Therapeutic Biomarkers in Friedreich's Ataxia: a Systematic Review and Meta-analysis.

Although a large array of biomarkers have been investigated in Friedreich's ataxia (FRDA) trials, the optimal biomarker for assessing disease progression or therapeutic benefit has yet to be identified. We searched PubMed, MEDLINE, and EMBASE databases up to June 2023 for any original study (with ≥ 5 participants and ≥ 2 months' follow-up) reporting the effect of therapeutic interventions on any clinical, cardiac, biochemical, patient-reported outcome measures, imaging, or neurophysiologic biomarker. We also explored the biomarkers' ability to detect subtle disease progression in untreated patients. The pooled standardized mean difference (SMD) was calculated using a random-effects model. The study's protocol was registered in PROSPERO (CRD42022319196). In total, 43 studies with 1409 FRDA patients were included in the qualitative synthesis. A statistically significant improvement was observed in Friedreich Ataxia Rating Scale scores [combining Friedreich Ataxia Rating Scale (FARS) and modified FARS (mFARS): SMD = - 0.32 (- 0.62 to - 0.02)] following drugs that augment mitochondrial function in a sensitivity analysis. Left ventricular mass index (LVMI) was improved significantly [SMD = - 0.34 (- 0.5 to - 0.18)] after 28.5 months of treatment with drugs that augment mitochondrial function. However, LVMI remained stable [SMD = 0.05 (- 0.3 to 0.41)] in untreated patients after 6-month follow-up. None of the remaining biomarkers changed significantly following any treatment intervention nor during the natural disease progression. Nevertheless, clinical implications of these results should be interpreted with caution because of low to very low quality of evidence. Further randomized controlled trials of at least 24 months' duration using a biomarker toolbox rather than a single biomarker are warranted.

Association between ambulatory blood pressure monitoring patterns with cognitive function and risk of dementia: a systematic review and meta-analysis.

BACKGROUND: The objective of this systematic review and meta-analysis is to investigate whether nocturnal blood pressure fall, expressed by dipping patterns according to 24 h ambulatory blood pressure monitoring (ABPM), is associated with abnormal cognitive function (cognitive impairment or dementia). METHODS: We systematically searched PubMed, Embase, and Cochrane databases to identify original articles through December 2022. We included any study with at least ten participants reporting on all-cause dementia or cognitive impairment incidence (primary outcome) or validated cognitive tests (secondary outcome) among ABPM patterns. We assessed risk of bias using Newcastle-Ottawa Quality Assessment Scale. We pooled odds ratios (OR) and standardized mean differences (SMD) using random-effect models for primary and secondary outcome, respectively. RESULTS: In the qualitative synthesis, 28 studies examining 7595 patients were included. The pooled analysis of 18 studies showed that dippers had a 51% [OR 0.49(0.35-0.69)] lower risk of abnormal cognitive function and a 63% [OR 0.37(0.23-0.61)] lower risk of dementia alone, compared to non-dippers. Reverse dippers presented an up to sixfold higher risk [OR 6.06(3.15-11.64)] of abnormal cognitive function compared to dippers and an almost twofold higher risk [OR 1.81(1.26-2.6)] compared to non-dippers. Reverse dippers performed worse in global function neuropsychological tests compared with both dippers [SMD - 0.66(- 0.93 to - 0.39)] and non-dippers [SMD - 0.35(- 0.53 to - 0.16)]. CONCLUSION: Dysregulation of the normal circadian BP rhythm, specifically non-dipping and reverse dipping is associated with abnormal cognitive function. Further studies are required to determine potential underlying mechanisms and possible prognostic or therapeutic implications. PROTOCOL REGISTRATION: PROSPERO database (ID: CRD42022310384).

Biomarkers of therapeutic efficacy in adolescents and adults with 5q spinal muscular atrophy: a systematic review.

BACKGROUND: The therapeutic landscape of spinal muscular atrophy (SMA) was dramatically transformed with the introduction of three disease-modifying therapies (DMTs). A systematic review was performed to assess available evidence regarding quantitative therapeutic biomarkers used in SMA patients older than 11 years under treatment with DMTs. METHODS: Latest literature search in MEDLINE, EMBASE, Cochrane databases and gray literature resources was performed in June 2021. Studies reporting only motor function or muscle strength scales or pulmonary function tests were excluded. Primary outcome was the change from baseline score of any serum, cerebrospinal fluid (CSF) or neurophysiologic biomarker examined. RESULTS: Database and gray literature search yielded a total of 8050 records. We identified 14 records published from 2019 until 2021 examining 18 putative serum, CSF or neurophysiologic biomarkers along with routine CSF parameters in 295 SMA nusinersen-treated type 2-4 patients older than 11 years of age. There is evidence based on real-world observational studies suggesting that serum creatinine, creatine kinase activity levels along with CSF Αß42, glial fibrillary acidic protein concentration as well as ulnar compound motor action potential amplitude and single motor unit potential amplitude changes may depict therapeutic response in this population. CONCLUSION: This systematic review explored for the first-time biomarkers used to monitor therapeutic efficacy in SMA adolescents and adults treated with DMTs. Research in this area is in its early stages, and our systematic review can facilitate selection of quantitative therapeutic biomarkers that may be used as surrogate measures of treatment efficacy in future trials. PROTOCOL REGISTRATION: PROSPERO CRD42021245516.

Endothelial Dysfunction in Psoriasis: An Updated Review.

Although psoriasis is predominantly a chronic inflammatory skin disorder, epidemiological data provide a solid link between psoriasis, especially in its more severe forms, and increased risk for cardiovascular morbidity and mortality. Apart from the increased prevalence of traditional cardiovascular risk factors, chronic inflammation appears to act synergistically with the underlying process of endothelial dysfunction toward the development of accelerated atherosclerosis, subclinical vascular injury and subsequently, clinically evident cardiovascular manifestations. Endothelial dysfunction is regarded as an early precursor of atherosclerosis with a predictive value for the development of future cardiovascular events. A thorough understanding of the mechanisms of endothelial dysfunction in psoriasis might pave the path for the development of more accurate cardiovascular risk prediction tools and possible therapeutic targets aiming to alleviate the increased cardiovascular burden associated with the disease. The present review summarizes the available evidence about the role of chronic inflammation and other important pathophysiological mechanisms involved in the development of endothelial dysfunction in psoriasis. An overview of studies implementing the most widely applied circulating and vascular biomarkers of endothelial dysfunction in psoriasis patients will be provided, and the impact of systemic psoriasis treatments on endothelial dysfunction and patients' cardiovascular risk will be discussed.

COVID-19 pandemic impact on neurologic emergencies: a single-center retrospective cohort study.

Introduction: COVID-19 pandemic caused a major disruption to healthcare system. A year after COVID-19 outbreak, the question remains to what extent the lockdowns changed the volume of non-infected patients who were admitted to the Neurologic Department (ND). To determine the impact of the pandemic´s first year on a tertiary ND. Methods: non-infected patients admitted to ND between March 2020 and February 2021 were examined. A control group was generated for the same time interval starting from March 2019. Primary outcomes were the number of patients presenting with neurologic complaint who were admitted to the hospital and the diagnosis type. Secondary outcomes were hospitalization length and patients´ outcome. Results: overall, 816 patients (49.4% females) were admitted during the predetermined periods. Median age was 55 years. Median length of hospitalization was six days. We observed a 47.2% reduction in our department´s admissions during pandemic (n=282). None of the examined variables (type of neurologic diagnosis, age, gender, hospitalization length and outcome) changed significantly during pandemic. However, the number of patients admitted during the pandemic with a diagnosis categorized as "other" was statistically significant lower compared to the year before COVID-19 (p=0.007). Hospitalization length was associated only with patients´ age. Conclusion: our study examined for the first-time the consequences of the first year of COVID-19 pandemic on ND admissions. COVID-19 outbreak resulted in decreased admissions. Delays in seeking medical consultation for urgent or undiagnosed neurologic conditions require rigorous long-term monitoring to fully understand the impact of COVID-19 pandemic on patients with neurologic diseases.

Difficulties in the Differential Diagnosis of Thrombotic Microangiopathy.

No Abstract.  DOI: 10.52547/ijkd.6916.

Nusinersen in Adults with 5q Spinal Muscular Atrophy: a Systematic Review and Meta-analysis.

Evidence for nusinersen administration in adult 5q spinal muscular atrophy (5q-SMA) patients is scarce and based on real-world observational data. The present systematic review and meta-analysis aimed to explore the efficacy and safety of nusinersen in patients older than 12 years of age with 5q-SMA. We searched MEDLINE, EMBASE, the Cochrane Library, and grey literature through April 2021. Cross-sectional studies, case reports, review articles, and studies with follow-up less than 6 months were excluded. We included 12 records (seven case-series, five cohorts) representing 11 population cohorts and enrolling 428 SMA patients. We observed statistically significant improvements on motor function Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores at the longest follow-up assessments [SMD = 0.17(95% CI 0.01-0.33), SMD = 0.22(95% CI 0.06-0.38), respectively]. HFMSE and RULM significant improvements were also detected at the subgroup analysis during 10 and 14 months. HFMSE and RULM amelioration occurred earlier in patients with SMA type 3 or 4 during short-term analysis (≤ 6 months). 6-min walk tests (6MWT) and pulmonary function tests did not change. Minimal clinically important differences in HFMSE and RULM were observed in 43.3% (95% CI 34.5-52.3) and 38.9% (95% CI 27.7-50.7), respectively. Severe adverse events were reported in 2% (95% CI 0-5.8). Treatment withdrawal rate was 3% (95% CI 0.5-6.6). Despite the low quality of evidence and the unmet need for randomized data to establish the safety and efficacy of nusinersen in adults, our meta-analysis confirms that nusinersen is a valuable treatment option for older patients with longer-disease duration.Trial registration: PROSPERO database CRD42020223109.

Biomarkers of disease progression in adolescents and adults with 5q spinal muscular atrophy: a systematic review and meta-analysis.

Since the introduction of disease modifying treatments there is an unmet need to identify biomarkers of spinal muscular atrophy (SMA) natural history. We performed a systematic review and meta-analysis to summarize available evidence. We searched MEDLINE, Embase, Cochrane Library and gray literature until February 2021. The primary outcome was biomarkers longitudinal course in adolescents and adults. The secondary outcome was the discrimination of patients from controls. We included 42 records examining 606 patients from 19 population cohorts over a maximum follow-up of 17-years. Lung function and serum biomarkers could not depict disease progression. We identified potential biomarkers of disease activity [SMA functional rating scale, MoviPlate, pinch strength, compound muscle action potential (CMAP), motor unit number estimation (MUNE)] that require further investigation. Data regarding Hammersmith functional motor scale expanded, Revised upper limb module, 6-minute walk test were contradictory impeding any pooled estimate. The pooled analysis regarding our secondary outcome revealed that upper limb CMAP amplitudes and MUNE mean values differed significantly between SMA patients and controls [mean difference -3.63(-6.2, -1.06), -119.74(-153.93, -85.56) respectively]. Given the lack of natural history data on this population, our qualitative synthesis and meta-analysis could provide valuable evidence and identify promising predictive biomarkers requiring further longitudinal examination. PROSPERO Registration: CRD42021235605.

Prevalence of markers of atrial cardiomyopathy in embolic stroke of undetermined source: A systematic review.

BACKGROUND: Emerging evidence suggests the potential role of atrial cardiomyopathy (AC) as a direct thromboembolic determinant in embolic stroke of undetermined source (ESUS). OBJECTIVE: We aimed to quantify the prevalence of potential AC markers among ESUS, non-cardioembolic (NCE) and cardioembolic (CE) stroke patients. METHODS: PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for publications from inception to October 2021, with duplicate data extraction and risk of bias assessment. The Newcastle-Ottawa assessment scale was used to evaluate study quality. RESULTS: Among 398 screened studies, 11 observational studies with 2009 ESUS patients (mean age 66.5 years) fulfilled the inclusion criteria. Of electrocardiographic markers, increased P-wave terminal force in lead V1 was more prevalent in ESUS vs NCE (OR=2.26, 95%CI: 1.40-3.66). Of imaging markers, left atrial volume index (LAVI) and left atrial diameter (LAd) were higher in ESUS vs NCE (OR=1.04, 95%CI: 1.02-1.06 and OR=3.41, 95%CI: 1.35-8.61 respectively). Non-chicken wing morphology of the left atrial appendage was more frequent in ESUS compared to NCE patients in the majority of studies. Of serum biomarkers, the prevalence of NT-proBNP >250 pg/ml did not differ among ESUS vs NCE (OR=0.73, 95%CI: 0.39 -1.35). CONCLUSIONS: Electrocardiographic, echocardiographic markers and advanced imaging modalities able to assess the morphologic characteristics of left atrial appendage and left atrial function may be important tools to discriminate AC among ESUS vs NCE stroke patients. Prospective studies exploring the association of potential AC markers with ESUS occurrence are warranted to validate their clinical utility.

A non-interventional study of microcirculation dynamics in allogeneic hematopoietic cell transplantation survivors compared to controls: evidence of impaired microvascular response regardless of conventional cardiovascular risk factors.

Allogeneic hematopoietic cell transplantation (alloHCT) survivors have been recently recognized as patients at increased cardiovascular risk. We hypothesized that vascular function remains impaired in alloHCT survivors free of graft-versus-host-disease or relapse. We enrolled consecutive adult alloHCT survivors and non-HCT control individuals (January 2019-March 2020), matched for traditional cardiovascular risk factors. Microvascular dysfunction was dynamically assessed in real time by Laser Speckle Contrast Analysis (LASCA). Carotid-femoral pulse-wave velocity (PWV) and carotid intima media thickness (IMT) were assessed as surrogate markers of cardiovascular disease. We studied 75 patients after a median of 3.2 (range 2.1-4.9) years from alloHCT, who had suffered from grade 2 to 3 acute (20%) and/or moderate/severe chronic GVHD (42%), and 75 controls. Although traditional cardiovascular risk factors and surrogate markers of cardiovascular disease did not differ between groups, alloHCT survivors showed significantly impaired microvascular function (baseline and peak flux, time to peak, base to peak and base to occlusion change). LASCA indices were also independently associated with alloHCT. Our study shows for the first-time impaired microcirculation dynamics in alloHCT survivors, independently of cardiovascular risk factors. Additional studies are needed to address the role of novel markers in cardiovascular risk prediction, along with effects of disease type, phase, and pre-transplant treatments.

Atrial High-Rate Episodes in Patients with Devices Without a History of Atrial Fibrillation: a Systematic Review and Meta-analysis.

PURPOSE: Atrial high-rate episodes (AHREs) recorded with cardiac implantable electronic devices (CIEDs) have been associated with the development of clinical atrial fibrillation (AF) and increase in stroke and death risk. We sought to perform a systematic review with a meta-analysis to evaluate the prevalence of AHREs detected by CIEDs, their association with stroke risk, development of clinical AF, and mortality among patients without a documented history of AF. METHODS: We searched several databases, ClinicalTrials.gov, references of reviews, and meeting abstract books without any language restrictions up to 9 September 2020. We studied patients with CIEDs in whom AHREs were detected. Exclusion criterion was AF history. Our primary outcome was the risk of ischemic stroke in patients with AHREs. RESULTS: We deemed eligible eight studies for the meta-analysis enrolling a total of 4322 patients with CIED and without a documented AF history. The overall AHRE incidence ratio was estimated to be 17.56 (95% CI, 8.61 to 35.79) cases per 100 person-years. Evidence of moderate certainty suggests that patients with documented AHREs were 4.45 times (95% CI 2.87-6.91) more likely to develop clinical AF. Evidence of low confidence suggests that AHREs were associated with a 1.90-fold increased stroke risk (95% CI 1.19-3.05). AHREs were not associated with a statistically significant increased mortality risk. CONCLUSION: The present systematic review and meta-analysis demonstrated that among patients without a documented history of AF, the detection of AHREs by CIEDs was associated with significant increased risk of clinical AF and stroke. REGISTRATION NUMBER (DOI): Available in https://doi.org/10.17605/OSF.IO/ZRF6M .

Intrathecal Administration of Nusinersen Using the Ommaya Reservoir in an Adult with 5q-Related Spinal Muscular Atrophy Type 1 and Severe Spinal Deformity.

Spinal muscular atrophy (SMA) is a hereditary neuromuscular disorder, typically caused by survival motor neuron 1 (SMN1) gene deletion in chromosome 5q resulting in loss of SMN protein. SMA type 1 progresses rapidly leading to increased mortality usually before the age of 2 years. Nusinersen, the first approved disease-modifying treatment for all 5q-SMA types and ages, is an antisense oligonucleotide administered intrathecally via repeated lumbar punctures. However, adult SMA patients typically present with severe scoliosis and spinal deformity. We present a 28-year-old patient with SMA type 1 and severe spinal deformity, who received nusinersen via a subcutaneously implanted Ommaya reservoir connected with an intrathecal catheter at the thoracic level. The repetitive administrations were completed uneventfully, obviating the need for repeated laborious lumbar punctures and eliminating radiation exposure. In adult SMA patients, performing recurrent lumbar punctures can be technically challenging raising the need for an alternative route of administration. The use of Ommaya reservoirs is a viable, practical for repeated infusions, and safe option for the intrathecal delivery of nusinersen for select cases such as an adult SMA type 1 survivor with severe spinal deformity.

Nighttime dipping status and risk of cardiovascular events in patients with untreated hypertension: A systematic review and meta-analysis.

The objective of this systematic review and meta-analysis is to determine whether nocturnal blood pressure fall, expressed by dipping patterns according to ambulatory blood pressure monitoring (ABPM), is a risk factor for cardiovascular events (CVEs) in untreated hypertensives. Α thorough systematic literature search at MEDLINE, Embase, Cochrane Library, and gray literature was conducted through March 2020. Two reviewers screened studies and assessed dipping patterns of untreated hypertensives using ABPM with a follow-up >6 months. Newcastle-Ottawa scale was used for risk of bias assessment. We initially identified 463 reports; of which, seven cohort studies were eligible for meta-analysis enrolling 10 438 untreated hypertensives. Untreated patients classified as dippers at baseline (n = 7081) had significant lower risk of CVEs and total mortality compared to non-dippers (n = 3,357) [RR = 0.67, 95% CI (0.49, 0.92); RR = 0.71, 95% CI (0.59, 0.86)]. However, when patients were further classified into four dipping groups, only reverse dippers, yet not extreme dippers or non-dippers, were at increased risk for CVEs compared to dippers [RR = 0.47, 95% CI (0.33, 0.66)]. Likewise, only reverse dippers had a higher stroke risk than dippers [RR = 0.39, 95% CI (0.22, 0.72)]. When compared with the whole group of dippers (including extreme dippers), non-dipping alone (excluding reverse dipping) was not a significant risk factor for CVEs [RR = 0.84, 95% CI (0.61, 1.16)] or total mortality [RR = 0.84, 95% CI (0.61, 1.16); RR = 0.78, 95% CI (0.53, 1.13), respectively]. Untreated hypertensives may benefit more from the evaluation of reverse dipping rather than the non-dipping phenomenon in general.

Precision Medicine in Neurology: The Inspirational Paradigm of Complement Therapeutics.

Precision medicine has emerged as a central element of healthcare science. Complement, a component of innate immunity known for centuries, has been implicated in the pathophysiology of numerous incurable neurological diseases, emerging as a potential therapeutic target and predictive biomarker. In parallel, the innovative application of the first complement inhibitor in clinical practice as an approved treatment of myasthenia gravis (MG) and neuromyelitis optica spectrum disorders (NMOSD) related with specific antibodies raised hope for the implementation of personalized therapies in detrimental neurological diseases. A thorough literature search was conducted through May 2020 at MEDLINE, EMBASE, Cochrane Library and ClinicalTrials.gov databases based on medical terms (MeSH)" complement system proteins" and "neurologic disease". Complement's role in pathophysiology, monitoring of disease activity and therapy has been investigated in MG, multiple sclerosis, NMOSD, spinal muscular atrophy, amyotrophic lateral sclerosis, Parkinson, Alzheimer, Huntington disease, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, stroke, and epilepsy. Given the complexity of complement diagnostics and therapeutics, this state-of-the-art review aims to provide a brief description of the complement system for the neurologist, an overview of novel complement inhibitors and updates of complement studies in a wide range of neurological disorders.

Endothelial Dysfunction in COVID-19: Lessons Learned from Coronaviruses.

PURPOSE OF REVIEW: To review current literature on endothelial dysfunction with previous coronaviruses, and present available data on the role of endothelial dysfunction in coronavirus disease-2019 (COVID-19) infection in terms of pathophysiology and clinical phenotype RECENT FINDINGS: Recent evidence suggests that signs and symptoms of severe COVID-19 infection resemble the clinical phenotype of endothelial dysfunction, implicating mutual pathophysiological pathways. Dysfunction of endothelial cells is believed to mediate a variety of viral infections, including those caused by previous coronaviruses. Experience from previous coronaviruses has triggered hypotheses on the role of endothelial dysfunction in the pathophysiology of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), which are currently being tested in preclinical and clinical studies. Endothelial dysfunction is the common denominator of multiple clinical aspects of severe COVID-19 infection that have been problematic for treating physicians. Given the global impact of this pandemic, better understanding of the pathophysiology could significantly affect management of patients.

A New Era in Endothelial Injury Syndromes: Toxicity of CAR-T Cells and the Role of Immunity.

Immunotherapy with chimeric antigen receptor T (CAR-T cells) has been recently approved for patients with relapsed/refractory B-lymphoproliferative neoplasms. Along with great efficacy in patients with poor prognosis, CAR-T cells have been also linked with novel toxicities in a significant portion of patients. Cytokine release syndrome (CRS) and neurotoxicity present with unique clinical phenotypes that have not been previously observed. Nevertheless, they share similar characteristics with endothelial injury syndromes developing post hematopoietic cell transplantation (HCT). Evolution in complement therapeutics has attracted renewed interest in these life-threatening syndromes, primarily concerning transplant-associated thrombotic microangiopathy (TA-TMA). The immune system emerges as a key player not only mediating cytokine responses but potentially contributing to endothelial injury in CAR-T cell toxicity. The interplay between complement, endothelial dysfunction, hypercoagulability, and inflammation seems to be a common denominator in these syndromes. As the indications for CAR-T cells and patient populations expand, there in an unmet clinical need of better understanding of the pathophysiology of CAR-T cell toxicity. Therefore, this review aims to provide state-of-the-art knowledge on cellular therapies in clinical practice (indications and toxicities), endothelial injury syndromes and immunity, as well as potential therapeutic targets.

The Impact of Antibiotic-Mediated Modification of the Intestinal Microbiome on Outcomes of Allogeneic Hematopoietic Cell Transplantation: Systematic Review and Meta-Analysis.

Accumulating evidence points toward a protective role of intestinal microbiota diversity in allogeneic hematopoietic cell transplantation (allo-HCT). The purpose of this systematic review and meta-analysis is to determine the effect of antibiotic-mediated disruption of microbiota on main allo-HCT outcomes (graft-versus-host disease [GVHD], treatment-related mortality [TRM], overall survival [OS]). Following literature search, 2 reviewers screened eligible studies and assessed risk of bias (RoB). Meta-analysis was performed using Review Manager Software. Among 443 screened references, 18 were eligible for meta-analysis. In studies with genomic markers, grade II to IV acute GVHD was significantly reduced in patients not receiving gut decontamination (GD) (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.20 to 2.04). In subgroup analysis, prophylaxis with systemic antibiotics conferred an increased risk of acute GVHD (OR, 1.65; 95% CI, 1.08 to 2.53). When we incorporated RoB, we found a positive correlation of intestinal GVHD with GD (OR, 1.77; 95% CI, 1.29 to 2.44). Patients with higher microbiota diversity presented increased OS (risk ratio [RR], 1.58; 95% CI, 1.19 to 2.09) and lower TRM (RR, 0.45; 95% CI, 0.26 to 0.76). Our findings confirm that GD and prophylaxis with systemic antibiotics increase acute and intestinal GVHD. Importantly, our meta-analysis was the first to show a significant effect of microbiota diversity on TRM and OS.

Neurologic complications after allogeneic transplantation: a meta-analysis.

OBJECTIVE: Neurologic adverse events remain challenging complications with poor morbidity and mortality post adult allogeneic hematopoietic cell transplantation (allo-HCT) for hematologic diseases. We conducted a systematic review and meta-analysis to determine their spectrum, incidence, and impact on survival. METHODS: We searched MEDLINE, COCHRANE, EMBASE through March 2019 for all types of primary studies. Two independent reviewers screened, extracted data, and assessed risk of bias (RoB). RESULTS: We identified 552 eligible studies describing 57.972 patients; one randomized controlled trial, two case-control, 17 prospective, 86 retrospective cohort studies, 21 case series, and 425 case reports. RoB ranged from fair to high although case series were low-risk. The majority of studies traced infectious or drug-related neurologic manifestations. Infectious complications were present in 2.7% (95% CI 1.9-3.6) and 3.3% (95% CI 0.8-7.1) of patients in retrospective and prospective cohort studies, respectively. In retrospective studies, 3.4% (95% CI 2.1-4.9) of patients suffered from drug-related neurologic events. In prospective cohorts the equivalent incidence was 13% (95% CI 4.2-24.8). Neurologic complications had a detrimental impact on survival. INTERPRETATION: Our study highlights the wide spectrum and significant impact of neurologic complications on survival post allo-HCT. This systematic review summarizes existing data and provides the necessary background information for every physician involved in the management of these patients.