Current approach to cerebral palsy.

This teaching review aims to provide an overview of the current approach to children with cerebral palsy (CP), retrieving the best available evidence and summarizing existing knowledge in the field of CP in children. We also highlight areas where more research is needed and novel strategies for diagnosing and treating cerebral palsy. CP includes a group of permanent disorders of movement and posture that cause activity limitation. Multiple risk factors, occurring preconceptionally, prenatally, perinatally, or postneonatally, are involved in the pathogenesis of CP, with the prenatal ones accounting for 80-90 % of cases. Due to its heterogeneity, CP has various classifications, but usually is classified based on clinical findings and motor impairment. Standardized function classification systems have been developed to address inconsistencies in previous classifications. The combination of clinical assessment and validated predictive tools is recommended for an early diagnosis, which is important for early intervention and prevention of secondary impairments. The therapeutic regimen in CP involves prevention and management of the motor and associated problems. It includes the enhancement of motor performance, the enrichment of cognition and communication skills, the prevention of secondary impairments, and the support of parents and caregivers. The care of CP children demands a multidisciplinary approach focused on improving motor skills, reducing comorbidities, enhancing the quality of life, and prolonging survival.

Neuropsychiatric manifestations associated with Juvenile Systemic Lupus Erythematosus: An overview focusing on early diagnosis.

Juvenile systemic lupus erythematosus (jSLE) is a chronic multisystem inflammatory disease that manifests before the age of 16 years, following a remitting - relapsing course. The clinical presentation in children is multifaceted, most commonly including constitutional, hematological, cutaneous, renal, and neuropsychiatric symptoms. Neuropsychiatric manifestations range widely, affecting approximately 14-95 % of jSLE patients. They are associated with high morbidity and mortality, particularly at a younger age. Headaches, seizures, cognitive dysfunction, and mood disorders are the most frequent neuropsychiatric manifestations. The pathophysiological mechanism is quite complex and has not yet been fully investigated, with autoantibodies being the focus of research. The diagnosis of neuropsychiatric jSLE remains challenging and exclusionary. In this article we review the clinical neuropsychiatric manifestations associated with jSLE with the aim that early diagnosis and prompt treatment is achieved in children and adolescents with the disease.

Is the prevalence of thyroid disease higher in children receiving antiepileptic medication? A systematic review and meta-analysis.

PURPOSE: Antiseizure medications (ASM) have long been examined for their potential to induce thyroid dysfunction. The aim of this systematic review and meta-analysis was to assess the prevalence of thyroid disease in children up to 16 years receiving monotherapy with valproate (VPA), carbamazepine (CBZ) and levetiracetam (LEV). METHODS: PubMed/MEDLINE, Cochrane/CENTRAL databases and the gray literature were searched to identify observational studies providing the prevalence of thyroid dysfunction in the target population under VPA, CBZ, or LEV monotherapy schemes. The results were pooled using a random-effects model, and additional subgroup analyses were performed for the three ASM groups. RESULTS: Fifteen and thirteen studies met inclusion criteria for the qualitative and the quantitative analysis, respectively, with a total of 945 pediatric patients with prevalence data. Only VPA and CBZ were associated with thyroid dysfunction. The overall prevalence of thyroid abnormality was higher in children receiving ASM [odds ratio (OR) 6.82, 95% confidence interval (CI) 3.96-11.75]. In the subgroup analysis, the prevalence of biochemical thyroid abnormality with increased TSH was higher in the VPA (OR 9.54, 95%CI 5.25-17.34) and the CBZ group (OR 4.08, 95%CI 1.84-9.04) compared with controls. CONCLUSION: This study confirms the higher prevalence of biochemical thyroid abnormality in children under VPA and CBZ monotherapy, whereas no such evidence is present for LEV. In children with a predisposition for thyroid disease, LEV should be considered over VPA and CBZ, if appropriate for seizure type and epilepsy syndrome. More studies are needed to reach a consensus on monitoring and management of thyroid dysfunction in children receiving ASM therapy.

The Complex Interplay of Cortex, Cerebellum, and Age in a Cohort of Pediatric Patients With Tuberous Sclerosis Complex.

BACKGROUND: The neurodevelopmental impairment in tuberous sclerosis complex (TSC) has a multifactorial origin. Various factors have been proposed as predictors of neurological outcome such as tuber load, seizure onset, and TSC2 mutation. Cerebellar lesions have been associated with worse neuroradiological phenotype, but their contribution is not well understood. METHODS: A partly retrospective and partly prospective pediatric cohort study was conducted at three hospitals in Greece between 2015 and 2020. Patients aged ≤ 18 years with a confirmed TSC daignosis were included and underwent brain imaging, a semistructured interview (authorized Greek version of the tuberous sclerosis-associated neuropsychiatric disorders, or TAND, checklist), and intellectual ability assessment. RESULTS: The study populations consisted of 45 patients with TSC (22 females, 23 males; mean age 9.53 years). Twenty patients (44.4%) had cerebellar lesions. Cerebellar involvement was the most powerful predictor of tuber load (P = 0.03). Cerebellar lesions were associated with giant cell astrocytomas (SEGAs) (P = 0.01) and severe neurological outcome (P = 0.01). Even though in the univariate analysis early seizure onset, tuber load, and cerebellar involvement were associated with intellectual impairment and neurological severity, none of them was an independent predictor of cognitive outcome and neurological severity. CONCLUSIONS: Cerebellar lesions are common among individuals with TSC. Cerebellar involvement correlates with supratentorial derangement and the development of SEGAs, which is suggestive of a more severe clinical and neuroradiological phenotype. Cerebellar involvement and early seizure onset were not independent predictors of either neurological severity or intellectual disability or neurobehavioral outcome; their role in TSC clinical phenotype should be further investigated.

Hemimegalencephaly and tuberous sclerosis complex: A rare yet challenging association.

Hemimegalencephaly is a rare malformation of cortical development characterised by enlargement of one cerebral hemisphere. The association between hemimegalencephaly and tuberous sclerosis complex, an autosomal dominant genetic disorder, is uncommon and has so far been reported only in a few cases. Intractable epilepsy and severe developmental delay are typical clinical manifestations. Aberrant activation of the mTOR signalling pathway is considered to be the hallmark of the pathogenesis of these two disorders. Thus, mTOR inhibitors such as everolimus represent a promising therapeutic approach to mTOR-associated manifestations. We present a thorough literature review of the association between hemimegaloencephaly and tuberous sclerosis complex.

Mild myopathic phenotype in a patient with homozygous c.416C > T mutation in TK2 gene.

The mitochondrial DNA depletion syndrome (MDDS) is characterized by extensive phenotypic variability and is due to nuclear gene mutations resulting in reduced mtDNA copy number. Thymidine kinase 2 (TK2) mutations are well known to be associated with MDDS. Few severely affected cases carrying the c.416C > T mutation in TK2 gene have been described so far. We describe the case of a 14months boy with the aforementioned TK2 gene pathogenic mutation at a homozygous state, presenting with a mild clinical phenotype. In addition to severe mitochondrial pathology on muscle biopsy, there was also histochemical evidence of adenylate deaminase deficiency. Overall, this report serves to further expand the clinical spectrum of TK2 mutations associated with MDDS.

Diagnosis of tuberous sclerosis complex in the fetus.

Tuberous sclerosis complex is a dominantly inherited genetic disorder of striking clinical variability. It is caused by mutations in either TSC1 or TSC2 gene, which regulate cell growth and proliferation by inhibition of mTORC1 signaling. TS is characterized by the development of benign tumors in many tissues and organs and its neurological manifestations include epilepsy, autism, cognitive and behavioral dysfunction, and giant cell tumors. With mechanism-based mTOR inhibitors therapy now available for many of its manifestations, early diagnosis of TSC is very important in order to offer appropriate care, long-term surveillance and parental counseling. Fetal ultrasound and MRI imaging techniques have evolved and may capture even earlier the following TSC-associated lesions: cardiac rhabdomyomas, subependymal nodules, cortical tubers and renal cysts. Often these represent an incidental finding during a routine ultrasound. Furthermore, in the past decades prenatal molecular diagnosis of TSC has emerged as an important option for families with a known affected member; however, the existing evidence with regards to the clinical characteristics and long-term outcome of babies diagnosed prenatally with TSC is yet limited and the path that follows early TSC detection merits further research.

Crossing the lines between epilepsy syndromes: a myoclonic epilepsy variant with prominent eyelid myoclonia and atonic components.

Accurate diagnosis of a distinct epilepsy syndrome is based on well-defined electroclinical features that differentiate separate nosological entities. In clinical practice, however, syndromes may overlap and cases may present with unusual manifestations posing a diagnostic challenge. This heterogeneity has been documented in several cases presenting with eyelid myoclonia with or without absences (EMA) diagnosed either as Jeavons syndrome (JS) variants or as genetic generalised epilepsies defined by the presence of this unique clinical entity. The hallmark of JS is the triad: (1) eyelid myoclonia with or without absences, (2) eye closure-induced paroxysms, and (3) photosensitivity. The presence of massive myoclonus, intellectual disability, or slowing of the EEG background are not typical features of the syndrome and may cause delay in making the correct diagnosis. Adding to the variability of clinical features, we describe two female paediatric patients with probable genetic epilepsy who presented with EMA but demonstrated clear atypical features, such as prominent myoclonic seizures, atonic components on video-EEG, and cognitive impairment. We also note the presence of interictal and ictal posterior discharges during eyelid myoclonia in one, supporting similar previous observations leading to consideration of EMA as an occipital cortex-initiated seizure activity. [Published with video sequences on www.epilepticdisorders.com].

Epilepsy with myoclonic-atonic seizures (Doose syndrome): When video-EEG polygraphy holds the key to syndrome diagnosis.

An electroclinical epilepsy syndrome diagnosis enables physicians to predict outcomes as well as select appropriate treatment options. We report a child who presented with reflex myoclonus at the age of 9 months and was initially diagnosed with myoclonic epilepsy in infancy. After 9 years of medically resistant myoclonic seizures, extensive investigations, and emerging learning difficulties, she was referred for video-telemetry to characterize her seizures in an attempt to make a syndromic diagnosis. A three-day video-telemetry assessment was performed to document seizures. Neck and deltoid EMG channels were applied from the onset of the recording. Frequent generalized bursts of 3- to 5-Hz spike/polyspike and slow wave discharges, associated with clinical manifestations, mostly myoclonic seizures, were noted. In addition, definite atonic components were noted on the neck EMG as well as the deltoids associated with the slow component of the ictal discharges. The EEG and polygraphy findings are suggestive of a generalized epilepsy characterized by predominantly myoclonic seizures with atonic components. This raises the possibility whether a variant of epilepsy with myoclonic-atonic seizures (Doose syndrome) may be the underlying diagnosis for this girl. A trial of the ketogenic diet would therefore be considered as an option in her future management in view of its beneficial effect in this condition.

Clinical course and seizure outcome of idiopathic childhood epilepsy: determinants of early and long-term prognosis.

BACKGROUND: Idiopathic epilepsies and epileptic syndromes predominate childhood and adolescence epilepsy. The aim of the present study was to investigate the clinical course and outcome of idiopathic childhood epilepsy and identify variables determining both early and long-term prognosis. METHODS: We followed 303 children with newly diagnosed idiopathic epilepsy aged 1-14 years old, both prospectively and retrospectively. Outcome was defined at one, 2 and 4 years of follow-up, as well as at the end of the study period for all patients. Based on the data collected, patients were classified in four patterns of clinical course: "excellent", "improving", "relapsing" and "poor". Variables defined at intake and after the initial year of treatment were analyzed for their prognostic relevance towards the clinical course and outcome of the patients. RESULTS: The mean age at seizure onset was 6.7 years and the mean duration of follow-up was 8.3 years (range 2,0-22,0,SD 4,24). During the initial year of treatment, 70,3% of patients were seizure-free. The course of epilepsy was "excellent" in 53,1% of the subjects, "improving" in 22,8%, "relapsing" in 22,1% whereas only 6 children with idiopathic epilepsy (2%) had a "poor" clinical course exhibiting drug-resistance. After multivariate analysis, variables predictive of a poor initial response to therapy were early seizure onset, multiple seizure types and history of status epilepticus. At the end of follow-up, early response to treatment was of significant positive predictive value, while the presence of multiple seizure types and the history of migraine had a negative impact on prognosis. CONCLUSIONS: In the vast majority of children, the long-term prognosis of idiopathic epilepsy is favorable. More than half of the patients attain seizure freedom immediately and their clinical course is considered "excellent". About one fifth exhibit either an improving or a fluctuating course. Early seizure onset, multiple seizure types and status epilepticus are predictive of an initial poor response to treatment in children with idiopathic epilepsy. Initial non-response to treatment, multiple seizure types and history of migraine are determinants of a less favorable final outcome after long-term follow-up.