National Hospital for Neurology and Neurosurgery

Abstract Cauda equina syndrome (CES) is a neurological emergency requiring timely surgical decompression within 24 h of MRI confirmation. Limited out-of-hours (OOH) MRI access often necessitates emergency patient transfers to acute spinal centres. This study assesses the justification for such transfers. This retrospective cohort study analysis from April 2019 to March 2025, utilised electronic health records and referral data to UCLH (NHNN) which totalled 5525 OOH referrals for suspected CES. 706 patients were accepted for transfer. 285 were referred with local MRIs before referral, leading to 135 surgeries for CES. 116 were transferred after awaiting a local MRI, leading to 61 surgeries for CES. 305 patients were transferred for an urgent MRI with 37 requiring surgeries for CES. There was a significant difference in time from MRI to surgery for patients who awaited a local MRI (21.74 ± 1.67 h) versus those transferred for an MRI (9.25 ± 2.11 h) although both groups met the guideline target of undergoing surgery within 24 h of a scan (MWUT = 309.0, P = 2.76e-9). OOH MRI sensitivity was 9.8%. Patients with a negative scan result remained hospitalised for a mean of 69.76 ± 8.37 h until discharge, with an average admission cost of £3014.55. OOH referrals predominantly originated from doctors below ST4, with diagnostic accuracy of 4.2% compared to 5.2% for those above ST4 (χ² = 0.031, P = 0.86). OOH MRI transfers yield limited surgical benefit, accrue significant costs, and align poorly with GIRFT guidelines advocating for local MRIs to reduce unnecessary referrals. These findings support minimising OOH transfers for suspected CES.

Abstract Background High-dose high-intensity upper limb neurorehabilitation can lead to meaningful clinical gains even in chronic stroke, yet substantial variability in recovery remains unexplained. Identifying neurophysiological markers linked to neuroplasticity and recovery could provide mechanistic insights and guide personalised rehabilitation. Objective To characterise stroke-related alterations in β-activity during movement and neural activity at rest and explore associations between brain activity and changes in upper limb clinical outcomes in chronic stroke survivors undergoing three-week high-dose rehabilitation. Methods Electroencephalography (EEG) was recorded during the three-week rehabilitation programme in 40 chronic stroke survivors participating in the Queen Square Upper Limb (QSUL) Programme, as well as in 26 healthy controls. Recordings were taken during passive movement of the affected and unaffected index fingers (∼70 movements per hand) and at rest (∼7 min). Clinical assessments included the Fugl-Meyer Upper Limb Assessment (FM-UE), reflecting impairment-level deficits, and the Chedoke Arm and Hand Activity Inventory (CAHAI-13), capturing real-world upper limb activity, to examine their differential relationships with movement-related β-activity. Results Stroke survivors showed significant improvements in FM-UE and CAHAI scores following the rehabilitation programme (Mean Δ: FM-UE = 7.5, CAHAI = 7.4), exceeding minimum clinically important differences. Compared to controls, stroke survivors exhibited less strong β-event-related desynchronization/synchronization (β-ERD/ERS) during passive movement of the affected and unaffected index finger, with effects lateralised to the lesioned hemisphere. No significant differences at rest were observed between stroke participants and healthy controls. Only improvements in CAHAI, but not FM-UE, were associated with stronger β-ERD (more negative) and stronger β-ERS (more positive) responses during passive movement. Conclusions Stronger movement-related β-activity is associated with improvements in upper limb activity following high-dose high-intensity neurorehabilitation, suggesting β-activity as a potential marker of neuroplasticity.

NDUFAF6 encodes a mitochondrial complex I assembly factor essential for the proper biogenesis and stability of the nicotinamide adenine dinucleotide (NAD) + hydrogen (H) (NADH)–ubiquinone oxidoreductase complex. Pathogenic variants in NDUFAF6 have been increasingly recognized as a cause of mitochondrial disease, particularly Leigh syndrome, a severe neurodegenerative disorder characterized by bilateral symmetrical lesions in the central nervous system. To date, fewer than 50 patients with NDUFAF6-related mitochondrial disease have been reported, displaying a broad phenotypic spectrum ranging from early-onset neurodevelopmental regression to milder, more chronic presentations. The molecular mechanisms underlying these phenotypes are linked to impaired complex I assembly and reduced enzymatic activity, highlighting the critical role of NDUFAF6 in mitochondrial function.Here we present a cohort of 27 patients (14 males and 13 females) from 18 families harbouring biallelic variants in the NDUFAF6 gene. The patient’s mean age was 9.15 ± 8.30 years (range: 4 weeks to 25 years); 12 patients (37%) had died by the time the data were collected for this article. The clinical presentation showed wide phenotypic variability, from mild to severe psychomotor regression (74%) most commonly before the age of 5 years, hypotonia (22%), movement disorders (30%), and hypertonia (15%). Bilateral striatal necrosis lesions were the most characteristic features on cranial MRI (67%) although white matter abnormalities were also noted (15%), occasionally accompanied by cystic formations, suggestive of early neurodevelopmental anomalies.Genomic sequencing was applied, leading to the identification of 19 distinct variants in the NDUFAF6 gene, including nine novel variants not previously reported and either absent or extremely rare in public population databases. Functional studies confirmed the pathogenicity of these variants, demonstrating a deleterious effect on NDUFAF6 protein expression and a consequent impairment in complex I assembly and stability.To date, this represents the largest reported cohort of patients with NDUFAF6-associated mitochondrial disease. Our findings provide a comprehensive overview of clinical characteristics—including age of symptom onset, phenotypic variability, and patient outcomes—aiming to improve prognostic information and facilitate genetic counselling in clinical practice.

Urinary dysfunction affects billions of individuals worldwide; however, the fundamental cellular and circuit properties that govern perineal motor control remain largely unknown, serving as a functional “black box”. Here, we describe several methods that, when used in concert, characterise cellular, synaptic, and motor unit properties underlying the control of urination in adult mice. High-density electromyography combined with real-time cystometry were used to study external urethral sphincter (EUS) motor units, which follow a hierarchical (“onion skin”) recruitment pattern during bladder filling. The transition to the voiding phase is marked by inhibition, followed by synchronised bursts. Furthermore, through concurrent recordings of ischiocavernosus (IC) muscles, the relationship between IC and EUS motor units could be studied to look for shared common inputs that could shed light on circuitry. Whole-cell patch-clamp recordings from retrogradely identified neurons revealed a fundamental biophysical divergence: urinary parasympathetic preganglionic neurons (PPGN) are significantly smaller and more excitable than somatic EUS and IC motoneurons and lack the recurrent excitatory and inhibitory circuits present in both EUS and IC motor pools. Finally, using a novel pressure-clamp preparation, we showed that acute tibial nerve stimulation (a widely used treatment for urinary dysfunction) evokes short-latency inhibition of EUS motor units. Collectively, these methods can be used to delineate patterns of motor unit recruitment, local recurrent microcircuit architecture, and distinct biophysical properties of the perineal motor system, providing mechanistic insights into urinary function.

The ontological categorization of the cellular elements of the brain was proposed over a century ago by Santiago Ramón y Cajal (neurons, astroglia) and Pío del Río-Hortega (oligodendroglia, microglia). It combines histochemical observations of morphology with allied inferences about the specialized functions and origins (ectoderm or mesoderm) of each cellular element. This ontology shapes modern neuroscience, with the main non-neuronal cells-astroglia, oligodendroglia and microglia-viewed as having distinct primary roles relating respectively to the metabolic support, myelination and immunoprotection of neurons, the information signaling cells. Yet contemporary techniques, ranging from electrophysiology to single-cell transcriptomics and ultrahigh resolution spectroscopy, are revealing intersecting molecular profiles and functional capacities of these cell groups, for example metabolic support, neuroimmune and signaling functions in oligodendroglia. Here we identify discrepancies in current glial paradigms, from empirical, evolutionary and pragmatic perspectives. We suggest a subset of small, iron-rich glial cells, usually with few processes, often viewed as oligodendroglia with myelin-related primary functions, instead have iron-related primary functions that are central to all aspects of brain activity. We call these 'ferriglia'. We discuss implications for pathogenesis across the spectrum of neuropsychiatric and neurological disorders, including neurodegenerative conditions such as Alzheimer's disease and other less common cognitive, movement and neurobehavioral disorders, stroke and cerebrovascular disease, glioblastoma and other brain cancers and neuroimmune conditions. We also briefly address the question of where ferriglia may reside within existing glial compartments and lineages, implications for the ontological classification of other glial cells, and research challenges that must be overcome going forward.

Cognitive offloading refers to the use of physical actions and the external environment to reduce cognitive demand. Offloading strategies such as creating external reminders instead of relying on internal memory are highly effective and play a key role in supporting real-world cognition. Previous work has shown that people have systematic biases in their offloading strategies, which are related to biased metacognitive evaluations of cognitive ability. While metacognitive interventions could potentially mitigate these biases, research investigating their effects has produced mixed results. Here, we examined the influence of a brief metacognitive intervention comprising just five trials during an initial practice session. After the intervention, participants performed a memory task where they decided between using internal memory (for maximum reward) or external reminders (for reduced reward), allowing us to determine the optimality of offloading strategies. Experiment 1 (N = 164) showed that making metacognitive predictions and subsequently receiving feedback led to improved metacognitive calibration and more optimal reminder-setting strategies. Experiment 2 (N = 416) replicated this pattern and found that making predictions alone was ineffective. These findings suggest that a metacognitive intervention combining prediction with feedback could potentially optimise cognitive offloading in everyday life.

While induced pluripotent stem cells (iPSCs) have gained popularity in studying neurodegenerative diseases, the heterogeneity of stem cells used across studies impacts cross-study comparison. The iPSC Neurodegenerative Disease Initiative (iNDI) selected the KOLF2.1J cell line and prioritized its use as a reference standard for studying the effects of pathogenic variants on cell biology due to its stability and neutral neurodegenerative disease genetic risk. This cell line, and its derivatives expressing over 100 variants related to Alzheimer’s disease, Parkinson’s disease, and other neurological diseases, are available for academic and industry access. Current genomic data analyses are limited by the use of a human reference genome that does not capture the complete genetic background of a given iPSC line. While in the future this issue may be partially mitigated by the creation of a comprehensive human pangenome, previous work has shown that generating custom genomes is of value both to characterize the variation present and to serve as a more appropriate genomic reference. Here, we generated and characterized a custom complete genome assembly from KOLF2.1J. Mapping of sequencing reads to a personalized diploid assembly results in more comprehensive mapping compared to traditional linear references (i.e GRCh38). In addition, we provide a comprehensive custom gene annotation along with isoform expression and differential methylation analyses across multiple cell types. The assembly and all additional data is browsable and publicly available. This resource will enable more accurate investigation of the KOLF2.1J cell line and any genomics data generated compared to using traditional generalized references, while also serving as a foundational approach for establishing custom reference assemblies for other high-value iPSC lines.

Alazami syndrome is a neurodevelopmental disorder characterized by postnatal growth retardation, moderate to severe intellectual disability, and facial dysmorphology. It is caused by biallelic variants in the transcriptional regulator La ribonucleoprotein 7 (LARP7), where frameshift variants accounted for the majority of cases. The current study presents 7 new patients, including 3 males and 4 females from 3 unrelated families. Careful and thorough clinical examination identified novel oro-dental disease abnormalities, including a prominent premaxilla and enamel defects. The detected variants (c.1113_1116del, c.997 + 2T > C and c.518T > C) were not reported in the previous studies. The substitution c.518T > C represented the second missense variant to be identified in patients with Alazami syndrome. Male patients from the three families fulfilled ≥ 2 clinical warning signs of primary immunodeficiency. Lymphocyte subset counts and immunoglobulin levels were estimated in patients from two families. The values were within reference ranges, with only minor non-significant alterations in cytotoxic T-cell counts. A functional assay of B lymphocyte response was performed in one family, demonstrating impaired Streptococcus pneumoniae IgG antibody production following Pneumovax vaccination in the male patient, while his female sibling mounted an adequate response. In conclusion, the disease has a wide range of symptoms, which vary greatly among the affected patients. Our study expanded the clinical and molecular spectrum of the disorder and highlighted immunodeficiency as an underrecognized disease feature, potentially with a male sex predilection.