Idiopathic epilepsies (IEs) are a group of disorders characterized by recurrent seizures in the absence of detectable brain lesions or metabolic abnormalities. IEs include common disorders with a ...complex mode of inheritance and rare Mendelian traits suggesting the occurrence of several alleles with variable penetrance. We previously described a large family with a recessive form of idiopathic epilepsy, named familial infantile myoclonic epilepsy (FIME), and mapped the disease locus on chromosome 16p13.3 by linkage analysis. In the present study, we found that two compound heterozygous missense mutations (D147H and A509V) in TBC1D24, a gene of unknown function, are responsible for FIME. In situ hybridization analysis revealed that Tbc1d24 is mainly expressed at the level of the cerebral cortex and the hippocampus. By coimmunoprecipitation assay we found that TBC1D24 binds ARF6, a Ras-related family of small GTPases regulating exo-endocytosis dynamics. The main recognized function of ARF6 in the nervous system is the regulation of dendritic branching, spine formation, and axonal extension. TBC1D24 overexpression resulted in a significant increase in neurite length and arborization and the FIME mutations significantly reverted this phenotype. In this study we identified a gene mutation involved in autosomal-recessive idiopathic epilepsy, unveiled the involvement of ARF6-dependent molecular pathway in brain hyperexcitability and seizures, and confirmed the emerging role of subtle cytoarchitectural alterations in the etiology of this group of common epileptic disorders.
Summary
Purpose
In relatively small series, autosomal dominant lateral temporal epilepsy (ADLTE) has been associated with leucine‐rich, glioma‐inactivated 1 (LGI1) mutations in about 50% of the ...families, this genetic heterogeneity being probably caused by differences in the clinical characteristics of the families. In this article we report the overall clinical and genetic spectrum of ADLTE in Italy with the aim to provide new insight into its nosology and genetic basis.
Methods
In a collaborative study of the Commission of Genetics of the Italian League Against Epilepsy (LICE) encompassing a 10‐year period (2000–2010), we collected 33 ADLTE families, selected on the basis of the following criteria: presence of at least two members concordant for unprovoked partial seizures with prominent auditory and or aphasic symptoms, absence of any known structural brain pathology or etiology, and normal neurologic examination. The clinical, neurophysiologic, and neuroradiologic findings of all patients were analyzed and a genealogic tree was built for each pedigree. The probands' DNA was tested for LGI1 mutations by direct sequencing and, if negative, were genotyped with single‐nucleotide polymorphism (SNP) array to search for disease‐linked copy‐number variation CNV. The disease penetrance in mutated and nonmutated families was assessed as a proportion of obligate carriers who were affected.
Key Findings
The 33 families included a total of 127 affected individuals (61 male, 66 female, 22 deceased). The age at onset ranged between 2 and 60 years (mean 18.7 years). Ninety‐one patients (72%) had clear‐cut focal (elementary, complex, or secondarily generalized) seizures, characterized by prominent auditory auras in 68% of the cases. Other symptoms included complex visual hallucinations, vertigo, and déjà vu. Aphasic seizures, associated or not with auditory features, were observed in 20% of the cases, whereas tonic–clonic seizures occurred in 86% of the overall series. Sudden noises could precipitate the seizures in about 20% of cases. Seizures, which usually occurred at a low frequency, were promptly controlled or markedly improved by antiepileptic treatment in the majority of patients. The interictal electroencephalography (EEG) studies showed the epileptiform temporal abnormalities in 62% of cases, with a slight predominance over the left region. Magnetic resonance imaging (MRI) or computerized tomography (CT) scans were negative. LGI1 mutations (missense in nine and a microdeletion in one) were found in only 10 families (30%). The patients belonging to the mutated and not mutated groups did not differ except for penetrance estimate, which was 61.3% and 35% in the two groups, respectively (chi‐square, p = 0.017). In addition, the disease risk of members of families with mutations in LGI1 was three times higher than that of members of LGI1‐negative families (odds ratio OR 2.94, confidence interval CI 1.2–7.21).
Significance
A large number of ADLTE families has been collected over a 10‐year period in Italy, showing a typical and homogeneous phenotype. LGI1 mutations have been found in only one third of families, clinically indistinguishable from nonmutated pedigrees. The estimate of penetrance and OR, however, demonstrates a significantly lower penetrance rate and relative disease risk in non–LGI1‐mutated families compared with LGI1‐mutated pedigrees, suggesting that a complex inheritance pattern may underlie a proportion of these families.
To evaluate the phenotypic spectrum associated with mutations in TBC1D24.
We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 ...mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24).
Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function.
TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.
Introduction
Sporadic cerebral amyloid angiopathy (CAA) is a common age-related cerebral small vessel disease characterized by progressive ß-amyloid deposition in the walls of small cortical ...arteries, arterioles, and capillaries in the cerebral cortex and overlying leptomeninges. CAA-related transient focal neurological episodes (CAA-TFNEs) represent a challenging clinical feature interesting from a pathophysiological point of view.
Case report
Here we present two cases of CAA-TFNEs in which we performed functional imaging with perfusion-weighted imaging MR and brain 18 F-FDG PET. In both cases, we found a topographic relationship between the involved cortical areas and the clinical expression of CAA-TFNEs. Cortical superficial siderosis in the first case and a convexity subarachnoid hemorrhage in the second case were found in the contralateral rolandic area corresponding to the clinical symptoms. The same areas showed a reduction of rCBV and rCBF on perfusion-weighted MR and were also associated in one case with hypometabolism on 18 F-FDG PET.
Discussion
These new findings strengthen the hypothesis that CAA involves the superficial leptomeningeal arteries but also the short penetrating arterioles reaching different depths in the cortex generating hypoperfusion and altered vascular reactivity and consequently reduced neuronal activity.
Conclusion
Understanding CAA-TFNEs is pivotal because they carry a very high risk of subsequent lobar intracerebral hemorrhage but are frequently misdiagnosed as TIAs and treated with antithrombotics enhancing the bleeding risk associated with CAA.
Background
Epilepsy and hypertension are common chronic conditions, both showing high prevalence in older age groups. This review outlines current experimental and clinical evidence on both direct ...and indirect role of hypertension in epileptogenesis and discusses the principles of drug treatment in patients with hypertension and epilepsy.
Methods
We selected English-written articles on epilepsy, hypertension, stroke, and cerebrovascular disease until December, 2018.
Results
Renin-angiotensin system might play a central role in the direct interaction between hypertension and epilepsy, but other mechanisms may be contemplated. Large-artery stroke, small vessel disease and posterior reversible leukoencephalopathy syndrome are hypertension-related brain lesions able to determine epilepsy by indirect mechanisms. The role of hypertension as an independent risk factor for post-stroke epilepsy has not been demonstrated. The role of hypertension-related small vessel disease in adult-onset epilepsy has been demonstrated. Posterior reversible encephalopathy syndrome is an acute condition, often caused by a hypertensive crisis, associated with the occurrence of acute symptomatic seizures. Chronic antiepileptic treatment should consider the risk of drug-drug interactions with antihypertensives.
Conclusions
Current evidence from preclinical and clinical studies supports the vision that hypertension may be a cause of seizures and epilepsy through direct or indirect mechanisms. In both post-stroke epilepsy and small vessel disease-associated epilepsy, chronic antiepileptic treatment is recommended. In posterior reversible encephalopathy syndrome blood pressure must be rapidly lowered and prompt antiepileptic treatment should be initiated.
A nationwide survey has been undertaken to evaluate the resources and the activities of Italian hospital neurology units (NU) in the emergency setting. NU are widely disseminated throughout the ...entire country and 220 (84%) are located in hospitals with an emergency room (ER). Complete data about hospital setting, structural and functional characteristics of each NU and clinical activities were obtained from 159 (72.3%). Each NU has, on average, 25 beds (7% bedside monitoring), 7 neurologists and 17 nurses. A neuroscience department is present in 25% of the hospitals. The ER is the source of 71% of the 148,040 annual admissions and of 57% of the 577,279 annual neurological consultations. Stroke is the most common cause of admission (29%), followed by epilepsy/headache and transient ischaemic attacks. Head trauma prevails in hospitals with no neurosurgical units. Cerebrovascular disorders are the main cause of neurological consultations (28%), followed by headache (22%), dizziness (13%), head trauma (13%), impairment of consciousness (12%) and epilepsy (9%). Only 36% of NU have a 24-h/day, 7 days/week on-duty neurologist and 28% have a stroke unit. The burden of neurological activities is unrelated to the geographical area and hospital’s complexity (size, structural and functional context, ER organisation, presence of stroke units, neurosurgery units or 24/7 neurological service).
Summary
Objective
Seizures may occur in close temporal association with a stroke or after a variable interval. Moreover, epilepsy is often encountered in patients with leukoaraiosis. Although early ...post‐stroke seizures have been studied extensively, less attention has been paid to post‐stroke epilepsy (PSE) and to epilepsy associated with leukoaraiosis (EAL). The aim of this paper is to review data concerning pathophysiology, prognosis, and treatment of PSE and EAL.
Methods
We performed an extensive literature search to identify experimental and clinical articles on PSE and EAL. We also conducted a systematic review of risk factors for PSE and EAL among eligible studies.
Results
PSE is caused by enhanced neuronal excitability within and near the scar. The role played by white matter changes in EAL remains to be elucidated. Meta‐analysis showed that cortical involvement (odds ratio OR 3.71, 95% confidence interval CI 2.34–5.90, p < 0.001), cerebral hemorrhage (OR 2.41, 95% CI 1.57–3.70, p < 0.001), and early seizures (OR 4.43, 95% CI 2.36–8.32, p < 0.001) are associated with an increased risk of PSE. As regards EAL, no prospective, population‐based studies evaluated the role of different variables on seizure risk. Studies about the management of PSE are limited. PSE is generally well controlled by drugs. Data about risk factors, prognosis, and treatment of EAL are lacking.
Significance
Pathophysiology and risk factors are well defined for PSE but need to be elucidated for EAL. Management of PSE and EAL relies on the clinician's judgment and should be tailored on an individual basis.
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