Ongoing challenges in diagnosing focal cortical dysplasia (FCD) mandate continuous research and consensus agreement to improve disease definition and classification. An International League Against ...Epilepsy (ILAE) Task Force (TF) reviewed the FCD classification of 2011 to identify existing gaps and provide a timely update. The following methodology was applied to achieve this goal: a survey of published literature indexed with ((Focal Cortical Dysplasia) AND (epilepsy)) between 01/01/2012 and 06/30/2021 (n = 1349) in PubMed identified the knowledge gained since 2012 and new developments in the field. An online survey consulted the ILAE community about the current use of the FCD classification scheme with 367 people answering. The TF performed an iterative clinico‐pathological and genetic agreement study to objectively measure the diagnostic gap in blood/brain samples from 22 patients suspicious for FCD and submitted to epilepsy surgery. The literature confirmed new molecular‐genetic characterizations involving the mechanistic Target Of Rapamycin (mTOR) pathway in FCD type II (FCDII), and SLC35A2 in mild malformations of cortical development (mMCDs) with oligodendroglial hyperplasia (MOGHE). The electro‐clinical‐imaging phenotypes and surgical outcomes were better defined and validated for FCDII. Little new information was acquired on clinical, histopathological, or genetic characteristics of FCD type I (FCDI) and FCD type III (FCDIII). The survey identified mMCDs, FCDI, and genetic characterization as fields for improvement in an updated classification. Our iterative clinico‐pathological and genetic agreement study confirmed the importance of immunohistochemical staining, neuroimaging, and genetic tests to improve the diagnostic yield. The TF proposes to include mMCDs, MOGHE, and “no definite FCD on histopathology” as new categories in the updated FCD classification. The histopathological classification can be further augmented by advanced neuroimaging and genetic studies to comprehensively diagnose FCD subtypes; these different levels should then be integrated into a multi‐layered diagnostic scheme. This update may help to foster multidisciplinary efforts toward a better understanding of FCD and the development of novel targeted treatment options.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective
Machado–Joseph disease (SCA3/MJD) is the most frequent spinocerebellar ataxia worldwide and characterized by brainstem, basal ganglia, and cerebellar damage. However, little is known about ...the natural history of the disease. This motivated us to determine the extension and progression of central nervous system involvement in SCA3/MJD using multimodal magnetic resonance imaging (MRI)‐based analyses in a large cohort of patients (n = 79) and presymptomatic subjects (n = 12).
Methods
All subjects underwent MRI in a 3T device to assess gray and white matter. To evaluate the cerebral and cerebellar cortices, we used measures from FreeSurfer and SUIT. T1‐multiatlas assessed deep gray matter. Diffusion tensor imaging multiatlas was used to investigate cerebral white matter (WM) and SpineSeg to assess the cervical spinal cord.
Results
There was widespread WM and cerebellar damage, in contrast to the restricted motor cortex involvement when all patients are compared to age‐ and sex‐matched controls. Presymtomatic patients showed WM microstructural abnormalities mainly in the cerebellar and cerebral peduncles and volumetric reduction of midbrain, spinal cord, and substantia nigra. To assess the disease progression, we divided patients into four subgroups defined by time from ataxia onset. There was a clear pattern of evolving structural compromise, starting in infratentorial structures and progressing up to the cerebral cortex.
Conclusion
Structural damage in SCA3/MJD begins in the spinal cord, cerebellar peduncles, as well as substantia nigra and progresses to cerebral areas in the long term. These structural differences reveal some insights into the pathogenesis of SCA3/MJD and suggest a staging scheme to map the progression of the disease. Ann Neurol 2018;84:401–408
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary
The best prognostic factors in early‐onset epilepsies are the response to the first antiepileptic drug (AED) trial, age at seizure onset, number of seizures prior to treatment, and the ...presence of a lesion or abnormal neurologic examination. However, early and adequate response to AED is most likely an epiphenomenon reflecting the nature of underlying epileptogenicity, which may be defined as a complex interaction of underlying pathology, genetics, and environment. Patients with the same type of epileptogenic lesion, for example, hippocampal sclerosis, may have a varying response to AED. Modern neuroimaging, in particular quantitative magnetic resonance imaging (MRI) techniques may be helpful to better understand this complex interaction of factors leading to refractoriness. Patients who respond well to AEDs have no or minor MRI abnormalities, and among those with underlying lesions there is an inverse correlation between outcome and the extent of MRI‐defined neuronal damage outside the main lesion, which may be undetectable by visual analyses of routine MRI. The extent of neuronal damage appears to be related to the severity of initial precipitating injuries, probably interacts with genetic factors, and may progress over time when seizures are uncontrolled. The presence and extent of abnormalities detected by quantitative MRI may also be helpful to guide AED withdrawal in those patients who are seizure free for >2 years. Combined MRI measures may have potential clinical value for predicting AED response in near future.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background:
Information concerning longitudinal cognitive trajectories in multiple sclerosis (MS) is relatively scarce. Moreover, it is unclear which factors are associated with cognitive decline and ...what is the clinical impact of cognitive impairment (CI) in the long run.
Objective:
To investigate cognitive trajectories in relapsing–remitting multiple sclerosis (RRMS) patients, analyzing clinical and magnetic resonance imaging (MRI) predictors of cognitive decline.
Methods:
We enrolled 42 patients and 30 controls. They underwent brain MRI and clinical/neuropsychological evaluation at baseline and after 1, 2, and 6 years. We evaluated cognitive domains with principal component analysis and performed multivariable regression analyzing predictors of clinical/cognitive deterioration. We also performed repeated measures analysis to assess whether clinical progression was different according to CI at baseline.
Results:
A total of 23 (62.2%) patients deteriorated in combined cognitive domains after 6 years, most in processing speed and memory. The number of baseline impaired cognitive domains was strongly associated with 6-year cognitive (R2 = 0.452; p < 0.001) and Expanded Disability Status Scale (EDSS) deterioration (R2 = 0.263; p < 0.001). Patients with baseline CI in combined domains had worse clinical progression.
Conclusion:
Isolated CI tends to become more widespread, affecting memory and processing speed alongside. The extent of baseline CI was the best predictor of both clinical and cognitive deterioration after 6 years.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Artificial intelligence (AI) is increasingly used in medical image analysis and has accelerated scientific discoveries across fields of medicine. In this review, we highlight how AI has been applied ...to neuroimaging in patients with epilepsy to enhance classification of clinical diagnosis, prediction of treatment outcomes, and the understanding of cognitive comorbidities. We outline the strengths and shortcomings of current AI research and the need for future studies using large datasets that test the reproducibility and generalizability of current findings, as well as studies that test the clinical utility of AI approaches.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The cerebellum is an important site for cortical demyelination in multiple sclerosis, but the functional significance of this finding is not fully understood.
To evaluate the clinical and cognitive ...impact of cerebellar grey-matter pathology in multiple sclerosis patients.
Forty-two relapsing-remitting multiple sclerosis patients and 30 controls underwent clinical assessment including the Multiple Sclerosis Functional Composite, Expanded Disability Status Scale (EDSS) and cerebellar functional system (FS) score, and cognitive evaluation, including the Paced Auditory Serial Addition Test (PASAT) and the Symbol-Digit Modalities Test (SDMT). Magnetic resonance imaging was performed with a 3T scanner and variables of interest were: brain white-matter and cortical lesion load, cerebellar intracortical and leukocortical lesion volumes, and brain cortical and cerebellar white-matter and grey-matter volumes.
After multivariate analysis high burden of cerebellar intracortical lesions was the only predictor for the EDSS (p<0.001), cerebellar FS (p = 0.002), arm function (p = 0.049), and for leg function (p<0.001). Patients with high burden of cerebellar leukocortical lesions had lower PASAT scores (p = 0.013), while patients with greater volumes of cerebellar intracortical lesions had worse SDMT scores (p = 0.015).
Cerebellar grey-matter pathology is widely present and contributes to clinical dysfunction in relapsing-remitting multiple sclerosis patients, independently of brain grey-matter damage.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epilepsy surgery is the treatment of choice for patients with drug‐resistant seizures. A timely evaluation for surgical candidacy can be life‐saving for patients who are identified as appropriate ...surgical candidates, and may also enhance the care of nonsurgical candidates through improvement in diagnosis, optimization of therapy, and treatment of comorbidities. Yet, referral for surgical evaluations is often delayed while palliative options are pursued, with significant adverse consequences due to increased morbidity and mortality associated with intractable epilepsy. The Surgical Therapies Commission of the International League Against Epilepsy (ILAE) sought to address these clinical gaps and clarify when to initiate a surgical evaluation. We conducted a Delphi consensus process with 61 epileptologists, epilepsy neurosurgeons, neurologists, neuropsychiatrists, and neuropsychologists with a median of 22 years in practice, from 28 countries in all six ILAE world regions. After three rounds of Delphi surveys, evaluating 51 unique scenarios, we reached the following Expert Consensus Recommendations: (1) Referral for a surgical evaluation should be offered to every patient with drug‐resistant epilepsy (up to 70 years of age), as soon as drug resistance is ascertained, regardless of epilepsy duration, sex, socioeconomic status, seizure type, epilepsy type (including epileptic encephalopathies), localization, and comorbidities (including severe psychiatric comorbidity like psychogenic nonepileptic seizures PNES or substance abuse) if patients are cooperative with management; (2) A surgical referral should be considered for older patients with drug‐resistant epilepsy who have no surgical contraindication, and for patients (adults and children) who are seizure‐free on 1–2 antiseizure medications (ASMs) but have a brain lesion in noneloquent cortex; and (3) referral for surgery should not be offered to patients with active substance abuse who are noncooperative with management. We present the Delphi consensus results leading up to these Expert Consensus Recommendations and discuss the data supporting our conclusions. High level evidence will be required to permit creation of clinical practice guidelines.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Autism spectrum disorder (ASD) is characterized by a core difference in theory-of-mind (ToM) ability, which extends to alterations in moral judgment and decision-making. Although the function of the ...right temporoparietal junction (rTPJ), a key neural marker of ToM and morality, is known to be atypical in autistic individuals, the neurocomputational mechanisms underlying its specific changes in moral decision-making remain unclear. Here, we addressed this question by using a novel fMRI task together with computational modeling and representational similarity analysis (RSA). ASD participants and healthy control subjects (HCs) decided in public or private whether to incur a personal cost for funding a morally good cause (Good Context) or receive a personal gain for benefiting a morally bad cause (Bad Context). Compared with HC, individuals with ASD were much more likely to reject the opportunity to earn ill gotten money by supporting a bad cause than were HCs. Computational modeling revealed that this resulted from heavily weighing benefits for themselves and the bad cause, suggesting that ASD participants apply a rule of refusing to serve a bad cause because they evaluate the negative consequences of their actions more severely. Moreover, RSA revealed a reduced rTPJ representation of the information specific to moral contexts in ASD participants. Together, these findings indicate the contribution of rTPJ in representing information concerning moral rules and provide new insights for the neurobiological basis underpinning moral behaviors illustrated by a specific difference of rTPJ in ASD participants.
Previous investigations have found an altered pattern of moral behaviors in individuals with autism spectrum disorder (ASD), which is closely associated with functional changes in the right temporoparietal junction (rTPJ). However, the specific neurocomputational mechanisms at play that drive the altered function of the rTPJ in moral decision-making remain unclear. Here, we show that ASD individuals are more inflexible when following a moral rule although an immoral action can benefit themselves, and experience an increased concern about their ill-gotten gains and the moral cost. Moreover, a selectively reduced rTPJ representation of information concerning moral rules was observed in ASD participants. These findings deepen our understanding of the neurobiological roots that underlie atypical moral behaviors in ASD individuals.
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