The onset of epilepsy in adulthood occurs most commonly after 55 years of age. Given the ageing global population, this disorder represents an increasing burden on healthcare and society. The bidirectional link between epilepsy and dementia is a focus of intense research with underlying tau pathology highlighted as a potential mechanistic link. In this review, we examine the evidence for tau-related neurodegenerative processes in epilepsy beginning with how changes in biochemical and structural properties of the tau protein can lead to abnormal phosphorylation and pathological aggregation. We consider the role of tau in seizure occurrence and cognitive difficulties in experimental animal epilepsy models to human epileptic syndromes. Seizure prevalence is evaluated across established primary and secondary tauopathies to understand the associated hyperexcitability phenotype. We discuss the use of neurophysiology, metabolic imaging and novel fluid biomarkers as non-invasive measures of potential underlying neurodegeneration in epilepsy. It may, for example, be that these can be combined with remote measures of cognition and other physiological parameters to provide accurate longitudinal monitoring of cognition and underlying pathology. We also explore clinical trials that have targeted pathological tau accumulation in neurodegenerative conditions and consider an ongoing clinical study with sodium selenate, an enhancer of protein phosphatase enzyme PP2A, in people with epilepsy. These efforts signify a novel disease-modifying era with treatments that reduce seizures and modify cognitive outcomes in people with epilepsy. Our analysis of the literature underscores the need for more in-depth characterization of tau pathology, at biochemical and structural levels in brain tissue and peripheral samples from people with epilepsy, as an important step to deciphering the role of tau in the pathogenesis of epilepsy and related disorders. Examining the relationships between tau pathology and cognitive impairment in those with epilepsy provides critical perspectives on potential causal tau pathomechanisms that may have important roles in epileptogenesis and dementia.

AbstractObjectiveThe Swiss guidelines for driving with epilepsy require that electroencephalogram (EEG) findings must be compatible with the fitness to drive (FTD) without specifying any criteria. This nationwide survey investigated how Swiss neurologists implement this requirement in clinical practice.MethodsAn online survey, including 19 EEG examples and statements about the compatibility of the EEG with FTD, was distributed to all members of the Swiss Society of Clinical Neurophysiology and all Swiss neurological clinics with residency programs. Descriptive statistics and Fleiss' Kappa for inter‐rater agreement were performed.Results102 participants (37% female, 45% <45 years) completed the survey, with 15% primarily working in a specialized epileptology center (EPI), 55% in a hospital setting without epileptological focus (HOS), and 30% in private practice (PP). Most participants of all three groups regarded EEG normal variants as compatible with FTD, while hyperventilation‐induced rhythmic slowing and some pathological patterns (e.g., frontal and temporal intermittent rhythmic delta activity [FIRDA, TIRDA], focal interictal epileptiform discharges [IED], focal seizure) were evaluated more heterogeneously. The EEG inter‐rater agreement for EPI was 0.4; 0.31 for PP; and 0.24 for HOS. No consensus was found for acceptable duration for generalized or focal IEDs. Among all participants, evaluation by an epilepsy center (85%) and reaction‐time testing (67%) were evaluated as the most useful additional examinations. However, reaction‐time testing is rarely or never performed by 58%. Most supported EEG results as part of the FTD assessment and demanded more research (both 82%).SignificanceOur survey indicates considerable heterogeneity among Swiss neurologists when evaluating the EEG findings for FTD. Inter‐rater agreement in all three groups was fair, with highest agreement among epileptologists. We noted a discrepancy between the usefulness and actual application of reaction‐time testing. More training and research are warranted to achieve rater‐independent consistency for FTD evaluation.Plain Language SummaryIn Switzerland, neurologists must consider the findings from EEG (brain waves) exams to evaluate driving safety in people with epilepsy. We surveyed Swiss neurologists, asking their opinions on this matter. We found that opinions differ among individual doctors, with the highest agreement among epilepsy specialists. We also found that some additional tests, such as reaction‐time testing, are perceived as useful but are rarely performed. The participating neurologists supported considering EEG results for driving fitness assessments but favored more precise guidelines and research.

Objective: To explore associations of the main component (P100) of visual evoked potentials (VEP) to preand postchiasmatic damage in multiple sclerosis (MS). Methods: 31 patients (median EDSS: 2.5), 13 with previous optic neuritis (ON), and 31 healthy controls had VEP, optical coherence tomography and magnetic resonance imaging. We tested associations of P100-latency to the peripapillary retinal nerve fiber layer (pRNFL), ganglion cell/inner plexiform layers (GCIPL), lateral geniculate nucleus volume (LGN), white matter lesions of the optic radiations (ORWML), fractional anisotropy of non-lesional optic radiations (NAOR-FA), and to the mean thickness of primary visual cortex (V1). Effect sizes are given as marginal R2 (mR2). Results: P100-latency, pRNFL, GCIPL and LGN in patients differed from controls. Within patients, P100latency was significantly associated with GCIPL (mR2 = 0.26), and less strongly with OR-WML (mR2 = 0.17), NAOR-FA (mR2 = 0.13) and pRNFL (mR2 = 0.08). In multivariate analysis, GCIPL and NAOR-FA remained significantly associated with P100-latency (mR2 = 0.41). In ON-patients, P100latency was significantly associated with LGN volume (mR2 = -0.56). Conclusions: P100-latency is affected by anterior and posterior visual pathway damage. In ON-patients, damage at the synapse-level (LGN) may additionally contribute to latency delay. Significance: Our findings corroborate post-chiasmatic contributions to the VEP-signal, which may relate to distinct pathophysiological mechanisms in MS. (c) 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background Assessment of prognosis and disease course in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) remains difficult based on clinical evaluation, fluid biomarker and neuroimaging. Multimodal evoked potentials ( mmEP) to quantify central conduction deficits, optical coherence tomography (OCT) to measure structural changes of the retina, repetitive transcranial magnetic stimulation (rTMS) to evaluate cortical plasticity and neuropsychological examination to characterize cognitive performance may add important complementary information. Methodology Short reviews on the use of mmEP, OCT, rTMS and neuropsychology in MS and NMOSD with clinical examples. Conclusion Functional diagnostics and OCT play an important role in the differentiated evaluation of people with MS and NMOSD for prognosis, monitoring of the disease course and individualized treatment strategies.

Background:Diagnosis of Amyotrophic Lateral Sclerosis (ALS) is challenging as initial presentations are various and diagnostic biomarkers are lacking. The diagnosis relies on the presence of both upper and lower motor neuron signs and thorough exclusion of differential diagnoses, particularly as receiving an ALS diagnosis has major implications for the patient. Sjögren's syndrome may mimic peripheral ALS phenotypes and should be considered in the work-up.Case:A 72-year-old female presented with a mono-neuropathy of the right leg and a complaint of dry eyes and mouth. Initial diagnostic work-up confirmed a regional sensorimotor neuropathy and a Sjögren's syndrome; a causal relationship was assumed. However, motor symptoms spread progressively despite immunosuppressive treatment, eventually including both legs, both arms and the diaphragm. Clinically, unequivocal central signs were lacking, but further along in the disease course, the atrophy pattern followed a split phenotype and deep tendon reflexes were preserved. Nerve biopsy did not show vasculitic infiltration; however, serum neurofilament light chain (sNfL) concentrations were and remained persistently highly elevated despite immunosuppressive treatment. Electrodiagnostic re-evaluation confirmed denervation in 3 regions. A diagnosis of familial ALS was finally confirmed by a C9orf 72 repeat expansion. Stationary sensory symptoms were best explained by a neuropathy associated with concomitant Sjögren's syndrome.Discussion:Our instructive case shows the difficulties of diagnosing ALS in the setting of a peripheral symptom onset and a concurrent but unrelated condition also causing neuropathy. Such cases require high clinical vigilance and readiness to reappraise diagnostic findings if the disease course deviates from expectation. Recently proposed simplified diagnostic criteria, genetic testing and body fluid biomarkers such as sNfL may facilitate the diagnostic process and lead to an earlier diagnosis of ALS.

Neurotoxicity is a well-described adverse effect of cefepime. Clinical presentation includes mild neurological deficits, aphasia, impairment of consciousness, and even nonconvulsive status epilepticus. Impaired kidney function is considered the most important risk factor for cefepime-induced neurotoxicity (CIN) and frequently occurs during the course of critical diseases with concomitant acute kidney injury (AKI). Physicians should be aware of situations with increased risk of AKI and the preventive actions required to reduce the risk of CIN. We present three patients with AKI who were treated with cefepime for healthcare-associated infections. Subsequently, two patients developed CIN demonstrating very high cefepime levels in plasma. In the third patient, CIN was likely prevented as the increased risk of neurotoxicity was noted and cefepime treatment was ceased immediately. Diagnosis of CIN might be challenging due to various causes of encephalopathy, in particular in the setting of severely ill patients. Electroencephalogram may assist in establishing the diagnosis, in particular when cefepime therapeutic drug monitoring is not available. As CIN is potentially reversible, it is an important differential diagnosis to consider especially in patients with impaired renal function or being susceptible to AKI. Preventive measures of CIN include therapeutic drug monitoring, consideration of a therapeutic alternative, awareness regarding a potential overestimation of the glomerular filtration rate, and electronic health record alerts about risk constellations for potential overdosing.

Objective: To validate the prognostic value of multimodal evoked potentials (mmEP) in primary progressive multiple sclerosis (PPMS) and to determine the most predictive EP-modalities.Methods: Thirty-nine patients with PPMS (expanded disability status scale (EDSS): 2.0-6.5; mean clinical follow-up: 2.8 years) had visual (VEP), upper and lower limb somatosensory (SEP) and motor EP (MEP) at baseline. Quantitative EP-scores for single (qVEP, qSEP, qMEP) and combined modalities were correlated to EDSS and compared to previously published data of 21 PPMS patients. Predictors of EDSS-change were analyzed in pooled data by linear regression.Results: Samples were comparable. Except qVEP, all EP-scores were correlated to EDSS at baseline (Rho: 0.45-0.69; p < 0.01) and follow-up (Rho: 0.59-0.80; p < 0.001). Combined EP-modalities significantly predicted EDSS-change (R2adj: 0.24), while EDSS and age did not. Tibial qSEP (R2adj: 0.22) and qMEP (R2adj: 0.26) were the best single modality predictors, outperformed by their combination (R2adj: 0.32).Conclusions: Quantitative EP-scores predict up to 32% of EDSS-change over three years. Modalities representing motor and long tract function carry the main prognostic information. Significance: Replication of previous results corroborates the use of mmEP as a prognostic biomarker candidate in PPMS.(c) 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Summary: Evoked potentials (EPs) measure quantitatively and objectively the alterations of central signal propagation in multiple sclerosis and have long been used for diagnosis. More recently, their utility for prognosis has been demonstrated in several studies, summarizing multiple EP modalities in a single score. In particular, visual, somatosensory, and motor EPs are useful because of their sensitivity to pathology in the frequently affected optic nerve, somatosensory tract, and pyramidal system. Quantitative EP scores show higher sensitivity to change than clinical assessment and may be used to monitor disease progression. Visual EP and the visual system have served as a model to study remyelinating therapies in the setting of acute and chronic optic neuritis. This review presents rationale and evidence for using multimodal EP as prognostic and response biomarkers in clinical trials, targeting remyelination or halting disease progression in multiple sclerosis.

Objective:To evaluate the sensitivity to change of differently calculated quantitative scores from motor evoked potentials (MEP) in patients with primary progressive multiple sclerosis (PPMS). Methods:Twenty patients with PPMS had MEP to upper and lower limbs at baseline, years 1 and 2 measured in addition to clinical assessment [Expanded Disability Status Scale (EDSS), ambulation score]; a subsample (n= 9) had a nine-hole peg test (NHPT) and a timed 25-foot walk (T25FW). Quantitative MEP scores for upper limbs (qMEP-UL), lower limbs (qMEP-LL), and all limbs (qMEP) were calculated in three different ways, based onz-transformed central motor conduction time (CMCT), shortest corticomuscular latency (CxM-sh), and mean CxM (CxM-mn). Changes in clinical measures and qMEP metrics were analyzed by repeated-measures analysis of variance (rANOVA), and a factor analysis was performed on change in qMEP metrics. Results:Expanded Disability Status Scale and ambulation score progressed in the rANOVA model (p< 0.05;post-hoccomparison baseline-year 2,p< 0.1). Lower limb and combined qMEP scores showed significant deterioration of latency (p< 0.01, MEP-LL_CxM-sh:p< 0.05) and inpost-hoccomparisons (baseline-year 2,p< 0.05), qMEP_CxM-mn even over 1 year (p< 0.05). Effect sizes were higher for qMEP scores than for clinical measures, and slightly but consistently higher when based on CxM-mn compared to CxM-sh or CMCT. Subgroup analysis yielded no indication of higher sensitivity of timed clinical measures over qMEP scores. Two independent factors were detected, the first mainly associated with qMEP-LL, the second with qMEP-UL, explaining 65 and 29% of total variability, respectively. Conclusions:Deterioration in qMEP scores occurs earlier than EDSS progression in patients with PPMS. Upper and lower limb qMEP scores contribute independently to measuring change, and qMEP scores based on mean CxM are advantageous. The capability to detect subclinical changes longitudinally is a unique property of EP and complementary to clinical assessment. These features underline the role of EP as candidate biomarkers to measure effects of therapeutic interventions in PPMS.

A 44-year-old night porter presented to our clinic with difficulty walking, instability, and stiffness—particularly in the muscles of his face—which had developed over the previous 3 weeks. His wife said that he had also been tired and lethargic for about 1 year.

Objective To study if the thalamic lateral geniculate nucleus (LGN) is affected in multiple sclerosis (MS) due to anterograde degeneration from optic neuritis (ON) or retrograde degeneration from optic radiation (OR) pathology, and if this is relevant for visual function. Methods In this cross-sectional study, LGN volume of 34 patients with relapsing-remitting MS and 33 matched healthy controls (HC) was assessed on MRI using atlas-based automated segmentation (MAGeT). ON history, thickness of the ganglion cell-inner plexiform layer (GC-IPL), OR lesion volume, and fractional anisotropy (FA) of normal-appearing OR (NAOR-FA) were assessed as measures of afferent visual pathway damage. Visual function was tested, including low-contrast letter acuity (LCLA) and Hardy-Rand-Rittler (HRR) plates for color vision. Results LGN volume was reduced in patients vs HC (165.5 +/- 45.5 vs 191.4 +/- 47.7 mm(3), B = -25.89, SE = 5.83, p < 0.001). It was associated with GC-IPL thickness (B = 0.95, SE = 0.33, p = 0.006) and correlated with OR lesion volume (Spearman. = -0.53, p = 0.001), and these relationships remained after adjustment for normalized brain volume. There was no association between NAOR-FA and LGN volume (B = -133.28, SE = 88.47, p = 0.137). LGN volume was not associated with LCLA (B = 5.5 x 10(-5), SE = 0.03, p = 0.998), but it correlated with HRR color vision (rho = 0.39, p = 0.032). Conclusions LGN volume loss in MS indicates structural damage with potential functional relevance. Our results suggest both anterograde degeneration from the retina and retrograde degeneration from the OR lesions as underlying causes. LGN volume is a promising marker reflecting damage of the visual pathway in MS, with the advantage of individual measurement per patient on conventional MRI.

Objective To study if the thalamic lateral geniculate nucleus (LGN) is affected in multiple sclerosis (MS) due to anterograde degeneration from optic neuritis (ON) or retrograde degeneration from optic radiation (OR) pathology, and if this is relevant for visual function. Methods In this cross-sectional study, LGN volume of 34 patients with relapsing-remitting MS and 33 matched healthy controls (HC) was assessed on MRI using atlas-based automated segmentation (MAGeT). ON history, thickness of the ganglion cell–inner plexiform layer (GC-IPL), OR lesion volume, and fractional anisotropy (FA) of normal-appearing OR (NAOR-FA) were assessed as measures of afferent visual pathway damage. Visual function was tested, including low-contrast letter acuity (LCLA) and Hardy-Rand-Rittler (HRR) plates for color vision. Results LGN volume was reduced in patients vs HC (165.5 ± 45.5 vs 191.4 ± 47.7 mm3, B = −25.89, SE = 5.83, p < 0.001). It was associated with GC-IPL thickness (B = 0.95, SE = 0.33, p = 0.006) and correlated with OR lesion volume (Spearman ρ = −0.53, p = 0.001), and these relationships remained after adjustment for normalized brain volume. There was no association between NAOR-FA and LGN volume (B = −133.28, SE = 88.47, p = 0.137). LGN volume was not associated with LCLA (B = 5.5 × 10−5, SE = 0.03, p = 0.998), but it correlated with HRR color vision (ρ = 0.39, p = 0.032). Conclusions LGN volume loss in MS indicates structural damage with potential functional relevance. Our results suggest both anterograde degeneration from the retina and retrograde degeneration from the OR lesions as underlying causes. LGN volume is a promising marker reflecting damage of the visual pathway in MS, with the advantage of individual measurement per patient on conventional MRI.

Background Motor and sensory evoked potentials (EP) are potential candidate biomarkers for clinical trials in multiple sclerosis. Objective To determine test -retest reliability of motor EP (MEP) and sensory EP (SEP) and associated EP-scores in patients with multiple sclerosis. Methods In three centres, 16 relapsing and five progressive multiple sclerosis patients had MEPs and SEPs 1–29 days apart. Five neurophysiologists independently marked latencies by central reading. By variance component analysis, we estimated the critical difference (absolute reliability) for cross-sectional group comparison, comparison of longitudinal group changes, within-subject minimal detectable change and defined within-subject improvement. Results Cortical SEP responses and cortico-muscular MEP latencies were more reliable than central conduction times. For comparison of 20 subjects per arm, cross-sectional group difference ranged from 0.7 to 3.9 ms and 1.1 to 1.7, group difference in longitudinal changes from 0.4 to 1.8 ms and 0.36 to 0.62, within-subject minimal detectable change from 1.2 to 5.8 ms and 1.2 to 2.0, within-subject improvement from 0.8 to 3.8ms and 0.8 to 1.3, for single EP modalities and EP scores, respectively. Conclusions Multicentre EP assessment with central EP reading is feasible and reliable. The critical difference is reasonably low to detect significant group changes and to define responders. The results support the concept of using EP and EP-scores as candidate response biomarkers for quantification of disease progression and for studying remyelination in multiple sclerosis.