study performed at our department showing a recurrence rate of 5% versus 12% when comparing irrigation fluid at body temperature versus fluid at room temperature (unpublished data). The primary endpoint is recurrence rate of cSDH analyzed at 6 months post treatment. Secondary endpoints are mortality rate, complications and health-related quality of life. DISCUSSION: Irrigation-fluid temperature might influence recurrence rates in the evacuation of chronic subdural hematomas. We present a study protocol for a multicenter randomized controlled trial investigating our hypothesis that irrigation fluid at body temperature is superior to room temperature in reducing recurrence rates following evacuation of cSDH. TRIALS REGISTRATION: ClinicalTrials.gov, ID: NCT02757235 . Registered on 2 May 2016.

Tau or neurofilament light-Which is the more suitable biomarker for Huntington's disease?

INTRODUCTION: Previous studies have suggested cerebrospinal fluid (CSF) levels of neurofilament light (NFL) and total tau are elevated in Huntington's disease (HD) and may be used as markers of disease stage. Biomarkers are needed due to the slow disease progression and the limitations of clinical assessment. This study aims to validate the role of NFL and tau as biomarkers in HD. METHODS: CSF was obtained from a cohort of HD patients and premanifest HD-mutation carriers. Unified Huntington's Disease Rating Scale (UHDRS) testing was performed on all subjects at the time of sampling. NFL and tau concentrations were determined by ELISA. Spearman correlations were calculated with R version 3.2.3. RESULTS: 11 premanifest HD and 12 manifest HD subjects were enrolled. NFL and tau levels were correlated. NFL showed strong correlations with all items included in the clinical assessment (for example the total functional capacity (TFC) (r = - 0.70 p < 0.01) and total motor score (TMS) (r = 0.83p < 0.01). Tau showed slightly weaker correlations (eg. TMS (r = 0.67 p < 0.01); TFC (r = - 0.59 p < 0.01)). NFL was significantly correlated with 5-year probability of disease onset, whereas tau was not. CONCLUSION: This study strengthens the case for NFL as a useful biomarker of disease stage. NFL was strongly correlated to all evaluated items in the UHDRS assessment. Tau also has a potential for use as a biomarker but correlations to clinical tests are weaker in this study. We suggest that NFL and possibly tau be used in clinical drug trials as biomarkers of disease progression that are potentially influenced by future disease-modifying therapies.

LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course.

OBJECTIVE: Duplication of the LMNB1 gene encoding lamin B1 causes adult-onset autosomal-dominant leukodystrophy (ADLD) starting with autonomic symptoms, which are followed by pyramidal signs and ataxia. Magnetic resonance imaging (MRI) of the brain reveals characteristic findings. This is the first longitudinal study on this disease. Our objective is to describe the natural clinical and radiological course of LMNB1-related ADLD. METHODS: Twenty-three subjects in two families with LMNB1 duplications were studied over two decades with clinical assessment and MRI of the brain and spinal cord. They were 29 to 70 years old at their first MRI. Repeated MRIs were performed in 14 subjects over a time period of up to 17 years. RESULTS: Pathological MRI findings were found in the brain and spinal cord in all examinations (i.e., even preceding clinical symptoms). MRI changes and clinical symptoms progressed in a definite order. Autonomic dysfunction appeared in the fifth to sixth decade, preceding or together with gait and coordination difficulties. Motor signs developed ascending from spastic paraplegia to tetraplegia and pseudobulbar palsy in the seventh decade. There were clinical, radiological, and neurophysiological signs of myelopathy. Survival lasted more than two decades after clinical onset. INTERPRETATION: LMNB1-related ADLD is a slowly progressive neurological disease. MRI abnormalities of the brain and spinal cord can precede clinical symptoms by more than a decade and are extensive in all symptomatic patients. Spinal cord involvement is a likely contributing factor to early autonomic symptoms and spastic paraplegia.