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1.
Neuropediatrics ; 54(6): 422-425, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36577449

RESUMEN

To describe a new phenotype and the diagnostic workup of a vitamin-B6-dependent epilepsy due to pyridoxal 5'-phosphate-binding protein (PLPBP) deficiency in an infant with early-onset epilepsy at the age of 5 years 6 months. Following immediate and impressive clinical response to treatment with pyridoxine, metabolic screening for vitamin-B6-dependent epilepsies and targeted next-generation sequencing (NGS)-based gene panel analysis were performed. Potentially pathogenic variants were confirmed by Sanger sequencing in the patient, and variants were analyzed in both parents to confirm biallelic inheritance. The clinical phenotype and course of disease were compared to the 44 cases reported in the literature, harboring variants in pyridoxal phosphate homeostasis protein (PLPHP) and with cases of vitamin-B6-dependent epilepsy due to other known causative genes. Levels of alpha-aminoadipic semialdehyde in urine and amino acids were normal. Two inherited pathogenic variations in PLPHP were found in compound heterozygosity, including one novel deletion. We here describe a previously unreported individual harboring biallelic pathogenic PLPHP variants presenting with paroxysmal eye-head movements followed by epileptic spasms and an almost normal interictal electroencephalogram, thus expanding the clinical spectrum of PLPBP deficiency. This warrants consideration of vitamin-B6-dependent epilepsies in patients with early-onset epilepsy, including epileptic spasms, and eye movement disorders also beyond the neonatal period even when metabolic screening for vitamin-B6-dependent epilepsies is negative. PLPHP should be included systematically in NGS epilepsy gene panels.


Asunto(s)
Epilepsia , Espasmos Infantiles , Recién Nacido , Humanos , Lactante , Preescolar , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/genética , Movimientos de la Cabeza , Epilepsia/diagnóstico , Epilepsia/tratamiento farmacológico , Epilepsia/etiología , Vitamina B 6/uso terapéutico , Piridoxina/uso terapéutico , Espasmo/complicaciones , Espasmo/tratamiento farmacológico , Vitaminas/uso terapéutico
3.
Epilepsy Res ; 177: 106771, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34562678

RESUMEN

OBJECTIVE: Epilepsy with myoclonic atonic seizure (EMAS) occurs in young children with previously normal to subnormal development. The outcome ranges from seizure freedom with preserved cognitive abilities to refractory epilepsy with intellectual disability (ID). Routine brain imaging typically shows no abnormalities. We aimed to compare the brain morphometry of EMAS patients with healthy subjects several years after epilepsy onset, and to correlate it to epilepsy severity and cognitive findings. METHODS: Fourteen EMAS patients (4 females, 5-14 years) and 14 matched healthy controls were included. Patients were classified into three outcome groups (good, intermediate, poor) according to seizure control and cognitive and behavioral functioning. Individual anatomical data (T1-weighted sequence) were processed using the FreeSurfer pipeline. Cortical volume (CV), cortical thickness (CT), local gyrification index (LGI), and subcortical volumes were used for group-comparison and linear regression analyses. RESULTS: Morphometric comparison between EMAS patients and healthy controls revealed that patients have 1) reduced CV in frontal, temporal and parietal lobes (p = <.001; 0.009 and 0.024 respectively); 2) reduced CT and LGI in frontal lobes (p = 0.036 and 0.032 respectively); and 3) a neat cerebellar volume reduction (p = 0.011). Neither the number of anti-seizure medication nor the duration of epilepsy was related to cerebellar volume (both p > 0.62). Poor outcome group was associated with lower LGI. Patients in good and intermediate outcome groups had a comparable LGI to their matched healthy controls (p > 0.27 for all lobes). CONCLUSIONS: Structural brain differences were detectable in our sample of children with EMAS, mainly located in the frontal lobes and cerebellum. These findings are similar to those found in patients with genetic/idiopathic generalized epilepsies. Outcome groups correlated best with LGI. Whether these anatomical changes reflect genetically determined abnormal neuronal networks or a consequence of sustained epilepsy remains to be solved with prospective longitudinal studies.


Asunto(s)
Electroencefalografía , Epilepsia , Encéfalo/diagnóstico por imagen , Niño , Preescolar , Epilepsia/complicaciones , Femenino , Humanos , Imagen por Resonancia Magnética , Estudios Prospectivos , Convulsiones/complicaciones , Convulsiones/diagnóstico por imagen
4.
Genet Med ; 23(10): 1922-1932, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34163037

RESUMEN

PURPOSE: CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype. METHODS: We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations. RESULTS: Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism. CONCLUSION: We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.


Asunto(s)
Trastorno Autístico , Canales de Calcio Tipo L , Síndrome de QT Prolongado , Sindactilia , Trastorno Autístico/genética , Canales de Calcio Tipo L/genética , Humanos , Fenotipo
5.
Handb Clin Neurol ; 174: 205-215, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32977878

RESUMEN

Despite rapidly evolving technologies, an accurate and thorough clinical neurologic assessment is still crucial to understanding presenting symptoms and signs. It is the most exciting but also challenging part of the diagnostic puzzle, essential to establishing a rational working hypothesis and a consistent management plan. Flexibility, creativity, and social skills are needed to elicit the child's participation. History taking is of the utmost importance, requiring not only time and perseverance, but also knowledge and effective communication to obtain relevant and precise information. Understanding what is being tested and distinguishing the normal from the abnormal are indispensable in reaching a correct clinical interpretation. The clinician needs to tailor an individualized approach for each patient according to the chief complaint, clinical context, and the child's chronologic and developmental age. The questions about the nature, localization, and etiology must be addressed first and then summarized and developed into a reasonable diagnostic hypothesis and differential diagnosis. This chapter aims to guide the reader through a situation-related approach from history taking and neurologic examination to a systematic, step-by-step interpretation of the information and findings. It also provides some practical advice on how to avoid common pitfalls.


Asunto(s)
Examen Neurológico , Niño , Humanos
6.
Neurosurg Focus ; 48(4): E10, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-32234977

RESUMEN

OBJECTIVE: Surgery for frontal lobe epilepsy remains a challenge because of the variable seizure outcomes after surgery. Disconnective procedures are increasingly applied to isolate the epileptogenic focus and avoid complications related to extensive brain resection. Previously, the authors described the anterior quadrant disconnection procedure to treat large frontal lobe lesions extending up to but not involving the primary motor cortex. In this article, they describe a surgical technique for unilateral disconnection of the prefrontal cortex, while providing an accurate description of the surgical and functional anatomy of this disconnective procedure. METHODS: The authors report the surgical treatment of a 5-month-old boy who presented with refractory epilepsy due to extensive cortical dysplasia of the left prefrontal lobe. In addition, with the aim of both describing the subcortical intrinsic anatomy and illustrating the different connections between the prefrontal lobe and the rest of the brain, the authors dissected six human cadaveric brain hemispheres. These dissections were performed from lateral to medial and from medial to lateral to reveal the various tracts sectioned during the three different steps in the surgery, namely the intrafrontal disconnection, anterior callosotomy, and frontobasal disconnection. RESULTS: The first step of the dissection involves cutting the U-fibers. During the anterior intrafrontal disconnection, the superior longitudinal fasciculus in the depth of the middle frontal gyrus, the uncinate fasciculus, and the inferior frontooccipital fasciculus in the depth of the inferior frontal gyrus at the level of the anterior insular point are visualized and sectioned, followed by sectioning of the anterior limb of the internal capsule. Once the frontal horn is reached, the anterior callosotomy can be performed to disconnect the genu and the rostrum of the corpus callosum. The intrafrontal disconnection is deepened toward the falx, and at the medial surface, the cingulum is sectioned. The frontobasal disconnection involves cutting the anterior limb of the anterior commissure. CONCLUSIONS: This technique allows selective isolation of the epileptogenic focus located in the prefrontal lobe to avoid secondary propagation. Understanding the surface and white matter fiber anatomy is essential to safely perform the procedure and obtain a favorable seizure outcome.


Asunto(s)
Cuerpo Calloso/cirugía , Epilepsia/cirugía , Corteza Prefrontal/cirugía , Epilepsia/diagnóstico , Lóbulo Frontal/cirugía , Humanos , Lactante , Masculino , Vías Nerviosas/cirugía , Psicocirugía/efectos adversos , Sustancia Blanca/patología , Sustancia Blanca/cirugía
7.
JAMA Neurol ; 75(4): 478-487, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-29305608

RESUMEN

Importance: Myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) are consistently identified in a range of demyelinating disorders in adults and children. Current therapeutic strategies are largely center specific, and no treatments have been formally evaluated. Objective: To examine the clinical phenotypes, treatment responses, and outcomes of children with relapsing MOG-Ab-associated disease. Design, Setting, and Participants: This study prospectively collected demographic, clinical, and radiologic data from 102 patients from 8 countries of the EU Paediatric Demyelinating Disease Consortium from January 1, 2014, through December 31, 2016. Patients were treated according to local protocols. Main Outcomes and Measures: Annualized relapse rates (ARRs) and Expanded Disability Status Scale (EDSS) scores before and during treatment with disease-modifying drugs (DMDs). Results: A total of 102 children were identified (median [range] age, 7.0 [1.5-7.9] years; male to female ratio, 1.0:1.8; white to other race/ethnicity ratio, 3.6:1.0). Original diagnoses were neuromyelitis optica spectrum disorder (44 patients [43.1%]), acute disseminated encephalomyelitis followed by optic neuritis (20 [19.6%]), multiphasic disseminated encephalomyelitis (20 [19.6%]), and relapsing optic neuritis (18 [17.6%]). In all, 464 demyelinating events were reported. Treated patients had more relapses (median, 3.0; range, 1.0-17.0) than untreated patients (median, 1.0; range 1.0-7.0) (P = .009) and higher EDSS scores (median, 1.5; interquartile range, 0-2.5) than untreated patients (median, 1.0; interquartile range, 0-1.5) (P < .001). Fifty-two children (51.0%) received DMDs: 28 (53.8%) were treated with 1 DMD, 17 (32.7%) with 2, and 7 (13.5%) with 3 or more sequential DMDs. Patients relapsed during all treatments, with a total of 127 relapses on treatment reported. No changes in median ARR and EDSS score were observed between the preinitiation and postinitiation phases of interferon beta and glatiramer acetate treatment (n = 11). The median ARR was reduced from 1.84 to 1.0 with azathioprine (n = 20, P < .001), 1.79 to 0.52 with mycophenolate mofetil (n = 15, P = .003), and 2.12 to 0.67 with rituximab (n = 9, P < .001), although the median EDSS score remained unchanged. An improvement in ARR (from 2.16 to 0.51, P < .001) and EDSS score (from 2.2 to 1.2, P = .01) was observed in the 12 patients treated with regular intravenous immunoglobulins. Conclusions and Relevance: Although commonly used to treat patients with multiple sclerosis, DMDs were not associated with clinical improvement in children with MOG-Ab-associated disease, whereas azathioprine, mycophenolate mofetil, rituximab, and particularly intravenous immunoglobulins were associated with a reduction in relapse frequency. A correct diagnosis of relapsing MOG-Ab-associated disorders is therefore important to optimize immune treatment.


Asunto(s)
Autoanticuerpos/sangre , Factores Inmunológicos/uso terapéutico , Glicoproteína Mielina-Oligodendrócito/inmunología , Neuromielitis Óptica , Resultado del Tratamiento , Estudios de Cohortes , Evaluación de la Discapacidad , Europa (Continente) , Femenino , Humanos , Cooperación Internacional , Masculino , Mercaptopurina/análogos & derivados , Mercaptopurina/uso terapéutico , Ácido Micofenólico/uso terapéutico , Neuromielitis Óptica/sangre , Neuromielitis Óptica/tratamiento farmacológico , Neuromielitis Óptica/inmunología , Recurrencia , Rituximab/uso terapéutico
8.
Curr Opin Neurol ; 31(2): 216-222, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29356691

RESUMEN

PURPOSE OF REVIEW: We aim to further disentangle the jungle of terminology of epileptic encephalopathy and provide some insights into the current understanding about the aetiology and pathophysiology of this process. We cover also the key features of epilepsy syndromes of infancy and childhood which are considered at high risk of developing an epileptic encephalopathy. RECENT FINDINGS: The concept of 'epileptic encephalopathy' has progressively been elaborated by the International League Against Epilepsy according to growing clinical and laboratory evidence. It defines a process of neurological impairment caused by the epileptic activity itself and, therefore, potentially reversible with successful treatment, although to a variable extent. Epileptic activity interfering with neurogenesis, synaptogenesis, and normal network organization as well as triggering neuroinflammation are among the possible pathophysiological mechanisms leading to the neurological compromise. This differs from the newly introduced concept of 'developmental encephalopathy' which applies to where the epilepsy and developmental delay are both because of the underlying aetiology and aggressive antiepileptic treatment may not be helpful. SUMMARY: The understanding and use of correct terminology is crucial in clinical practice enabling appropriate expectations of antiepileptic treatment. Further research is needed to elucidate underlying pathophysiological mechanisms, define clear outcome predictors, and find new treatment targets.


Asunto(s)
Encefalopatías/clasificación , Discapacidades del Desarrollo/clasificación , Epilepsia/clasificación , Terminología como Asunto , Anticonvulsivantes/uso terapéutico , Encefalopatías/complicaciones , Encefalopatías/tratamiento farmacológico , Encefalopatías/fisiopatología , Niño , Preescolar , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/fisiopatología , Epilepsia/complicaciones , Epilepsia/tratamiento farmacológico , Epilepsia/fisiopatología , Humanos , Lactante
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