Late-onset Pompe disease (LOPD) is a genetic myopathy causing severe limb girdle and diaphragmatic weakness. Pre-symptomatic diagnosis of LOPD is increasing. Enzyme replacement therapy (ERT) has shown dramatic efficacy i...Late-onset Pompe disease (LOPD) is a genetic myopathy causing severe limb girdle and diaphragmatic weakness. Pre-symptomatic diagnosis of LOPD is increasing. Enzyme replacement therapy (ERT) has shown dramatic efficacy in infantile-onset forms of the disease, supporting early diagnosis and treatment initiation, whereas the benefit of ERT on muscle weakness and respiratory insufficiency is moderate and not sustained over time in LOPD, raising questions about presymptomatic screening. Here, we present three presymptomatic cases of LOPD, showing that clinical symptoms can occur long after the diagnosis, resulting in a close monitoring without the need for treatment over several years. Several tests, such as walking tests, pulmonary function tests or whole-body muscle magnetic resonance imaging are sensitive for detecting early disease progression. Current guidelines provide no clear recommendations regarding the optimal timing of treatment initiation in presymptomatic patients. Nevertheless, in the context of a disease with a highly variable course, regular clinical, physiological and radiological assessments of each patient may allow for early detection of disease progression and support the decision to initiate treatment.
Hereditary transthyretin amyloidosis (ATTRv) is a rare, lethal, autosomal dominant adult-onset genetic disorder provoked by mutations in the TTR gene. Until recently, therapeutic options were limited to liver transplanta...Hereditary transthyretin amyloidosis (ATTRv) is a rare, lethal, autosomal dominant adult-onset genetic disorder provoked by mutations in the TTR gene. Until recently, therapeutic options were limited to liver transplantation and TTR stabilizers. Antisense oligonucleotides (ASO) and small interfering RNA (siRNA) treatments, now commercially available, have dramatically improved ATTRv neurological outcome, and affected patients' relatives are increasingly being identified at the presymptomatic stage. Guidelines for monitoring presymptomatic patients have been established by different groups. ATTRv disease onset is defined by a combination of pathologically proven amyloid TTR deposits, symptoms attributed to ATTRv, and clinical changes in comparison with initial assessment. However, several studies have shown that many presymptomatic patients present with subclinical abnormalities before amyloid deposits are observed, blurring the boundary between presymptomatic and symptomatic statuses. Future challenges include identifying biomarkers for better delineating the transition between presymptomatic and symptomatic, e.g., neurofilament light chain (NfL), and considering prophylactic treatment to prevent the onset of the disease.
Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterized by progressive degeneration of motoneurons, which used to lead in many cases to severe motor impairment and early death without treat...Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterized by progressive degeneration of motoneurons, which used to lead in many cases to severe motor impairment and early death without treatment. In recent years, three disease-modifying treatments have dramatically changed the patient outcome, especially when initiated in the presymptomatic phase. This review examines the scientific rationale, practical implications as well as ethical, economic and political considerations of presymptomatic detection of SMA in the era of transformative therapies. The need for early detection and early treatment of SMA has prompted the implementation of newborn screening programs. All clinical trials and real-life surveys have consistently demonstrated the clear benefits of this strategy for patients. This DNA-based newborn screening method followed by gene-related treatments has inaugurated a new paradigm and has challenged the organization of healthcare systems. This strategy has raised ethical questions about management of uncertainties, which should be overcome by long-term follow-up and transparent information given to the parents. Cost-effectiveness studies have shown that the SMA newborn screening strategy is always dominant over post-symptomatic treatment. Despite the compelling evidence accumulating in favor of newborn screening for SMA, the implementation of systematic routine programs has faced political hurdles in many cases and is not yet effective even in all EU countries. The experience of SMA newborn screening will probably be helpful for upcoming genomic newborn screenings.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an identified genetic origin in 10-15% of cases, mainly involving C9orf72 and SOD1 mutations. The increasing number of genetically confirmed ALS cas...Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an identified genetic origin in 10-15% of cases, mainly involving C9orf72 and SOD1 mutations. The increasing number of genetically confirmed ALS cases has led to a growing identification of asymptomatic mutation carriers. While riluzole remains the standard treatment, mutation-specific therapies such as tofersen, that was recently approved in SOD1-ALS, are emerging. In this context, the identification of presymptomatic biomarkers is crucial for monitoring genetically at-risk individuals. Plasma neurofilament light chain can increase up to 3.5years before symptom onset in C9orf72 carriers. Metabolic and neuroimaging alterations together with cognitive or behavioral changes, that are sometimes detectable decades prior to diagnosis, have also been observed. These biomarkers may support early surveillance and intervention strategies. The present review provides an overview of current evidence on presymptomatic biomarkers in ALS mutation carriers and their potential role in genetic counseling, monitoring, and early therapeutic decisions.
Alzheimer's disease (AD) is increasingly recognized as a decades-long process that begins before any first cognitive symptoms. Neuropathology and in vivo biomarker studies have revealed a silent preclinical phase. Howeve...Alzheimer's disease (AD) is increasingly recognized as a decades-long process that begins before any first cognitive symptoms. Neuropathology and in vivo biomarker studies have revealed a silent preclinical phase. However, its precise definition and boundaries remain debated. Elucidating the biological events and temporal sequence that characterize this stage is essential, while researchers try to identify the optimal window to prevent or postpone cognitive decline. At the same time, "preclinical AD" raises unresolved challenges in diagnosis, prognosis, therapeutic intervention and ethics. This narrative review synthesizes the current evidence, from clinical characterization to prevention trials and societal considerations, with an emphasis on original findings for amyloid, tau and neurodegeneration biomarkers. We critically contrast the two principal research frameworks that structure the field and examine how each shapes patient classification and trial design. By integrating these lines of evidence, we explore persistent gaps in prognostic modeling and in the clinical efficacy of disease-modifying strategies. The review aims to provide a concise but comprehensive overview of the preclinical concept for clinicians and researchers developing the next generation of preventive interventions for AD.
The neurodegenerative process responsible for Parkinson's disease (PD) begins years before the level of dopamine denervation of the basal ganglia leads to the characteristic clinical phenotype of the disease. During the...The neurodegenerative process responsible for Parkinson's disease (PD) begins years before the level of dopamine denervation of the basal ganglia leads to the characteristic clinical phenotype of the disease. During the past 20years, numerous symptoms that may occur during the prodromal stage of the disease have been identified: subtle motor symptoms, psychocognitive disorders, sleep disorders, sensorial dysfunction, and dysautonomia. Among them, rapid eye movement sleep behaviour disorder (RBD) is one of the most specific. The follow-up of cohorts of subjects affected by this disorder has provided valuable information about the prodromal stage, including evidence of various biological or imaging biomarkers associated with the pre-clinical stage of the disease. From all the knowledge acquired about this stage of the disease, criteria for diagnosing prodromal PD have been proposed and have progressively improved in sensitivity and specificity. The strong focus on the RBD-associated prodromal stage has, however, tended to conceal other, less florid forms of prodromal PD, such as those beginning with mild cognitive impairment or mild motor symptoms, which affected subjects are less likely to notice. Here, we review the various symptoms observed in the prodromal stage of PD, progress on identifying relevant imaging and biological biomarkers, and recent insights into the pathogenesis of a disease having such a wide spectrum of presentation and progression. Advances in knowledge about prodromal PD will lead to earlier diagnosis and better identification of prognostic factors, and, subsequently, to the capacity to initiate personalized treatment and potentially slow down the degenerative process.
Presymptomatic testing allows individuals to undergo genetic testing for inherited diseases before symptoms manifest. While valuable in conditions with available preventive strategies, no therapeutic prevention currently...Presymptomatic testing allows individuals to undergo genetic testing for inherited diseases before symptoms manifest. While valuable in conditions with available preventive strategies, no therapeutic prevention currently exists for Huntington disease, making testing a personal choice rather than a medical recommendation. Available in France since 1992 - following the identification of CAG repeat expansions (>35) in the huntingtin gene - presymptomatic testing is governed by guidelines emphasizing autonomy, benevolence, informed consent, confidentiality, and equity. Its implementation requires an interdisciplinary approach, including genetic counseling and psychological support, to ensure comprehensive care. One of the many lessons learned is that despite the large availability of presymptomatic testing centers, less than 20% of at-risk individuals choose to be tested, reflecting complex psychological and familial dynamics. In addition, motivations for testing vary widely, more often identified as the desire to know rather than family planning, which explains the even lower opting in for prenatal testing. Psychological support is essential, as an unfavorable result puts individuals in a prolonged liminal state, waiting for disease onset. Favorable results are the happy ending of testing, but can, in some instances, also trigger complex emotional responses, such as survivor's guilt. Involving presymptomatic carriers in research programs has offered important scientific benefits and also a sense of agency and meaning for participants. Our experience with presymptomatic testing in Huntington disease has established a paradigm for predictive genetic medicine, highlighting the importance of interdisciplinary care and ethical considerations. As genomic medicine advances, the core principles of presymptomatic testing remain relevant, ensuring the protection and consent of individuals and their families. These lessons help to disseminate information about the utility of genetic counseling and call for an informed approach to presymptomatic testing in neurogenetics.
The presence of focal lesions suggestive of multiple sclerosis (MS) seen with magnetic resonance imaging (MRI) in asymptomatic individuals defines the radiologically isolated syndrome (RIS). Pathologically, tissue change...The presence of focal lesions suggestive of multiple sclerosis (MS) seen with magnetic resonance imaging (MRI) in asymptomatic individuals defines the radiologically isolated syndrome (RIS). Pathologically, tissue changes in RIS subjects recapitulate, although being less extensive and pronounced, those observed in definite MS, with an amount of innate immune cell activation, myelin loss, gliosis, metabolic modifications, and structural damage affecting the neuro-axonal compartment. Conventional MRI, however, is not able to capture these biological abnormalities at the cellular and molecular level. Positron emission tomography (PET) with specific radiolabeled compounds could fill this gap, identifying in vivo and with higher granularity the processes underling the abnormal MRI signals. This review presents data obtained with PET in RIS individuals and discusses the potential application of this technique in exploring the different pathophysiologic changes going on in the RIS brain, with technical considerations on radiotracers already tested in MS or newly developed. By breaking up the study of complex tissular changes into single biological phenomena, the use of PET in RIS could encourage early interventions to selectively target each one of them, with potential consequences on the clinical conversion to MS.
Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) often exhibit a prolonged presymptoma...Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) often exhibit a prolonged presymptomatic phase during which neuropathological changes silently progress. Recent advances in biomarker research have revealed molecular and imaging signatures that precede clinical onset by years, offering a critical window for early intervention. This review synthesizes current knowledge on the most promising presymptomatic biomarkers across these conditions, highlighting their biological origins, diagnostic performance, and clinical utility. Particular emphasis is placed on the development and validation of biomarker panels, which combine multiple markers to enhance diagnostic sensitivity and specificity, enabling more accurate detection of disease in its earliest stages. Minimally invasive approaches, such as blood-based assays, are also discussed for their potential to facilitate widespread screening and longitudinal monitoring. As these biomarkers begin to integrate into clinical workflows, particularly in AD and MS, international collaboration will be essential to standardize methodologies and ensure equitable implementation. Ultimately, presymptomatic biomarkers hold transformative potential for shifting neurology toward a proactive and precision-based paradigm.
INTRODUCTION: Transient ischemic attacks (TIAs) are associated with a high risk of early ischemic stroke. Timely and organized care is essential to prevent recurrence, as recommended by national guidelines. This survey a...INTRODUCTION: Transient ischemic attacks (TIAs) are associated with a high risk of early ischemic stroke. Timely and organized care is essential to prevent recurrence, as recommended by national guidelines. This survey aimed to describe current TIA management practices in French Stroke Units (SUs) and identify gaps relative to national and international recommendations. METHOD: A declarative survey was sent by email to 139 French SU managers. Six reminders were sent to non-responders and partial responders. A link to the survey was also available on the French Neurovascular Society website from March 18 to November 1, 2023. RESULTS: A total of 123 SUs (88.5%) responded. A TIA clinic was identified in 15 SU (12% of respondents). In the other 108 SUs, no specific written procedure (63%), or a written procedure was applied at the SU (32%), and the corresponding healthcare territory (5%). The median time from admission to extra- and intra-cervical vessel imaging was 6hours (IQR: 3-24), but in 25% of SUs, it was not provided in the first 24hours after hospitalization. The median times to transthoracic echocardiogram and transesophageal echocardiogram were 4days (IQR: 2-7) and 7days (IQR: 4-14), respectively. CONCLUSIONS: This study shows that dedicated TIA clinics are uncommon in France, but they are associated with faster diagnostic work-ups and shorter hospital stays. Expanding such structured care models within SUs could enhance the timeliness, consistency, and quality of TIA management nationwide, ultimately reducing the risk of recurrent stroke.
Sexual difficulties are common but under-recognized in Parkinson's disease (PD), significantly affecting quality of life. They include both sexual dysfunction (SD) - a non-motor symptom - and hypersexuality (HS) - an imp...Sexual difficulties are common but under-recognized in Parkinson's disease (PD), significantly affecting quality of life. They include both sexual dysfunction (SD) - a non-motor symptom - and hypersexuality (HS) - an impulse control disorder (ICD). SD often presents as reduced libido, arousal issues, or orgasmic problems, while HS involves compulsive sexual thoughts or behaviors, often linked to dopamine agonists. These opposing symptoms may coexist, adding to diagnostic complexity. Sexual health in PD is influenced by neurological, vascular, endocrine, psychological, and medication-related factors. Despite its impact, sexual difficulties are rarely discussed in clinical settings due to limited time and patient reluctance. A proactive, nonjudgmental approach is essential. This review aims to equip neurologists with practical, time-efficient strategies to identify and manage sexual difficulties in both men and women with PD.
BACKGROUND: Foreign accent syndrome is a rare entity with neural underpinnings that are not yet fully understood. Cases of neurogenic foreign accent syndrome due to right hemisphere lesion are very uncommon. We investiga...BACKGROUND: Foreign accent syndrome is a rare entity with neural underpinnings that are not yet fully understood. Cases of neurogenic foreign accent syndrome due to right hemisphere lesion are very uncommon. We investigated the cortical and white matter lesions in a patient to better understand this syndrome. CASE REPORT: A 39-year-old French woman had a right middle cerebral artery stroke. This French native speaker was now perceived as speaking with an English accent, without signs of dysarthria or aphasia. Lesions involved right insula, pre-central gyrus and surrounding white matter tracts. After transformation in MNI-152 coordinate system, we compared the lesions in our patient with Tractotron software, a white matter tract tool providing a probability of fiber disconnection. DISCUSSION: Speech evaluation suggested a disruption in the speech output motor system. We found lesions within this system, in anterior frontal and insular cortices, in accordance with previous descriptions. Besides structural grey matter damage, white matter also exhibited damage related to the stroke, particularly the frontal aslant tract. Very few studies have focused on the specific role of this tract in speech motor programming, but a role in speech production and stuttering have been described. Some cases of foreign accent syndrome appeared consecutively to right hemisphere lesions. There is growing evidence suggesting that right hemisphere lesions might lead to subclinical alteration of prosody contributing to the emergence of foreign accent syndrome. CONCLUSION: This study emphasizes the importance of analyzing subcortical areas and their associated tracts, which could play a crucial role in better understanding symptoms and anatomical correlation.
BACKGROUND AND AIMS: Data on factors associated with new-onset epilepsy in the follow-up of patients with brain arteriovenous malformations (BAVM) are scarce. We aimed to characterize the baseline patient and BAVM charac...BACKGROUND AND AIMS: Data on factors associated with new-onset epilepsy in the follow-up of patients with brain arteriovenous malformations (BAVM) are scarce. We aimed to characterize the baseline patient and BAVM characteristics related to epilepsy and the predictive factors of new-onset epilepsy in BAVM patients during their follow-up. PATIENTS AND METHODS: We retrospectively analyzed 200 BAVM patients treated between 2000 and 2023. We used univariate and multivariate analyses to assess the association between baseline characteristics and seizures. The risk of developing seizures during follow-up was estimated using nonparametric survival analysis for interval-censored data. RESULTS: In the present cohort, 90/200 patients (45%) had epilepsy at baseline. Patients with epilepsy were predominantly men (71.1%), and alcohol users (18.8%), and presented with BAVM located more often in the frontal lobe (55.6%) as compared to patients without epilepsy (40%, 7.4%, 23.6% respectively). Male gender was associated with higher prevalence of seizures at inclusion (OR 3.81 [95%CI, 1.77; 8.24]), while headaches (OR 0.19 [95% CI, 0.09; 0.41]), focal deficit (OR 0.22 [0.09; 0.49]) and BAVM occipital localization (OR 0.16 [95% CI, 0.05; 0.47]) remained associated with lower prevalence of epilepsy at inclusion. Among patients without epilepsy at baseline, 20.6% had new-onset epilepsy after five years. Baseline predictors of seizure occurrence included ruptured BAVM (HR 3.77 [95%CI 1.50; 9.44]) and surgery (HR 7.75, 95%CI, [2.04; 29.45]). CONCLUSIONS: For patients with newly diagnosed BAVM, male gender, and frontal topography were baseline characteristics associated with a higher risk of epilepsy. Among patients without epilepsy, ruptured BAVM and surgery at baseline were predictors of epilepsy at five years follow-up.
BACKGROUND: Radiologically isolated syndrome (RIS) is characterized by incidental brain lesions suggestive of demyelination without symptoms of multiple sclerosis (MS). We systematically assessed the use, benefits, and a...BACKGROUND: Radiologically isolated syndrome (RIS) is characterized by incidental brain lesions suggestive of demyelination without symptoms of multiple sclerosis (MS). We systematically assessed the use, benefits, and adverse effects of DMTs for RIS. METHODS: MEDLINE, EMBASE, and Web of Science were searched to identify English language studies including individuals with RIS treated with a DMT. Extracted data included patient characteristics, clinical progression, and adverse events. We conducted a meta-analysis using inverse probability weighting. Risk of bias (RoB) assessments used Cochrane's RoB-2 tool and Newcastle-Ottawa cohort study scale. RESULTS: A total of 1012 abstracts were screened: 20 studies were included consisting of 2 RCTs, 12 observational cohort studies, and 6 case reports. A total of 1401 individuals with RIS were included; 291 (21%) received a DMT. The two RCTs randomized people with RIS to teriflunomide or dimethyl fumarate versus placebo and followed patients for at least 96weeks. In all other studies, follow-up ranged from 2months to 18years; only 3 studies exceeded 5years. DMT treatment was associated with a lower risk of a clinical demyelinating event (4 studies with different DMTs, adjusted hazard ratio=0.37 95% confidence interval [CI]: 0.15-0.95, high certainty). There was a higher rate of adverse events in DMT treated patients with RIS versus placebo (risk ratio=1.44, 95% CI: 1.09-1.90, moderate certainty). RoB was low for both RCTs, but high for 83% (10/12) of cohort studies. CONCLUSIONS: DMTs reduced the risk of a clinical demyelinating event in individuals with RIS, albeit with more adverse events compared to placebo. However, no literature addressed longer-term benefits/adverse effects.
BACKGROUND: Surgery for lobar intracerebral hemorrhages (ICH) associated with cerebral amyloid angiopathy (CAA) is believed to carry a high risk of postoperative rebleeding. The diagnosis of CAA is increasing with an agi...BACKGROUND: Surgery for lobar intracerebral hemorrhages (ICH) associated with cerebral amyloid angiopathy (CAA) is believed to carry a high risk of postoperative rebleeding. The diagnosis of CAA is increasing with an aging population and external validation of the Edinburgh criteria on computed tomography (CT) scans. The aim of this study was to assess the postoperative risk of CAA-related ICH compared to non-CAA-related ICH. METHODS: We included patients admitted between 2008 and 2022 for spontaneous lobar ICH who underwent surgery at three university hospitals. A single-blinded neuroradiologist analyzed the Edinburgh criteria on the initial CT scan before surgery and assessed rebleeding on a repeat CT scan performed within 48hours after surgery. Patients were classified into the "CAA group" according to the Edinburgh or Boston criteria, and into the "non-CAA group" if they had another cause of ICH. RESULTS: A total of 140 patients were included, with 23 in the CAA group, 93 in the non-CAA group, and 24 in the undetermined group. The postoperative rebleeding rate at 24-48hours did not differ significantly between groups (13% in the CAA group vs. 15% in the non-CAA group, P>0.99). The overall rate of rebleeding associated with clinical deterioration did not differ between groups (9% in the CAA group vs. 6% in the non-CAA group, P=0.66). The overall mortality rate during the acute phase did not significantly differ between groups (4% in the CAA group vs. 12% in the non-CAA group, P=0.46). The modified Rankin scale score three months after discharge ranged from 0 to 3 for 63% of CAA patients compared to 53% of non-CAA patients, with no significant difference (P=0.59). CONCLUSION: We did not find a significant difference in the postoperative rebleeding rate after ICH associated with CAA compared to other causes.
Dumurgier J, Défontaines B, Gallouj K
… +9 more, Garcin B, Garnier-Crussard A, Lagarde J, Pauly JM, Rollin Sillaire A, Rouch-Leroyer I, Sarazin M, Verny M, Wallon D
Alzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of major neurocognitive disorder in older adults. Its diagnosis has evolved from clinical to clinico-biological criteria, integ...Alzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of major neurocognitive disorder in older adults. Its diagnosis has evolved from clinical to clinico-biological criteria, integrating biomarkers such as beta-amyloid and phosphorylated tau in cerebrospinal fluid or specific positron emission tomography (PET) imaging. Recent therapeutic advances, including anti-amyloid immunotherapies, highlight the need for early and accurate diagnosis. Clinical presentation is heterogeneous and may include amnestic or non-amnestic forms. Diagnosis should be suspected in patients with progressive cognitive decline and confirmed through neuropsychological assessment and biomarker testing. Blood-based biomarkers are promising but not yet validated for routine use. Magnetic resonance imaging (MRI) is recommended for all patients with recent cognitive decline. The role of general practitioners in early detection is critical. These recommendations, developed by the French federation of memory clinics, provide guidance on diagnosis stages, biomarker indications, first-line assessments, referral criteria, and communication of diagnosis. They aim to standardize clinical practice and support timely, individualized care.
BACKGROUND: Rituximab and other anti-CD20 therapies are increasingly used in the treatment of autoimmune and hematologic disorders. These treatments are associated with persistent immune impairment, potentially leading t...BACKGROUND: Rituximab and other anti-CD20 therapies are increasingly used in the treatment of autoimmune and hematologic disorders. These treatments are associated with persistent immune impairment, potentially leading to severe infections. We describe a resolutive case of proven chronic enterovirus A71 (EV A71) meningoencephalitis complicating rituximab maintenance therapy for non-Hodgkin lymphoma. METHODS: This article combines an original case report and a literature review of cases of enteroviral meningoencephalitis complicating rituximab treatment. RESULTS: A 38-year-old man was treated with rituximab and chemotherapy for a mantle cell lymphoma. During maintenance treatment with rituximab, he developed a "hand-foot-mouth disease", and one month later severe neurological deterioration including quadriparesis and major neurocognitive disorder leading to a diagnosis of chronic enteroviral meningoencephalitis. A treatment associating monthly intravenous immunoglobulins (IVIg) and fluoxetine was initiated two months after neurological symptoms onset, resulting in dramatic clinical improvement within six months. A brief literature review shows that a treatment with high-dose IVIg often results in clinical improvement. Fluoxetine was added in recent reports based on in vitro evidence of anti-viral activity against enteroviruses. DISCUSSION: Enteroviral infection should be evoked in patients treated with rituximab presenting with an encephalitic symptomatology, and restoring humoral immunity with high-dose IVIg might improve their condition.