Carotid near occlusion, abbreviated NO, refers to a severe stenosis of the internal carotid artery that reduces the diameter of the vessel distal to the blockage. Unlike conventional stenosis, which can be expressed as a percentage reduction in luminal diameter using the NASCET criteria, the severity of near occlusion cannot be reliably quantified this way. The distal artery has already been squeezed by the inability of blood flow to sustain adequate pressure past the critical narrowing, so the usual yardstick breaks down. This complicates both diagnosis and clinical decision-making, and it explains why the condition has remained controversial since the era of the North American Symptomatic Carotid Endarterectomy Trial and the European Carotid Surgery Trial, which together included only 262 patients with near occlusion, a mere 4.4 percent of their combined cohorts.

The Finnish team, led by Henrietta Törmänen and Petra Ijäs, reanalyzed preoperative CT angiograms from 443 consecutive carotid stenosis patients scheduled for carotid endarterectomy between October 2012 and September 2015 as part of the Helsinki Carotid Endarterectomy Study 2. The cohort drew from a catchment area of approximately 1.6 million people, and the decision to operate was made according to institutional guidelines aligned with European Society for Vascular Surgery recommendations. Crucially, the study cohort was established based on the decision to perform surgery, not the operation itself, so patients who suffered adverse events while waiting were retained in the analysis.

The researchers applied precise, reproducible measurement-based definitions. Subtle near occlusion, or s-NO, was defined as a difference of at least 1.0 millimeter in distal luminal diameter between the ipsilateral and contralateral internal carotid artery, a threshold derived from the normal variation of the healthy internal carotid artery using a 2.5 times standard deviation cut-off. Near occlusion with full collapse, or fc-NO, was defined as an ipsilateral distal internal carotid artery diameter of 2.0 millimeters or less, and/or an ipsilateral-to-contralateral diameter ratio of 0.42 or less. All measurements were conducted by two experienced neuroradiologists and a trained radiology resident, ensuring diagnostic consistency across the entire cohort.

The headline finding is striking: near occlusion was detected in 143 patients, or 32 percent of the cohort, with 124 cases, or 87 percent, being the subtle form and only 19 cases, or 13 percent, showing full collapse. This prevalence vastly exceeds what was seen in the NASCET and ECST study cohorts, a difference the authors attribute to the superior sensitivity of CT angiography compared with digital subtraction angiography, which was typically performed unilaterally in the early trials and likely underestimated the prevalence of subtle collapse. The mean age of patients was 70 years, 68 percent were male, and the most prevalent index symptom was hemispheric stroke at 27 percent, followed by amaurosis fugax at 18 percent and transient ischemic attack at 17 percent.

Contrary to expectations, patients with near occlusion did not carry a higher risk of preoperative recurrent stroke or procedural stroke or death within 30 days of surgery compared with those with conventional stenosis. The age-adjusted odds ratio for preoperative ischemic cerebrovascular events was 1.82 with a 95 percent confidence interval of 0.96 to 3.47, which did not reach statistical significance. For procedural stroke or death, the odds ratio was 1.73 with a confidence interval of 0.67 to 4.50, again not significant. The 30-day stroke or death rate in near occlusion patients was 5.6 percent, with 5.6 percent in the subtle group and 5.3 percent in the full collapse group. These figures contrast sharply with some earlier reports, including one study that documented a 43 percent risk of recurrent ipsilateral ischemic stroke within 90 days for patients with full collapse treated with best medical therapy alone, and another that found a 6 percent stroke or death rate after revascularization.

However, the study uncovered a genuinely important procedural risk that has been underappreciated: hyperperfusion syndrome after carotid endarterectomy was nearly three times more frequent in near occlusion patients, occurring in 7.0 percent versus 2.7 percent of conventional stenosis patients, with an age-adjusted odds ratio of 2.78 and a confidence interval of 1.06 to 7.12. Hyperperfusion syndrome was diagnosed when typical symptoms such as hypertension, headache, confusion, focal neurological deficits, or seizures occurred in association with elevated flow velocity in the middle cerebral artery territory ipsilateral to the surgery, as measured by transcranial doppler. One patient with subtle near occlusion suffered a fatal intracranial hemorrhage due to hyperperfusion. The predominance of the subtle form among affected patients, with 55 percent of hyperperfusion cases having s-NO, suggests that impaired cerebrovascular reserve and autoregulation may promote post-revascularization hyperperfusion even in milder forms of collapse.

The study also revealed a curious pattern in symptom distribution. Amaurosis fugax, the transient loss of vision in one eye, was significantly more common as an index symptom in near occlusion patients, occurring in 26 percent versus 14 percent of conventional stenosis patients, and it tended to be repetitive in nature, with a median of three attacks per patient before hospital admission. The authors interpret this finding as partly a consequence of patient selection, since near occlusion patients are typically managed with best medical therapy after their first symptom, with invasive treatments reserved for recurrent symptoms. Yet they cannot rule out a true biological association, because high-grade carotid stenosis reduces arterial flow, increasing embolic risk and predisposing to ocular hypoperfusion, which can lead to repetitive transient visual symptoms through both frank hemodynamic failure and microemboli.

The clinical implications are substantial. Because optimal treatment strategies for near occlusion remain uncertain, with the 2023 European Society for Vascular Surgery guidelines providing only a Class IIb recommendation for revascularization in symptomatic full collapse patients with recurrent events despite best medical therapy, this study contributes to an evolving understanding of the condition. The finding that near occlusion patients face a higher risk of hyperperfusion syndrome, which can predispose to intracerebral hemorrhage if left untreated, makes strict perioperative blood pressure control essential. The authors call for further observational studies comparing near occlusion patients with and without collapse to better guide clinical decisions, and their precise measurement-based criteria offer a reproducible tool for future research into this common yet enigmatic variant of carotid artery disease.

Subject of Research: Neurology

Article Title: Risk of early stroke recurrence and procedural stroke or death in carotid near occlusion patients scheduled for carotid endarterectomy

Article References: Törmänen, H., Koskinen, S., Nuotio, K., Tulamo, R., Vikatmaa, P., Soinne, L., Lindsberg, P. J., & Ijäs, P. (2026). Risk of early stroke recurrence and procedural stroke or death in carotid near occlusion patients scheduled for carotid endarterectomy. Journal of Neurology, 273(11), 667. https://doi.org/10.1007/s00415-026-14198-x

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14198-x

Keywords: stroke, carotid near occlusion, carotid endarterectomy, hyperperfusion syndrome, CT angiography, Journal of Neurology, Risk, early, recurrence, procedural, death, carotid

OCT is a workhorse of modern ophthalmology. The technique uses low-coherence light waves to build cross-sectional images of the retina, resolving its ten distinct layers with micrometer precision. Because the retina is embryologically and physiologically an outpost of the central nervous system, its delicate microvasculature offers what the researchers describe as a noninvasive, side-effect-free quick look into the brain. Ophthalmologists already rely on OCT to screen for glaucoma, diabetic retinopathy, and macular degeneration. What the new study adds is the suggestion that the same scan, already fast and comparatively cheap, might also carry a hidden cardiovascular report card.

The research team, led by Martin Hänsel, Julian Deseoe, and Susanne Wegener of the University Hospital Zurich, focused on two inner retinal layers: the retinal nerve fiber layer (RNFL), a thin sheet of axons funneling visual signals toward the optic nerve, and the ganglion cell-inner plexiform layer (GCIPL), which contains the cell bodies and synaptic connections of retinal neurons. Earlier studies had shown that patients who had already survived a stroke or heart attack tend to have thinner RNFL and GCIPL measurements. The open question was whether thinning could be detected before the event, in seemingly healthy people, and whether it carried information beyond conventional risk factors.

To answer it, the team mined the UK Biobank, a population-based cohort of more than half a million adults aged 40 to 69 recruited between 2006 and 2010. Roughly a tenth of participants underwent OCT imaging with a spectral-domain Topcon device using a standardized 6 by 6 millimeter macular raster scan of 128 B-scans. Custom segmentation software automatically delineated the retinal boundaries, and the investigators applied strict quality control, discarding the poorest 20 percent of images based on quality scores, excluding participants who reported eye disease, and requiring complete data on cardiovascular risk factors. After these filters, 51,293 participants remained, of whom 1,506, or 2.9 percent, had already experienced a stroke or myocardial infarction before their eye scan.

The first finding concerned the past rather than the future. Participants with prior cardiovascular disease had measurably thinner inner retinas than their event-free peers: the RNFL averaged 28.97 micrometers in the CVD group versus 29.70 micrometers in those without, the GCIPL 72.99 versus 74.21 micrometers, and a photoreceptor-related measure called ISOS.RPE also differed significantly. The other layers examined showed no such difference. The researchers then turned to the 49,787 participants with no prior cardiovascular events and asked a forward-looking question: did retinal thickness at baseline predict who would go on to suffer a major adverse cardiovascular event, a composite of stroke, myocardial infarction, and cardiovascular death, during follow-up?

The answer was yes. In cause-specific hazard models, which properly account for the competing risk of dying from non-cardiovascular causes, each standard deviation increase in RNFL thickness was associated with an 8 percent lower risk of a future event (adjusted hazard ratio 0.92, 95 percent confidence interval 0.89 to 0.96, p < 0.001), while each standard deviation of additional GCIPL thickness carried a 4 percent reduction (adjusted hazard ratio 0.96, 95 percent confidence interval 0.92 to 1.00, p = 0.04). Crucially, these associations survived adjustment for a wide range of traditional cardiovascular risk factors, including age, sex, blood pressure, diabetes, cholesterol, body mass index, smoking, and atrial fibrillation. The relationship was linear, with no evidence of nonlinear effects, and it did not differ between men and women.

The absolute differences were striking when participants were sorted into thin, medium, and thick groups. Over ten years, people with the thinnest RNFL had a cumulative incidence of major cardiovascular events of 5.19 percent, nearly double the 2.78 percent seen in those with the thickest RNFL. The same gradient appeared for the GCIPL: 4.76 percent of the thinnest group suffered an event within a decade, compared with 2.42 percent of the thickest group, roughly a halving of risk across the retinal spectrum.

Perhaps the most intriguing technical detail is a double dissociation between the two layers and the two event types. RNFL thickness was more strongly associated with myocardial infarction (adjusted hazard ratio 0.94, p = 0.02), while GCIPL thickness was more strongly linked to incident stroke (adjusted hazard ratio 0.90, p = 0.003), with the complementary layer showing weaker, non-significant associations in each case. The authors propose a microvascular explanation. The RNFL is fed primarily by the radial peripapillary capillary plexus, whose capillaries run parallel to the nerve fibers, whereas the GCIPL is supplied by the superficial vascular plexus with a lobular architecture. Because atherosclerosis is a systemic disease, subclinical narrowing of the central retinal artery and its branches would chronically starve these layers of oxygen, and the two distinct vascular bed architectures may respond differently to the risk factor profiles that predispose to coronary versus cerebral events. A recent Mendelian randomization study supports the idea of shared underlying causes between retinal layer thickness and cardiovascular disease.

How much does the eye scan actually add to prediction? The honest answer: modestly. Adding RNFL and GCIPL thickness to a simple model based on age and sex alone nudged the area under the receiver operating characteristic curve for 10-year event prediction from 0.708 to 0.710, a statistically significant but small improvement, with even smaller gains when the layers were added to fully adjusted models. The authors are candid about this gap between statistical significance and clinical relevance. They also emphasize that their cohort excluded people over 69, precisely the age group with the highest cardiovascular risk, as well as anyone with pre-existing eye disease, and that the observational design cannot establish causation. Whether RNFL and GCIPL thinning actually contributes to disease or merely mirrors it in the retinal microcirculation remains unresolved.

Still, the study offers practical building blocks for the future. The team generated age- and sex-specific normative values for RNFL and GCIPL thickness in healthy adults, giving clinicians a reference frame should retinal measurements ever be folded into risk screening, particularly for people with a family history of cardiovascular disease. The authors sketch a roadmap for improving performance: combining layer thickness with OCT angiography measures such as vessel density, tracking individual retinal trajectories over time rather than single snapshots, and disentangling ischemic from hemorrhagic stroke, which was not done here. Prospective validation studies will be needed before any ophthalmology practice doubles as a cardiac screening station. For now, the message is one of cautious excitement: the eye has long been called a window to the soul, but a growing body of evidence suggests it may also be a window to the heart, and the view is getting clearer with every scan.

Subject of Research: Retinal layer thickness measured by optical coherence tomography as a predictor of future major adverse cardiovascular events in the UK Biobank cohort

Article Title: Retinal layer thickness as a potential marker for future cardiovascular events – a UK Biobank cohort study using optical coherence tomography

Article References: Hänsel, M., Deseoe, J., Herzog, L., Davoudi, N., Kana, V., Menze, B., Sick, B., & Wegener, S. (2026). Retinal layer thickness as a potential marker for future cardiovascular events – a UK Biobank cohort study using optical coherence tomography. Journal of Neurology, 273(11), Article 662. https://doi.org/10.1007/s00415-026-14175-4

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14175-4

Keywords: optical coherence tomography, retinal nerve fiber layer, ganglion cell-inner plexiform layer, cardiovascular risk prediction, UK Biobank, stroke, myocardial infarction, major adverse cardiovascular events, retinal microvasculature, risk screening, Journal of Neurology, population cohort study

The cerebellum, tucked beneath the rear of the skull, is best known for fine-tuning movement. But a substantial portion of it, the vestibulocerebellum, is devoted to calibrating the vestibulo-ocular reflex, or VOR, the automatic eye movement that keeps images stable on the retina when the head moves. When this calibration fails, patients experience the world as a blur of motion and feel profoundly unsteady. The Korean team’s report shows that when inflammation strikes this region, the resulting eye-movement abnormalities can be so distinctive that they point directly to cerebellar disinhibition, the loss of the cerebellum’s normal restraining influence on vestibular circuits.

The most striking finding in the case involves what the authors call reversed corrective saccades. During the head impulse test, a bedside maneuver in which the examiner turns the patient’s head rapidly and unexpectedly while the patient fixes their gaze on a target, a healthy vestibular system generates a compensatory eye movement that keeps the eyes locked on the target. If the reflex is weak, the eyes are dragged off target with the head, and the patient makes a quick corrective saccade back to the target. In cerebellar disease, however, the corrective movement can go the wrong way, jumping in the same direction as the head turn rather than back toward the target. This paradoxical sign, previously documented in acute cerebellar dysfunction by Choi and colleagues in a 2014 study, indicates that the inhibitory brake normally applied by the cerebellum has been released, allowing the vestibular response to overshoot rather than undershoot.

Equally revealing was the frequency-dependent behavior of the vestibulo-ocular reflex. The team observed VOR hyperactivity that varied with the frequency of head rotation, a pattern that helps localize the problem to specific cerebellar structures. The nodulus and uvula, midline structures of the vestibulocerebellum, are known from decades of experimental work, including classic studies by Cohen and colleagues published in 2002, to control the spatial orientation of the angular vestibulo-ocular reflex and to regulate the velocity storage mechanism, a central process that prolongs and shapes vestibular signals. The flocculus, by contrast, exerts direct inhibitory control over the VOR gain itself. When the flocculus is damaged, as Yacovino and colleagues described in isolated floccular infarction, the VOR gain rises, producing hyperactive eye responses and oscillopsia, the distressing sensation that the visual world is jumping.

Acute cerebellitis is an uncommon diagnosis, and its presentation in adults is rarer still. Most of the literature concerns children, in whom the condition frequently follows viral infections or arises with autoimmune antibodies against neural targets. A large Italian multicenter retrospective study published in 2017 by Lancella and colleagues documented the pediatric experience over eleven years, while a 2023 European study by Quack and colleagues systematically examined autoantibody status, neuroradiological findings, and clinical features in children with the condition. In adults, reports are largely confined to individual case descriptions, such as the review by Van Samkar and colleagues published in BMC Research Notes in 2017. The scarcity of adult cases means that each well-documented patient adds meaningful weight to the clinical map of the disease.

What makes this case particularly instructive is the predominance of vestibular symptoms. A patient who complains primarily of dizziness and imbalance is far more likely to be evaluated for benign paroxysmal positional vertigo, vestibular neuritis, or other inner ear disorders than for brain inflammation. Yet the eye-movement examination, performed with modern video head impulse testing, can separate these possibilities with remarkable precision. Video head impulse testing has become a cornerstone of the assessment of central vestibular disorders, as summarized by Choi, Kim, and Kim in a 2018 review in Neurology, because it measures the gain of the vestibulo-ocular reflex across individual semicircular canals and captures the corrective saccades that reveal where in the vestibular pathway the fault lies.

The frequency dependence of the VOR abnormality carries specific mechanistic significance. The vestibulo-ocular reflex operates across a range of head movement frequencies, from slow postural sway to rapid voluntary head turns. Different cerebellar regions modulate the reflex at different points along this spectrum. Studies of patients with chronic degeneration of the vestibulocerebellum by Bertolini and colleagues suggested that vestibular self-motion perception is shaped by the velocity storage mechanism, and work by Lee and colleagues on spinocerebellar ataxia type 6 traced how vestibular function evolves during head impulses in a degenerative disease. Against this background, the acute, frequency-dependent hyperactivity seen in the present case of cerebellitis stands out as a signature of sudden disinhibition rather than gradual degeneration, offering a dynamic window into cerebellar physiology that chronic conditions cannot provide.

The concept of cerebellar disinhibition unifies the two key signs in the case. Under normal conditions, the vestibulocerebellum continuously calibrates the vestibulo-ocular reflex, comparing the expected sensory consequences of a head movement with the actual signals arriving from the labyrinth and adjusting the reflex gain accordingly. This internal model computation, as Cullen described in a 2023 review in Trends in Neurosciences, is one of the cerebellum’s central contributions to the perception of self-motion. When inflammation disables this computation, the inhibitory control is lost, the reflex gain climbs above normal, and corrective saccades reverse direction because the eyes have overshot rather than undershot the target. The same logic explains other cerebellar eye signs, such as vibration-induced downbeat nystagmus, which Kim and colleagues reported in 2023 as a new cerebellar sign observed in a paraneoplastic syndrome.

For clinicians, the practical lesson is that a predominantly vestibular presentation does not exclude cerebellar inflammation. The authors emphasize that reversed corrective saccades during head impulse testing and frequency-dependent VOR hyperactivity should be recognized as clues to cerebellar disinhibition, prompting appropriate neuroimaging and further workup rather than discharge with a diagnosis of uncomplicated inner ear disease. The case was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Keimyung University Dongsan Hospital, with written informed consent obtained from the patient’s parent for publication of the report and accompanying images. The authors report no conflicts of interest, and the work received no dedicated funding.

Beyond its immediate clinical message, the report illustrates how a single carefully examined patient can sharpen our understanding of a brain region that remains incompletely mapped. The cerebellum’s role in vestibular processing has been built up over decades through lesion studies, animal experiments, and increasingly sophisticated bedside testing, and acute, reversible insults such as cerebellitis offer some of the cleanest natural experiments available. As video head impulse testing and related technologies spread through emergency departments and vestibular clinics, signs that were once obscure, such as reversed corrective saccades, are likely to be recognized more often, turning a rare case report into a practical diagnostic lesson for the many patients who arrive complaining simply that the room will not stop spinning.

Subject of Research: Acute cerebellitis presenting with vestibular symptoms and distinctive eye-movement signs of cerebellar disinhibition

Article Title: Acute cerebellitis presenting predominantly with vestibular symptoms: reversed corrective saccades and frequency-dependent VOR hyperactivity as clues to cerebellar disinhibition

Article References: Kwon, H., Kim, H. W., & Kim, H. A. (2026). Acute cerebellitis presenting predominantly with vestibular symptoms: reversed corrective saccades and frequency-dependent VOR hyperactivity as clues to cerebellar disinhibition. Journal of Neurology, 273(11), Article 660. https://doi.org/10.1007/s00415-026-14204-2

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14204-2

Keywords: acute cerebellitis, vestibular symptoms, vestibulo-ocular reflex, reversed corrective saccades, head impulse test, cerebellar disinhibition, vestibulocerebellum, flocculus, nodulus, dizziness, neuro-otology, Journal of Neurology

The core of the report lies in that disconnect between appearance and underlying cause. Stroke-like lesions, particularly when they recur and cluster in the posterior brain territories, typically send clinicians down a well-worn diagnostic path toward cerebrovascular disease, mitochondrial encephalopathy, or inflammatory conditions such as posterior reversible encephalopathy syndrome. The letter’s authors detail a clinical course in which the patient’s lesions heralded a condition few emergency departments or even stroke units would place high on their differential list. By the time the correct diagnosis was reached, the case had already accumulated the hallmarks of an ataxia syndrome, the slowly progressive loss of coordination that defines the cerebellar disorders.

COQ8A, once known by the name ADCK3, encodes a protein kinase that sits at the heart of the biochemical machinery producing coenzyme Q10, also called ubiquinone. This small, lipid-soluble molecule is not a genetic curiosity; it is an essential shuttle in the mitochondrial electron transport chain, ferrying electrons between the complexes that generate most of the cell’s energy in the form of ATP. Biallelic mutations in COQ8A disrupt this production line, and the result is primary coenzyme Q10 deficiency, one of a small family of inherited disorders in which the body’s own ubiquinone manufacturing falters. Because neurons, and particularly cerebellar Purkinje cells, are metabolically voracious, the clinical signature often emerges as cerebellar ataxia.

The condition first entered the medical literature in 2008, when Lagier-Tourenne and colleagues identified ADCK3 mutations in families with recessive ataxia associated with coenzyme Q10 deficiency, and Mollet and coworkers independently linked CABC1, the same gene under another name, to ubiquinone deficiency with cerebellar ataxia and seizures. In the years since, the phenotype has been progressively clarified. A multicenter study published in Annals of Neurology in 2020 by Traschütz and colleagues delineated the clinico-genetic, imaging and molecular features of COQ8A-ataxia in a cohort of 59 patients, establishing a core phenotype of slowly progressive gait ataxia with variable additional features, including epilepsy, cognitive involvement and, in some individuals, dystonia. That study remains a cornerstone for clinicians who suspect the disorder.

What makes the new Indian case noteworthy is the prominence of stroke-like episodes in the presentation. These episodes are a recognized but infrequent feature of COQ8A disease, and the letter’s authors are careful to position their report within a small body of prior evidence. Hikmat and colleagues described ADCK3 mutations with epilepsy, stroke-like episodes and ataxia as far back as 2016, explicitly noting the resemblance to POLG-related mitochondrial disease, a better-known condition famous for its own stroke-like presentations. More recently, Ramesh and coworkers reported stroke-like episodes and epilepsy in a patient with COQ8A-related deficiency, and Radhakrishnan’s group documented young-onset ataxia-dystonia caused by the same gene. The recurrent posterior localization of the lesions in the present case adds a distinctive imaging dimension to this accumulating picture.

The mechanistic story behind stroke-like lesions in mitochondrial and energy-deficiency disorders is one of metabolic failure rather than vascular occlusion. In a true stroke, a blocked or ruptured blood vessel starves tissue of perfusion. In a stroke-like episode, the brain tissue itself fails, often triggered by metabolic stressors such as infection, seizures or the energy demands of normal neural activity, which become unsustainable when the electron transport chain cannot deliver sufficient ATP. Neurons in energy-hungry regions deplete their reserves, cytotoxic edema follows, and imaging shows lesions that can migrate, resolve and recur in a pattern that defies the fixed vascular territories of ischemic infarcts. This behavior is precisely what makes such lesions confusing, since the initial radiological read frequently favors stroke or PRES before the underlying metabolic cause is considered.

The stakes of this confusion are high for one crucial reason: COQ8A-related coenzyme Q10 deficiency is widely described in the literature as a potentially treatable genetic disease. High-dose oral coenzyme Q10 supplementation, when initiated early, can theoretically bypass the block in endogenous synthesis and restore some measure of electron transport function. Chang and colleagues made this point explicitly in 2018 in the journal Movement Disorders Clinical Practice, framing ADCK3-related deficiency as a treatable condition, and Mantle, Millichap, Castro-Marrero and Hargreaves updated the landscape of primary coenzyme Q10 deficiency in a 2023 review in Antioxidants. Treatment does not always reverse established neurological damage, and outcomes vary, but the contrast with the untreatable trajectories of many other ataxias makes an early, correct diagnosis transformative for patients and families.

The case also carries a sobering dimension that the authors handle with care. The patient described has died, and written informed consent for publication was obtained from the patient’s next of kin, with the case fully de-identified and identifying annotations removed from the images. The retrospective, anonymized account of the clinical course involved no intervention or deviation from standard care, and the Institutional Ethics Committee determined that formal ethical approval was not required under the Indian Council of Medical Research’s national ethical guidelines. The authors report no conflicts of interest and received no specific funding for the work. This transparency matters, because case reports that capture missed or delayed diagnoses often face reluctance to publish, and yet they are among the most educationally valuable contributions a clinical team can make.

From the perspective of the wider neurology community, the message is one of diagnostic vigilance. The authors and their supporting literature sketch a recognizable pattern: a patient presenting with what appears to be recurrent posterior circulation stroke or PRES, whose episodes recur atypically, whose imaging shows lesions that do not respect vascular territories or who develops progressive gait ataxia over time, should trigger consideration of a primary coenzyme Q10 deficiency. Confirming the diagnosis today rests on genetic testing of the COQ8A gene, alongside biochemical assessments of coenzyme Q10 status where available, and the expanding availability of affordable sequencing is steadily lowering the barrier to making this diagnosis in resource-limited settings, where such cases are often first encountered.

The broader significance of this letter extends beyond a single gene. It joins a growing catalogue of metabolic epilepsies and encephalopathies that masquerade as vascular emergencies, from POLG-related disease to lysinuric protein intolerance and beyond. Each such report sharpens the pattern recognition that emergency physicians, radiologists and neurologists bring to the initial hours of a patient’s care. A stroke-like lesion in a young patient with an unexplained progressive gait disorder is not merely a puzzle; it may be a metabolic alarm. In the case of COQ8A-related coenzyme Q10 deficiency, recognizing that alarm early and starting targeted supplementation represents one of the few genuine windows of intervention in the world of inherited ataxias, and every published account of the diagnostic path broadens that window for the next patient who arrives in an emergency department with lesions that look like strokes but are nothing of the kind.

Subject of Research: COQ8A-related coenzyme Q10 deficiency presenting as recurrent posterior stroke-like lesions

Article Title: Recurrent posterior stroke-like lesions heralding COQ8A-related coenzyme Q10 deficiency: a potentially treatable ataxia mistaken for stroke: a case report

Article References: Mutyala, S., Prateek, Gupta, A., & Kona, C. (2026). Recurrent posterior stroke-like lesions heralding COQ8A-related coenzyme Q10 deficiency: a potentially treatable ataxia mistaken for stroke: a case report. Journal of Neurology, 273(11), Article 661. https://doi.org/10.1007/s00415-026-14209-x

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14209-x

Keywords: COQ8A, coenzyme Q10 deficiency, stroke-like episodes, cerebellar ataxia, mitochondrial disease, posterior reversible encephalopathy syndrome, genetic diagnosis, neurogenetics, ubiquinone, Journal of Neurology, ADCK3, treatable ataxia

The brevity of Narasimhan’s life, cut short at forty-six, invites reflection on how much of the early history of Indian neurology remains scattered across obituaries, institutional records, and the memories of successive generations of trainees. Historical scholarship in medicine depends on this kind of archival reconstruction, and the authors of the new profile situate their subject within the broader narrative of how neurological practice developed in mid-twentieth-century India, a period when the country had very few dedicated neurologists, no large neurological research infrastructure, and limited access to the diagnostic technologies that were transforming the field elsewhere.

Understanding why profiles like this matter requires some appreciation of what neurology looked like in India during Narasimhan’s working years. Electroencephalography, which records the brain’s electrical activity through electrodes placed on the scalp, was still a young technology globally, having been applied to human subjects in the late 1920s and 1930s. Its spread to Indian institutions came slowly, and for most of the period in question, diagnosis rested on meticulous clinical examination: the detailed mapping of weakness, reflexes, sensation, and cranial nerve function that remains the foundation of neurological training today. In that environment, the authority of a neurologist rested on clinical acumen and teaching rather than on laboratory resources, and the reputations of the pioneers were built case by case, ward round by ward round.

The institutional history of Indian neurology provides the backdrop against which the new profile should be read. The Neurological Society of India, the professional body that united the country’s neurologists, neurosurgeons, and allied specialists, was founded in 1951, a milestone that marked the transition from isolated individual practice to an organized specialty with meetings, journals, and shared standards. Madras, now Chennai, emerged as one of the crucial centers of this development. The Madras Institute of Neurology at Madras Medical College, whose history has been documented in earlier reviews, became a training hub that produced generations of neurologists who then spread across the country, establishing departments in medical colleges and teaching hospitals from the south of India to the north.

Chennai’s role in this story is one reason the new profile is notable: one of its co-authors is based at Kilpauk Medical College in that city, and the lineage connecting mid-century Madras neurology to the present-day departments of Tamil Nadu is a living professional inheritance. The historians of Indian neurology who have written on this period, including the authors of a widely cited 2013 review of the field’s historical development, emphasize that the specialty’s growth was driven by a handful of interconnected figures, many of whom trained together, corresponded across institutions, and collectively argued for the resources needed to build dedicated neurological units. Biographical profiles are the raw material of that argument, because they demonstrate concretely what individual physicians contributed in an era of scarcity.

Epilepsy offers a particularly clear example of how the foundations laid by early Indian neurologists grew into a modern subspecialty. Reviews of epilepsy surgery in India describe a trajectory that began with a small number of pioneering centers performing surgical procedures for drug-resistant epilepsy and expanded, over decades, into a network of comprehensive epilepsy programs using video-electroencephalographic monitoring, magnetic resonance imaging, and invasive electrode recordings to localize seizure origins in the brain. Epidemiological analyses of epilepsy surgery in India published in the last decade show both the growth of surgical capacity and the persistent treatment gap, with millions of people with epilepsy in the country lacking access to specialist care. The clinicians of Narasimhan’s generation, working without any of these technologies, established the clinical frameworks for seizure classification and medical management on which that later surgical enterprise depended.

The Pioneers in Neurology series, in which the new profile appears, serves a function that goes beyond commemoration. By publishing short biographical accounts in a major international neurology journal, the series makes the history of the discipline visible to a global readership that may know little about how neurology developed in different parts of the world. This matters for scientific reasons as well as cultural ones. The epidemiology of neurological disease in India differs in important ways from that of high-income countries, including a higher burden of infections affecting the nervous system, distinct patterns of stroke etiology, and genetic variations that influence conditions such as muscular dystrophy and movement disorders. Knowing who built the clinical and research base in India helps explain why certain research questions were prioritized there, and why contemporary Indian neuroscience looks the way it does.

There is also a methodological point worth making about historical profiles of this kind. Because the authors state that no datasets were generated or analyzed in preparing the manuscript, the profile is a work of synthesis, drawing on previously published literature and historical records rather than new data collection. The reference list of the article points to the key secondary sources on Indian neurology’s history, including the 2013 historical perspective in the Annals of the Indian Academy of Neurology, the account of the Madras Institute of Neurology published in Neurology India, the memoir of the celebrated neurosurgeon B. Ramamurthi, and reviews of epilepsy surgery and its epidemiology in India. This citation network shows how the history of a medical specialty is assembled: from autobiographies, institutional histories, society records, and earlier biographical sketches, each source preserving fragments that later historians piece together.

For readers encountering Narasimhan’s name for the first time, the profile is an invitation to think about the contingency of medical history. A physician who dies at forty-six, in 1959, just as organized neurology was taking institutional shape in India, leaves behind an incomplete record, and the survival of his reputation depends on whether later colleagues judge the record worth preserving. The decision by neurologists at NIMHANS, today one of India’s premier neuroscience institutions, to document his career signals a deliberate effort to keep the founding generation in view. NIMHANS itself grew out of the mid-century expansion of mental health and neurosciences in the country, and its faculty writing about a predecessor from the 1940s and 1950s illustrates the continuity between the pioneers and the modern specialty.

The broader lesson of the profile is that the history of neuroscience is global, uneven, and still being written. The technologies that dominate headlines today, from transcranial magnetic stimulation to brain-machine interfaces, rest on generations of clinical work that was often unglamorous, poorly funded, and carried out in conditions very different from those of well-equipped research hospitals. In India, that work was done by a small cohort of physicians who built departments, founded a society, trained students, and treated enormous numbers of patients with limited means. Recovering the individual stories within that cohort, as the Journal of Neurology profile of S.T. Narasimhan does, is how the specialty understands its own origins, and how contemporary researchers and clinicians measure how far the field has traveled in the seven decades since his death.

Subject of Research: Historical profile of early Indian neurologist S.T. Narasimhan (1913–1959) and the development of neurology in India

Article Title: S.T. Narasimhan (1913–1959)

Article References: Harish, S., Gowda, N., & Balachandar, N. (2026). S.T. Narasimhan (1913–1959). Journal of Neurology, 273(11), Article 655. https://doi.org/10.1007/s00415-026-14197-y

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14197-y

Keywords: S.T. Narasimhan, history of neurology, Indian neurology, Pioneers in Neurology, Journal of Neurology, NIMHANS, Madras Institute of Neurology, Neurological Society of India, epilepsy surgery, electroencephalography, medical history, Chennai

The numbers tell a strikingly clean story. Among people with subjective cognitive decline, 28.3 percent carried at least one APOE ε4 allele. Among those with mild cognitive impairment, the figure climbed to 41.0 percent, while cognitively normal individuals carried the allele at a rate of just 22.0 percent. In statistical terms, the odds of being an ε4 carrier were significantly higher in the subjective decline group than in healthy controls, with an odds ratio of 1.28, and significantly higher still in the mild impairment group compared with the subjective decline group, at 1.48. That stepped gradient—rising steadily from normal cognition through subjective complaints to objective impairment—is exactly the pattern one would expect if subjective cognitive decline truly represents a transitional stage on the Alzheimer’s continuum rather than a clinically meaningless complaint.

To appreciate why this matters, it helps to understand how the field’s thinking has evolved. Alzheimer’s disease, which accounts for roughly 60 percent of all dementia cases worldwide, is no longer viewed as a binary diagnosis that arrives only when memory loss becomes undeniable. Instead, clinicians and researchers now describe a biological and clinical continuum: an asymptomatic stage in which amyloid and tau biomarkers are positive but cognition is intact, followed by a transitional phase in which very mild changes are perceived by the patient but remain within normal limits on formal testing, and finally mild cognitive impairment and overt dementia. The 2024 revised criteria from the Alzheimer’s Association Workgroup formalized this staging, and the transitional phase maps directly onto the syndrome of subjective cognitive decline. Interventions, most studies suggest, work best when applied early—which makes identifying who in this earliest phase is genuinely at risk a matter of urgent practical importance.

The trouble has always been definition. Before 2014, researchers used a bewildering array of overlapping labels—subjective memory impairment, subjective cognitive complaints, subjective memory concerns—often interchangeably and inconsistently. That year, Frank Jessen and colleagues provided a unified framework, defining subjective cognitive decline as a persistent, self- or informant-reported worsening of cognition, most often memory, in people whose performance on standardized tests remains normal and who show no abnormalities on neurological examination. The same group proposed a set of enrichment features, the so-called SCD-plus criteria, designed to flag cases more likely to reflect preclinical Alzheimer’s: onset at age 60 or older, symptoms beginning within the past five years, a sense of decline relative to peers, and genuine worry about the changes. Even with these tools, however, biomarker findings in this population have remained stubbornly heterogeneous, and previous reviews had produced conflicting results about whether APOE ε4 was enriched at all.

That is precisely the discrepancy the new analysis resolves. An earlier systematic review had concluded that APOE ε4 prevalence in subjective decline was essentially the same as in cognitively normal people—a finding that seemed to undercut the whole staging framework. The authors of the new meta-analysis, led by Paolo Alonge and Roberto Monastero of the University of Palermo, argue that the conflict stems largely from how studies defined the syndrome. The earlier review included studies using the older, looser classifications, whereas the new analysis applied stringent inclusion criteria aligned with the Subjective Cognitive Decline Initiative: a cognitive complaint in one or more domains, exclusion of objective impairment through formal neuropsychological testing, and exclusion of psychiatric, neurological, or systemic conditions that could muddy the picture. Under those stricter standards, the genetic gradient emerges clearly.

The methodological machinery behind the result is considerable. The team searched MEDLINE, Web of Science, and Scopus from inception to April 15, 2026, screening 474 records after duplicate removal and ultimately including 49 studies—26 cross-sectional and 23 prospective—conducted across Europe, North America, Asia, Australia, and the Middle East, with publication years ranging from 2005 to 2026. They used random-effects models with restricted maximum likelihood estimation, logit-transformed the response variable to satisfy normality assumptions, assessed heterogeneity with Cochran’s Q and the I-squared statistic, and probed publication bias with Egger’s test supplemented by Duval and Tweedie’s trim-and-fill adjustment. A leave-one-out influence analysis, using diagnostics such as Cook’s distance and DFFITS, confirmed that no single study was driving the pooled estimates. Notably, the funnel plot asymmetry pointed in the direction opposite to classical publication bias, with smaller studies tending to report lower ε4 prevalence—a known artifact of Egger’s test when applied to proportions—so the authors concluded that true publication bias was unlikely to distort the findings.

One of the most technically interesting aspects of the analysis is how the team handled correlated effect sizes. Because the odds ratios comparing mild impairment versus subjective decline and normal cognition versus subjective decline share a common reference group, they are not statistically independent. Pooling them naively would understate uncertainty. Instead, the researchers used a multivariate meta-analytic framework via the Mixmeta package, incorporating the variance–covariance matrix of the odds ratios so that within-study correlations were properly accounted for. Twenty-six studies contributed to this model. Meta-regressions added another layer, testing whether the proportion of female participants, mean age, and years of education explained the substantial between-study heterogeneity, which reached an I-squared of 90.2 percent in the subjective decline cohort.

Those meta-regressions produced findings with real biological intrigue. In the subjective decline groups, mean age showed a significant negative association with ε4 carrier prevalence, accounting for about 15 percent of the between-study variance, while education showed a significant positive association. The authors offer two plausible interpretations for the age effect: a survival bias, or the possibility that ε4 carriers convert more rapidly to more advanced stages of disease, depleting them from older subjective-decline cohorts. The education effect may reflect cognitive reserve—the idea that highly educated individuals notice and report subtle cognitive changes earlier, even while their test performance remains formally normal—or simply selection bias in who ends up in memory clinic studies. Sex distribution, by contrast, showed no significant effect. In the cognitively normal groups, both age and education correlated positively with ε4 prevalence, with education alone explaining a remarkable 91.9 percent of the between-study variance.

The cross-sectional picture is complemented by a more consistent longitudinal one. The three prospective studies that directly examined APOE ε4 in subjective decline all reported an increased risk of conversion to objective cognitive impairment among carriers, and observational cohorts linked ε4 status to faster cognitive decline and greater changes in cerebrospinal fluid and plasma biomarkers—though not uniformly, with a few studies reporting no biomarker association. This matters therapeutically as well: APOE ε4 is now a reliable predictor of amyloid-related imaging abnormalities during treatment with the new anti-amyloid monoclonal antibodies, and the allele itself is being pursued as a drug target through gene editing, gene silencing, and expression regulation. Studies of APOE genotype disclosure suggest that learning one’s genetic risk influences future planning and health behaviors, with psychological effects that appear generally manageable—raising clinical and ethical questions as genetic testing edges into early cognitive assessment.

The authors are careful about limitations. Heterogeneity remained high even after meta-regression, reflecting the fact that subjective cognitive decline, like mild cognitive impairment, is an umbrella syndrome encompassing vascular, degenerative, and other etiologies rather than a single disease. Many studies were conducted in memory clinics, potentially enriching samples with higher-risk individuals, and genotype data were often reported merely as descriptive characteristics rather than primary outcomes. Regional differences in ε4 frequency—lower in Mediterranean and Asian populations than in Northern European and North American cohorts—could not be formally subgrouped. Still, the central conclusion stands: the prevalence of APOE ε4 in subjective cognitive decline falls squarely between normal cognition and mild impairment, vindicating the staging model. The path forward, the authors argue, lies in multimodal risk models that integrate genetics with fluid and imaging biomarkers, clinical variables, and other genes—a strategy that could eventually deliver personalized counseling and earlier, better-targeted intervention for the people who need it most.

Subject of Research: APOE ε4 allele prevalence in subjective cognitive decline as an intermediate stage of the Alzheimer's disease continuum

Article Title: APOE in subjective cognitive decline: a systematic review and meta-analysis

Article References: Alonge, P., Baiamonte, L., Gerardi, G., Torrente, A., Lo Mauro, E., Veronese, N., Labate, A., & Monastero, R. (2026). APOE in subjective cognitive decline: a systematic review and meta-analysis. Journal of Neurology, 273(9), Article 556. https://doi.org/10.1007/s00415-026-14077-5

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14077-5

Keywords: Alzheimer's disease, APOE ε4, subjective cognitive decline, mild cognitive impairment, meta-analysis, genetic risk factor, dementia, biomarkers, neuropsychology, risk stratification, Journal of Neurology, preclinical Alzheimer's

Frontotemporal dementia is an umbrella term covering several clinically distinct syndromes that share a common target: the frontal and temporal lobes of the brain. While the behavioural variant, marked by apathy, disinhibition, and loss of empathy, is the most widely recognised form, the temporal lobe variants present a different and often deceptive picture. The left-sided temporal variant, known as semantic variant primary progressive aphasia, erodes the patient’s knowledge of words, objects, and meanings, producing profound language difficulties while leaving other cognitive faculties relatively intact for years. The right-sided temporal variant, sometimes described in the literature as right temporal lobe atrophy, is even more elusive, producing subtle changes in personality, social conduct, and emotional processing that can be mistaken for psychiatric illness for years before a neurological diagnosis is made.

These syndromes have long been studied through the lens of language and behaviour, but a growing body of evidence suggests that sleep may offer an equally revealing window into the underlying disease. Previous work has documented sleep disturbances across the frontotemporal dementia spectrum, and researchers have proposed that the orexin system, a neuropeptide network in the hypothalamus that governs arousal and wakefulness, may be a key player. Studies have reported reduced orexin-A levels in patients with frontotemporal dementia, and a possible association between this loss and the severity of sleep disruption. More recently, investigators have linked changes in cerebral and hypothalamic structure to sleep dysfunction in people with genetic forms of the disease, raising the possibility that the hypothalamus, the brain’s master clock, is drawn into the neurodegenerative process earlier than previously appreciated.

The UCL-led study set out to address a conspicuous gap in this literature. Although sleep symptoms have been characterised in the behavioural variant of frontotemporal dementia and in Alzheimer’s disease, the temporal lobe variants have been largely overlooked, despite their distinctive pattern of brain atrophy. The research brought together a carefully characterised patient cohort from the Dementia Research Centre, where patients undergo detailed clinical, neuropsychological, and imaging assessment, and combined this clinical expertise with the sleep science methodology of the Surrey Sleep Research Centre, one of the United Kingdom’s leading centres for the study of human sleep and circadian rhythms.

Technically, the investigation relied on validated subjective sleep instruments, most notably the Pittsburgh Sleep Quality Index, a questionnaire widely regarded as the gold standard for capturing the multidimensional nature of sleep quality, spanning sleep duration, latency, disturbances, efficiency, and daytime dysfunction. The team also employed the Epworth Sleepiness Scale, a measure of generalised daytime sleepiness that quantifies the propensity to doze in everyday situations such as reading, watching television, or sitting in conversation. By applying these standardised tools to patients with temporal lobe variants, the researchers could characterise sleep disturbance in a way that is comparable with the wider dementia literature, allowing direct comparison with previous findings in behavioural variant frontotemporal dementia and Alzheimer’s disease.

The rationale for this approach is grounded in a broader conceptual shift in neurodegeneration research. Rather than viewing sleep disturbance as a mere consequence of dementia, an increasing number of researchers argue that sleep and circadian disruption may be intertwined with the disease process itself, potentially reflecting the spread of pathological protein deposits into sleep-regulating circuitry. In Alzheimer’s disease, excessive daytime napping has been linked to dementia risk in what may be a bidirectional relationship, with poor sleep promoting the accumulation of amyloid and amyloid pathology in turn fragmenting sleep. Whether a similar reciprocal dynamic operates in frontotemporal dementia remains an open question, but the involvement of the hypothalamus and the orexin system provides a plausible mechanistic bridge between temporal lobe degeneration and disordered arousal.

The temporal lobes themselves are not passive bystanders in this story. Anatomical studies have shown that the anterior and medial temporal structures, including the amygdala and hippocampus, are densely connected with hypothalamic and brainstem arousal systems, and that atrophy in these regions reshapes the networks that govern emotional and physiological states. In semantic variant primary progressive aphasia, tissue loss typically begins in the left anterior temporal lobe and progresses asymmetrically, while right temporal variant disease mirrors this pattern on the opposite side. Because these variants damage the temporal lobes in a relatively focal and lateralised fashion, they offer neurologists a natural experiment: by comparing sleep profiles across left- and right-predominant disease, researchers can begin to map which aspects of sleep regulation are tied to which temporal networks.

The clinical implications of characterising sleep disturbance in these patients are considerable. Sleep problems are among the most burdensome symptoms for family caregivers, frequently precipitating care home admission and compounding the behavioural symptoms that already strain daily life. If sleep disruption in temporal lobe variants follows a recognisable clinical signature, clinicians could screen for it systematically, counsel families proactively, and potentially intervene with targeted behavioural or pharmacological strategies. Moreover, because sleep symptoms may emerge early in the disease course, as has been suggested for the behavioural variant in recent polysomnographic work documenting altered nocturnal sleep dynamics in early-stage patients, they could serve as diagnostic clues in cases where the temporal variant syndrome is still masquerading as a primary psychiatric or language disorder.

The study also reflects a wider trend toward interdisciplinary collaboration in dementia research. The partnership between the UCL Dementia Research Centre, with its decades of expertise in rare dementia syndromes, and the Surrey Sleep Research Centre, with its deep methodological grounding in circadian physiology, exemplifies the kind of cross-disciplinary approach that the field increasingly demands. The work was supported by Alzheimer’s Research UK, the Alzheimer’s Society, the Royal National Institute for Deaf People, and the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, alongside a Frontotemporal Dementia Research Studentship funded through The National Brain Appeal. The authors, including joint senior authors Jason D. Warren and Jessica Jiang, report no conflicts of interest, and the study received ethical approval from the joint research ethics committees of University College London, the University of Surrey, and the National Hospital for Neurology and Neurosurgery, with all participating patients giving written informed consent.

For patients and families affected by these rare temporal lobe dementias, the message is one of cautious optimism. Sleep, long relegated to the margins of the clinical conversation, is now being taken seriously as a core feature of the disease, one that may illuminate both the mechanisms of neurodegeneration and the practical realities of daily care. As the evidence base grows, the hope is that a better understanding of sleep disturbance in temporal lobe variants of frontotemporal dementia will translate into earlier diagnosis, more comprehensive symptom management, and, ultimately, therapies that target the sleep-regulating circuits caught in the path of the disease. The full findings are published in the Journal of Neurology, and the datasets generated during the study are available from the corresponding author in anonymised form on reasonable request, in keeping with the ethical and confidentiality requirements that govern research with this vulnerable patient population.

Subject of Research: Sleep disturbance in temporal lobe variants of frontotemporal dementia

Article Title: Clinical features of sleep disturbance in temporal lobe variants of frontotemporal dementia

Article References: Larsen, E. K., Levett, B. A., Core, L. B., della Monica, C., Hassanin, H., Atzori, G., Harding, E., Dijk, D.-J., Revell, V. L., Eriksson, S. H., Rohrer, J. D., Warren, J. D., & Jiang, J. (2026). Clinical features of sleep disturbance in temporal lobe variants of frontotemporal dementia. Journal of Neurology, 273(9), Article 558. https://doi.org/10.1007/s00415-026-14104-5

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14104-5

Keywords: frontotemporal dementia, sleep disturbance, temporal lobe atrophy, semantic variant primary progressive aphasia, orexin, hypothalamus, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, neurodegeneration, circadian rhythms, dementia care, Journal of Neurology

The rationale for immunomodulation is biologically plausible. In herpes simplex virus encephalitis, much of the neurological damage is attributed not only to direct viral cytolysis but also to the host immune response, including cytokine release, edema, and secondary inflammatory cascades that can extend injury well beyond infected neurons. Corticosteroids, by suppressing this inflammation, could in theory reduce swelling, limit tissue damage, and improve outcomes. The idea is not new; discussions of dexamethasone in herpes simplex encephalitis appeared in the medical literature as early as the 1970s, and the approach has been incorporated into some clinical guidelines as an option for patients with life-threatening cerebral edema. Yet the clinical evidence base has remained fragmented, small, and methodologically uneven.

To resolve the uncertainty, Zhang and colleagues searched PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from their inception through 4 July 2026, and also examined trial registries and reference lists of relevant publications. They included randomized controlled trials and comparative observational studies that evaluated systemic corticosteroids added to background antiviral therapy against the same antiviral therapy alone or with placebo. Acyclovir was the background antiviral agent in every study that specified the regimen, ensuring that the comparison isolated the effect of the steroid rather than differences in antiviral care. The co-primary outcomes were study-defined unfavorable global neurological or functional outcome and all-cause mortality, with secondary endpoints covering serious adverse events, seizures during follow-up, cognition, persistent herpes simplex virus DNA in cerebrospinal fluid, relapse, and functional independence measured by the Barthel Index.

The yield from more than five decades of literature was strikingly thin. Only four comparative studies, encompassing 209 patients, met the inclusion criteria: two randomized trials and two retrospective studies. The randomized trials were pooled using Mantel-Haenszel random-effects methods for risk ratios, while mean differences were combined with inverse-variance random-effects approaches. Because non-randomized treatment allocation introduces substantial clinical heterogeneity and confounding by indication, the observational evidence was analyzed and interpreted separately from the randomized data, a decision that reflects contemporary standards for evidence synthesis.

The pooled results from the randomized trials were uniformly inconclusive. For unfavorable global outcome, the pooled risk ratio was 1.00 with a 95 percent confidence interval of 0.68 to 1.47, a point estimate of exactly no effect flanked by intervals wide enough to accommodate both meaningful benefit and meaningful harm. Mortality showed a risk ratio of 0.92 (95 percent confidence interval 0.35 to 2.40), serious adverse events a risk ratio of 1.14 (95 percent confidence interval 0.54 to 2.44), and seizures during follow-up a risk ratio of 0.73 (95 percent confidence interval 0.33 to 1.62). None of these estimates approached conventional thresholds for statistical significance, and all were imprecise, reflecting the small number of patients contributing to each analysis.

Functional and cognitive endpoints fared no better. Barthel Index scores, a standard measure of activities of daily living, showed a mean difference of 3.05 points (95 percent confidence interval, minus 6.99 to 13.09) at approximately six months and 0.30 points (95 percent confidence interval, minus 13.84 to 14.45) at discharge or day 30, differences that are clinically negligible and statistically indistinguishable from zero. Cognitive findings across studies were not consistently favorable. In short, on every endpoint the meta-analysis examined, the randomized evidence could neither confirm benefit nor exclude harm, a pattern the authors attribute to the limited and imprecise nature of the underlying data rather than to demonstrated equivalence.

The observational studies added little clarity and, in some respects, raised concerns. Their estimates conflicted with one another and were judged to be seriously compromised by confounding, since clinicians tend to give steroids to the sickest patients, biasing any naive comparison. The randomized trials did, however, generate two signals worth noting. In the DexEnceph trial, a multicenter, observer-blind, phase 3 study of adjunct dexamethasone in adults with herpes simplex virus encephalitis conducted in the United Kingdom, herpes simplex virus DNA remained detectable in cerebrospinal fluid at approximately day 14 in 4 of 36 dexamethasone recipients compared with 9 of 43 controls, a numerical difference of uncertain significance. More strikingly, five relapses were reported among dexamethasone-treated patients and none among controls, although the authors caution that so few events do not permit a causal conclusion. The possibility that corticosteroid-induced immunosuppression might prolong viral clearance or provoke relapse has long been a theoretical worry, and these findings keep it alive without settling it.

The meta-analysis also highlights a critical gap. The one scenario in which corticosteroids are most often deployed in practice, life-threatening cerebral edema with impending herniation, was never specifically evaluated in any included study. The evidence is therefore insufficient to determine whether steroids help or harm this selected subgroup, leaving clinicians to make high-stakes decisions on physiological reasoning alone. The authors call for future adequately powered, multicenter randomized trials that use standardized treatment protocols and prespecify severity- and edema-defined subgroups, so that the question of immunomodulation can be answered separately for the broad population and for the narrow emergency indication.

For now, the practical message is one of restraint. With roughly 209 randomized and comparative patients studied across half a century, the field has generated data too sparse to justify routine adjunctive corticosteroids, yet too imprecise to close the door entirely. Clinicians managing herpes simplex virus encephalitis should continue to prioritize early acyclovir, the intervention with proven mortality benefit, and reserve corticosteroids for circumstances where cerebral edema threatens immediate deterioration, ideally within the framework of clinical trials or prospective registries. The new synthesis in the Journal of Neurology does not declare steroids useless; it declares the question still open, and in doing so it sets a clear agenda for the trials the field has, until now, failed to deliver.

Subject of Research: Adjunctive corticosteroid therapy for herpes simplex virus encephalitis

Article Title: Adjunctive corticosteroids in herpes simplex virus encephalitis: a meta-analysis of randomized and observational studies

Article References: Zhang, D., Yang, M., Huang, Y., Liang, M., Yao, L., Liang, J., Deng, M., & Shen, R. (2026). Adjunctive corticosteroids in herpes simplex virus encephalitis: a meta-analysis of randomized and observational studies. Journal of Neurology, 273(10), Article 567. https://doi.org/10.1007/s00415-026-14128-x

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14128-x

Keywords: herpes simplex virus encephalitis, corticosteroids, dexamethasone, acyclovir, meta-analysis, neurological outcome, cerebral edema, randomized controlled trials, Barthel Index, relapse, cerebrospinal fluid HSV DNA, Journal of Neurology

Myasthenia gravis arises when the immune system produces antibodies that attack the neuromuscular junction, the microscopic relay where nerves hand signals to muscles. In many patients, the thymus, a gland tucked behind the breastbone that trains immune cells in early life, appears to drive this misguided attack. Surgical removal of the gland, known as thymectomy, has been practiced since the mid-twentieth century, but the evidence base was transformed in 2017 by the MGTX trial, a randomized study published in the New England Journal of Medicine. That trial showed convincingly that thymectomy improved outcomes and reduced the need for immunosuppressive drugs in patients aged fifty and under.

The catch was that MGTX included only seventeen patients aged fifty or older, far too few to say anything definitive about older adults. This matters because late-onset myasthenia gravis is increasingly common as populations age, and the biology of the disease appears to shift with time. In younger patients, the thymus is often enlarged and studded with ectopic germinal centers, structures where antibody-producing cells are actively generated. In older patients, the gland is typically atrophied and replaced by fat, raising the possibility that removing it accomplishes less. Several recent studies, including a 2021 meta-analysis and a 2026 multi-center longitudinal study, have produced conflicting results about whether older patients benefit.

To resolve the uncertainty, a team led by neurologist Morgan E. Heber and Yuebing Li combed the electronic medical records of their institution for patients who underwent thymectomy without thymoma, a tumor of the thymus, between 1999 and 2022. They divided the cohort into a young group of forty-five patients under fifty and an older group of thirty-four patients aged fifty or above. Because the study was retrospective, the researchers relied on data already collected during routine care, including the Myasthenia Gravis Foundation of America classification, the MG-Activities of Daily Living score, surgical approach, postoperative complications, and rates of medication reduction and disease flare.

The results were striking in their uniformity. When the two groups were compared after surgery, the researchers found no statistically significant difference in the proportion of patients whose MGFA classification improved, with a p-value of 0.48. Corticosteroid reduction, a key practical measure of whether patients can safely taper the drugs that carry long-term side effects, was likewise indistinguishable between groups, at p equal to 0.75. Postoperative complications, cancer diagnoses, and new autoimmune diagnoses showed no differences either, with p-values of 0.87, 0.57, and 0.13 respectively.

Functional outcomes told the same story. Rates of myasthenic exacerbation, the frightening episodes in which weakness escalates to threaten breathing, were similar across age groups at p equal to 0.22. The need for rescue therapy during follow-up, the MG-ADL score at final assessment, and the percentage of patients achieving minimal symptom expression, the closest thing the field has to a remission benchmark, were all statistically equivalent, with p-values of 0.29, 0.84, and 0.31. In plain terms, older patients who had their thymus removed fared about as well as younger ones, both in safety and in benefit.

The authors conclude that thymectomy in patients aged fifty or older with non-thymomatous myasthenia gravis appears comparable in safety and efficacy to the same operation in younger patients, providing support for its use in the management of older patients. For clinicians, this is a meaningful data point. Current international consensus guidance for myasthenia gravis, updated in 2020, has had to navigate thin evidence for late-onset disease, and the new findings add to a growing body of work suggesting that age-based exclusion from surgery is not justified by outcomes alone.

The biology behind these results remains an open question. If the atrophic thymus of an older patient is less immunologically active, why would removing it help as much? One possibility is that even involuted thymic tissue continues to harbor autoreactive cells or antibody-secreting populations; laboratory work has shown that cells from atrophic thymus can secrete acetylcholine receptor antibodies. Genetic studies have also linked late-onset disease to a CTLA4-low genotype and reduced output of naive T cells, hinting that the aging thymus is not merely dormant but subtly deranged in ways that surgery might still interrupt. Pathological studies showing that ectopic germinal centers predict better post-surgical prognosis add a further layer, suggesting that the relevant question may be what the thymus is doing, not simply how old the patient is.

There are also broader considerations that any patient weighing the operation should discuss with their doctors. A 2023 study in the New England Journal of Medicine found that thymus removal in adults was associated with measurable long-term health consequences, including altered immune profiles, underscoring that the gland is not dispensable even in adulthood. The Cleveland Clinic study did not set out to measure those risks, and its retrospective design means that patients were not randomized to surgery, leaving open the possibility of selection effects. The cohort of seventy-nine patients, while respectable for a single institution, is modest, and the study spanned more than two decades, during which surgical techniques evolved from open transsternal approaches to video-assisted and robotic methods.

Even with those caveats, the study lands at a moment of genuine momentum in the field. Standardization efforts by a Myasthenia Gravis Foundation of America task force are harmonizing how outcomes are measured in clinical practice, and new antibody-targeted therapies are reshaping the pharmacological landscape. Against that backdrop, the question is no longer whether thymectomy works, but for whom, and how best to combine it with modern immunotherapy. By showing that the calendar is a poor predictor of surgical benefit, the Cleveland Clinic team has widened the door for older patients who might otherwise have been told the operation was not for them. For a disease that so often strikes at the most visible moments of life, speaking, smiling, swallowing, that is news worth spreading.

Subject of Research: Outcomes of thymectomy in young versus older patients with non-thymomatous myasthenia gravis

Article Title: A comparison study of thymectomy outcomes in young and older patients with non-thymomatous myasthenia gravis

Article References: Heber, M. E., Li, Y., Raymond, D. P., & Li, Y. (2026). A comparison study of thymectomy outcomes in young and older patients with non-thymomatous myasthenia gravis. Journal of Neurology, 273(10), Article 566. https://doi.org/10.1007/s00415-026-14110-7

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14110-7

Keywords: myasthenia gravis, thymectomy, non-thymomatous myasthenia gravis, late-onset myasthenia gravis, thymus, autoimmune disease, neuromuscular junction, MGTX trial, immunosuppression, Cleveland Clinic, Journal of Neurology, retrospective study

The research team, led by Antonio Esposito and Marcello Moccia of Federico II University of Naples, followed 34 adults with multiple sclerosis who started ofatumumab and remained on treatment for at least two years, with paired immune assessments at baseline and follow-up. Ofatumumab is administered as 20 milligram subcutaneous injections at weeks 0, 1, and 2, and monthly thereafter. Unlike intravenous anti-CD20 agents such as ocrelizumab and rituximab, ofatumumab acts primarily in the peripheral lymphatic compartment, and its distinct epitope binding and complement-dependent cytotoxicity have fueled speculation that its broader immunological footprint might differ from its intravenous cousins.

To map that footprint, the investigators used a standardized whole-blood flow-cytometry workflow. Fifty-microliter blood samples were incubated with fluorochrome-conjugated antibody mixtures, red blood cells were lysed, and the remaining nucleated cells were acquired on a Beckman Coulter Navios cytometer equipped with 405-, 488-, and 638-nanometer lasers. Sequential gating identified the major lymphocyte lineages: CD3-positive T cells and their CD4 and CD8 subsets, CD19- and CD20-positive B cells, CD56-positive natural killer cells, CD27-positive populations, memory B cells carrying both CD27 and CD19, and the small CD3-positive CD20-positive T-cell subset that anti-CD20 therapy is known to eliminate. Absolute counts were obtained using a double-platform approach under routine quality-control standards, including instrument calibration and participation in the UK-NEQAS external quality assessment scheme.

The longitudinal analysis relied on linear mixed-effects regression, with fixed effects for age, sex, follow-up duration, comorbidities, body mass index, and previous disease-modifying therapy, and a random intercept for each participant. The results were striking. Over roughly two years of treatment, total lymphocyte counts rose by an average of about 251 cells per microliter, while CD3-positive T cells increased by roughly 369, CD4-positive T cells by about 240, CD8-positive T cells by about 132, CD27-positive cells by about 275, and CD27-positive CD3-positive T cells by about 452. All of these increases were statistically significant, with confidence intervals that excluded the null. In parallel, the expected depletion was unmistakable: CD19-positive and CD20-positive B cells fell by about 182 cells per microliter, and CD27-positive CD19-positive memory B cells dropped sharply as well.

Not everything moved, however. The ratio of CD4 to CD8 T cells remained stable, as did CD56-positive natural killer cells and the CD3-positive CD20-positive T-cell subset. That stability of the CD4-to-CD8 ratio is important, because it suggests that no major rebalancing occurred between the two broad arms of the T-cell compartment, even as absolute T-cell numbers climbed. The authors are careful to note that the rise in CD27-positive cells cannot be taken as evidence of naive T-cell expansion. CD27 is expressed across both naive and central memory T-cell compartments and also appears on subsets of natural killer and natural killer T cells. Without additional differentiation markers such as CD45RA, CD45RO, and CCR7, the specific CD27-expressing population driving the increase cannot be resolved with the panel used.

What, then, explains the T-cell rise? The authors propose that the pattern may reflect broad reorganization of the T-cell compartment following sustained B-cell depletion, a phenomenon that has been hinted at in other anti-CD20 studies. Previous short-term real-world investigations of ofatumumab generally found CD3, CD4, and CD8 counts to be broadly stable, which makes the two-year increases reported here particularly noteworthy. The discrepancy may be a matter of timing: early immune kinetics differ from the intermediate and long-term reorganization that unfolds as the immune system adapts to life without circulating CD20-positive B cells. Other variables complicate the picture, including prior exposure to therapies such as natalizumab or fingolimod, which reshape peripheral immune pools and trafficking patterns, and differences in measurement approaches, such as whether studies use surface-epitope or intracellular CD20 staining, the latter avoiding steric hindrance by therapeutic antibodies still circulating in the blood.

The study also looked for clinical meaning behind these immune shifts. Using multivariable logistic regression, the team tested whether the annualized percentage change in each laboratory measure predicted relapses, magnetic resonance imaging activity, progression on the Expanded Disability Status Scale, improvement on that scale, or the composite outcome of no evidence of disease activity, known as NEDA-3. The answer, in every case, was no. No significant associations emerged between changes in any lymphocyte population and any clinical or radiological outcome. Several models could not be reliably estimated at all because clinical and MRI events were so rare, a consequence of treating patients with a highly effective therapy, and because near-complete B-cell depletion left little variability to model.

The authors are refreshingly candid about what these negative findings do and do not mean. With only 34 participants and a low frequency of disease-activity events, the study was never powered to detect subtle immunological-clinical relationships, and the absence of statistical significance should not be read as evidence that such relationships do not exist. The analyses were explicitly designed to be hypothesis-generating rather than to establish mechanistic pathways or predictive biomarkers. Most participants had prior exposure to other disease-modifying therapies, and although previous treatment was included as a covariate, residual carry-over effects on immune composition cannot be excluded. There was also no parallel comparator group receiving ocrelizumab or rituximab, which limits direct inference about how ofatumumab’s subcutaneous route and pharmacology might differ from intravenous anti-CD20 agents, and no standardized intermediate sampling at six and twelve months to reconstruct the early-to-late kinetics of immune change.

Those limitations point directly toward the next generation of experiments. The immunophenotyping panel used here captured broad lymphocyte populations but could not resolve the smaller, functionally critical subsets that other work has implicated in anti-CD20 responses, including Th17 and Th17.1 cells, T follicular helper cells, and their regulatory counterparts. Cross-sectional research during ofatumumab treatment has documented improved Th17.1-to-regulatory-T-cell and T follicular helper-to-follicular regulatory T-cell ratios, reduced pro-inflammatory cytokine production, and impaired migration of residual CD20-positive T cells across an inflamed model of the blood-brain barrier. A multicenter comparison of ocrelizumab and ofatumumab found more pronounced reductions of B and CD8-positive cells with ocrelizumab, while total lymphocytes, CD4 cells, and natural killer cells remained similar between the two drugs. Functional readouts such as cytokine profiling, migration assays, standardized immunoglobulin tracking, and assessments of vaccine responses and infection risk would round out the safety picture.

For now, the study delivers a clear and reassuring headline finding: two years of ofatumumab produces sustained, near-complete depletion of circulating CD19- and CD20-positive B cells, exactly as its mechanism of action predicts, alongside a measurable and statistically robust expansion of broad T-cell compartments that remains clinically silent, at least as far as conventional outcome measures can detect. Whether that T-cell expansion represents a benign consequence of B-cell depletion, a compensatory homeostatic response, or a subtle repositioning of the immune system toward a more anti-inflammatory profile remains an open question. Answering it will require larger prospective cohorts, repeated longitudinal sampling, deeper immunophenotyping panels, and the functional assays that can translate cell counts into biological meaning. Until then, this two-year window into the immune life of ofatumumab-treated patients stands as a valuable benchmark for what long-term B-cell depletion actually looks like in the blood of people living with multiple sclerosis.

Subject of Research: Longitudinal immune profiling of lymphocyte subsets in multiple sclerosis patients treated with the anti-CD20 antibody ofatumumab

Article Title: Ofatumumab in multiple sclerosis: 2-year immune profiling and clinical correlates

Article References: Esposito, A., Corsaro, L., Cave, I. D., Capasso, F., Corsini, G., Matrone, G., Cerbone, V., Petracca, M., Carotenuto, A., Lanzillo, R., Scalia, G., Castaldo, G., Morra, V. B., & Moccia, M. (2026). Ofatumumab in multiple sclerosis: 2-year immune profiling and clinical correlates. Journal of Neurology, 273(10), Article 579. https://doi.org/10.1007/s00415-026-14088-2

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14088-2

Keywords: multiple sclerosis, ofatumumab, anti-CD20, B-cell depletion, T cells, flow cytometry, immune profiling, lymphocytes, NEDA-3, clinical outcomes, immunotherapy, Journal of Neurology