Efficacy and safety of corticosteroids and ACTH in epileptic syndromes beyond Infantile Epileptic Spasms Syndrome (IESS): A systematic review and meta-analysis.

We conducted a systematic review investigating the efficacy and tolerability of adrenocorticotropic hormone (ACTH) and corticosteroids in children with epilepsies other than infantile epileptic spasm syndrome (IESS) that are resistant to anti-seizure medication (ASM). We included retrospective and prospective studies reporting on more than five patients and with clear case definitions and descriptions of treatment and outcome measures. We searched multiple databases and registries, and we assessed the risk of bias in the selected studies using a questionnaire based on published templates. Results were summarized with meta-analyses that pooled logit-transformed proportions or rates. Subgroup analyses and univariable and multivariable meta-regressions were performed to examine the influence of covariates. We included 38 studies (2 controlled and 5 uncontrolled prospective; 31 retrospective) involving 1152 patients. Meta-analysis of aggregate data for the primary outcomes of seizure response and reduction of electroencephalography (EEG) spikes at the end of treatment yielded pooled proportions (PPs) of 0.60 (95% confidence interval [CI] 0.52-0.67) and 0.56 (95% CI 0.43-0.68). The relapse rate was high (PP 0.33, 95% CI 0.27-0.40). Group analyses and meta-regression showed a small benefit of ACTH and no difference between all other corticosteroids, a slightly better effect in electric status epilepticus in slow sleep (ESES) and a weaker effect in patients with cognitive impairment and "symptomatic" etiology. Obesity and Cushing's syndrome were the most common adverse effects, occurring more frequently in trials addressing continuous ACTH (PP 0.73, 95% CI 0.48-0.89) or corticosteroids (PP 0.72, 95% CI 0.54-0.85) than intermittent intravenous or oral corticosteroid administration (PP 0.05, 95% CI 0.02-0.10). The validity of these results is limited by the high risk of bias in most included studies and large heterogeneity among study results. This report was registered under International Prospective Register of Systematic Reviews (PROSPERO) number CRD42022313846. We received no financial support.

Autoimmune Encephalitis with Autoantibodies to NMDAR1 following Herpes Encephalitis in Children and Adolescents.

Herpes simplex virus (HSV) type 1 is a frequent pathogen causing infectious encephalitis (HSVE). Early treatment with intravenous acyclovir has led to a significant decrease in mortality. However, especially in children, deterioration during or after HSVE may occur without any evidence of HSV reactivation or improvement following repeated antiviral therapy. Here, we report 15 patients (age range 3 months to 15 years) who suffered from autoimmune encephalitis with autoantibodies to NMDAR1 following Herpes encephalitis, presenting with movement abnormalities (young children) or neuropsychiatric symptoms (older children) as major complaints, respectively. The diagnosis was based on positive cerebrospinal fluid (CSF) and/or serum anti-NMDAR-antibodies with two children showing only positive CSF antibody findings. The time lag between first symptoms and diagnosis of autoimmune encephalitis was significantly longer than between first symptoms and diagnosis of HSVE (p <0.01). All patients improved during immunosuppressive treatment, during which plasmapheresis or rituximab treatments were applied in 11 patients, irrespective of their age. Despite immunotherapy, no patients relapsed with HSVE. Early diagnosis and treatment of autoimmune encephalitis after HSVE may be associated with a better outcome so that high clinical awareness and routine testing for anti-NMDAR-antibodies after HSVE seems advisable. If autoimmune encephalitis is suspected, antibody testing should also be performed on CSF if negative in serum.

Treatment of Infantile Spasm Syndrome: Update from the Interdisciplinary Guideline Committee Coordinated by the German-Speaking Society of Neuropediatrics.

OBJECTIVES: The manuscript serves as an update on the current management practices for infantile spasm syndrome (ISS). It includes a detailed summary of the level of current evidence of different treatment options for ISS and gives recommendations for the treatment and care of patients with ISS. METHODS: A literature search was performed using the Cochrane and Medline Databases (2014 to July 2020). All studies were objectively rated using the Scottish Intercollegiate Guidelines Network. For recommendations, the evidence from these studies was combined with the evidence from studies used in the 2014 guideline. RECOMMENDATIONS: If ISS is suspected, electroencephalography (EEG) should be performed within a few days and, if confirmed, treatment should be initiated immediately. Response to first-line treatment should be evaluated clinically and electroencephalographically after 14 days. The preferred first-line treatment for ISS consists of either hormone-based monotherapy (AdrenoCorticoTropic Hormone [ACTH] or prednisolone) or a combination of hormone and vigabatrin. Children with tuberous sclerosis complex and those with contraindications against hormone treatment should be treated with vigabatrin. If first-line drugs are ineffective, second-line treatment options such as ketogenic dietary therapies, sulthiame, topiramate, valproate, zonisamide, or benzodiazepines should be considered. Children refractory to drug therapy should be evaluated early for epilepsy surgery, especially if focal brain lesions are present. Parents should be informed about the disease, the efficacy and adverse effects of the medication, and support options for the family. Regular follow-up controls are recommended.

Severe Locked-In-Like Guillain-Barré's Syndrome: Dilemmas in Diagnosis and Treatment.

Guillain-Barré's syndrome in childhood can follow an atypical course, increasing the challenges in diagnosis and decisions regarding immunomodulatory treatment. Here, we report the case of on a 13-year-old boy with acute onset Guillain-Barré's syndrome progressing over 40 days to a very severe, locked-in-like syndrome despite intensive immunomodulatory treatment. After a plateau phase lasting 3 months and characterized by fluctuating signs of ongoing inflammatory disease activity, we were prompted to perform repeated and maintenance immunomodulatory treatment, which resulted in a continuous and nearly complete recovery of function. Atypical features at disease onset, the severe "total" loss of all peripheral and cranial nerve function, and an apparent late response to treatment give rise to reviewing the dilemmas of diagnosis and treatment in such severe and protracted courses of Guillain-Barré syndrome.

Thiamine Treatment and Favorable Outcome in an Infant with Biallelic TPK1 Variants.

Episodic encephalopathy due to mutations in the thiamine pyrophosphokinase 1 (TPK1) gene is a rare autosomal recessive metabolic disorder. Patients reported so far have onset in early childhood of acute encephalopathic episodes, which result in a progressive neurologic dysfunction including ataxia, dystonia, and spasticity. Here, we report the case of an infant with TPK1 deficiency (compound heterozygosity for two previously described pathogenic variants) presenting with two encephalopathic episodes and clinical stabilization under oral thiamine and biotin supplementation. In contrast to other reported cases, our patient showed an almost normal psychomotor development, which might be due to an early diagnosis and subsequent therapy.

The Brighton Collaboration case definition: Comparison in a retrospective and prospective cohort of children with Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is an immune-mediated polyradiculoneuropathy frequently preceded by an infection with Campylobacter jejuni or nonspecific infections, and rarely by a vaccination. Due to a lack of a pathognomonic finding or biomarker, its diagnosis is based on a typical constellation of clinical and paraclinical symptoms and findings. The Brighton Collaboration GBS Working Group published in 2011 GBS case definitions and guidelines for diagnosis to improve the registration of GBS cases occurring in conjunction with vaccination programs worldwide. We applied these criteria to two historical studies on GBS in children and adolescents performed retrospectively from 1989 to 1994 and prospectively from 1998 to 2002. The clinical criteria were met in 91% of the retrospective and all of the prospective cases. CSF investigations were conducted in all patients and revealed cytoalbuminologic dissociation in 80% of the retrospective and 75% of the prospective cohort. Nerve conduction studies were performed in 61% and 69% of the cohorts, respectively, and were pathological in 92% each. The Brighton criteria are well suited to capture GBS in retro- and prospective studies. However, because they are designed to diagnose classical symmetric and ascending GBS and Fisher syndrome, very rare topographical variants of GBS such as the pharyngo-cervico-brachial variant and others could be missed.

A new era in the management of Duchenne muscular dystrophy.

The management of Duchenne muscular dystrophy (DMD) has changed considerably over the last few decades. Standards of care have recently been updated, based on systematic reviews of the literature and structured, case-based consensus discussions of experts. Besides addressing muscular function, these recommendations cover most areas of organ involvement and psychosocial issues. Studies employing animal models investigating basic disease mechanisms have increased considerably. Development of valid functional outcome measures enabled high-evidence, clinical trials in males with DMD. Stop codon readthrough with ataluren has revealed some effect in patients with moderate disability and has been approved for males with suitable mutations who are still ambulant. Exon 51 skipping with eteplirsen demonstrated a structural and functional effect in a small group of patients and received restricted approval in the USA. Further trials investigating a broad range of mechanisms are underway. However, much more work is needed to develop more active treatments that stop disease progression. Likewise, the distribution of complex and expensive therapies to underprivileged patients and those in poorer regions must be improved. WHAT THIS PAPER ADDS: Updated standards of care covering most clinical aspects of Duchenne muscular dystrophy (DMD) are available. Adequately controlled clinical trials have allowed initial approval of disease-modifying drugs for small groups of patients. Scientific, economic, and political efforts are needed to make effective therapies available more quickly. Effective therapies should be made available more quickly to patients in low-income regions.

Cystic Encephalomalacia following Vasculopathy and Vasospasm of Proximal Intracranial Arteries Due to Pneumococcal Meningitis in a Infant.

Despite the availability of modern antibiotics, pneumococcal meningitis in both children and adults remains a severe disease-one known to frequently cause grave complications and residual disability. Although the appearance of arterial vasospasms in bacterial meningitis systematically has been investigated and reported on for adult patients, such research is lacking when it comes to infants. We report on a 4-week-old infant who, 6 days after onset of pneumococcal meningitis, suffered severe neurological deterioration with treatment-resistant seizures and coma. Generalized cortical and subcortical edema developed in conjunction with diminished cerebral blood flow, as depicted in magnetic resonance angiography and serial Doppler-sonographic examinations. The ischemia resulted in extensive cystic encephalomalacia. We propose that the degree of variation in cerebral blood flow in the acute phase was the result of an extensive arterial vasculopathy involving vasospasms. Awareness of this complication and prospective serial Doppler-sonographic examinations may improve our understanding of the connection between brain edema and vasculopathy. At present, however, no effective treatment appears available.

Posterior cortex epilepsy surgery in childhood and adolescence: Predictors of long-term seizure outcome.

OBJECTIVE: We aimed to investigate the long-term seizure outcome of children and adolescents who were undergoing epilepsy surgery in the parietooccipital cortex and determine their predictive factors. METHODS: We retrospectively analyzed the data of 50 consecutive patients aged 11.1 (mean) ± 5.1 (standard deviation) years at surgery. All patients but one had a magnetic resonance imaging (MRI)-visible lesion. Resections were parietal in 40%, occipital in 32%, and parietooccipital in 28% cases; 24% patients additionally underwent a resection of the posterior border of the temporal lobe. Etiology included focal cortical dysplasia in 44%, benign tumors (dysembryoplastic neuroepithelial tumor, ganglioglioma, angiocentric glioma, and pilocystic astrocytoma) in 32%, peri- or postnatal ischemic lesions in 16%, and tuberous sclerosis in 8% cases. RESULTS: At last follow-up (mean 8 years, range 1.5-18 years), 60% patients remained seizure-free (Engel class I): 30% had discontinued and 20% had reduced antiepileptic drugs. Most seizure recurrences (71%) occurred within the first 6 months, and only three patients presented with seizures ≥2 years after surgery. Independent predictors of seizure recurrence included left-sided as well as parietal epileptogenic zones and resections. Longer epilepsy duration to surgery was identified as the only modifiable independent predictor of seizure recurrence. SIGNIFICANCE: Our study demonstrates that posterior cortex epilepsy surgery is highly effective in terms of lasting seizure control and antiepileptic drug cessation in selected pediatric candidates. Most importantly, our data supports the early consideration of surgical intervention in children and adolescents with refractory posterior cortex epilepsy.

Vitamin B6-Responsive Epilepsy due to a Novel KCNQ2 Mutation.

Mutations in KCNQ2, encoding for subunits of potassium channels, are known to cause neonatal epileptic encephalopathy (NEE). Therapeutic options for these children are often limited. Recently, there are indications that some patients with KCNQ2 NEE show seizure response to vitamin B6 (VB6) therapy. We present a young infant with severe KCNQ2 encephalopathy resulting from a novel de novo mutation (c.1023G>C; p.(Gln341His)). In our patient, VB6 responsiveness could be demonstrated clearly by remarkable seizure-response to VB6 therapy and seizure exacerbation to discontinuation of VB6 therapy. The pathophysiology of VB6 response in potassium channel mutations is not understood. Some hypothetical mechanisms are currently in discussion. To identify the group of patients who benefits from VB6 therapy, further investigations are necessary.

Oligoclonal bands predict multiple sclerosis in children with optic neuritis.

We retrospectively evaluated predictors of conversion to multiple sclerosis (MS) in 357 children with isolated optic neuritis (ON) as a first demyelinating event who had a median follow-up of 4.0 years. Multiple Cox proportional-hazards regressions revealed abnormal cranial magnet resonance imaging (cMRI; hazard ratio [HR] = 5.94, 95% confidence interval [CI] = 3.39-10.39, p < 0.001), presence of cerebrospinal fluid immunoglobulin G oligoclonal bands (OCB; HR = 3.69, 95% CI = 2.32-5.86, p < 0.001), and age (HR = 1.08 per year of age, 95% CI = 1.02-1.13, p = 0.003) as independent predictors of conversion, whereas sex and laterality (unilateral vs bilateral) had no influence. Combined cMRI and OCB positivity indicated a 26.84-fold higher HR for developing MS compared to double negativity (95% CI = 12.26-58.74, p < 0.001). Accordingly, cerebrospinal fluid analysis may supplement cMRI to determine the risk of MS in children with isolated ON.

Treatment of Infantile Spasms: Report of the Interdisciplinary Guideline Committee Coordinated by the German-Speaking Society for Neuropediatrics.

Objectives This report aims to define treatment goals, to summarize the evidence level (EL) of different treatment options for infantile spasms (IS), both in terms of efficacy and adverse effect, and to give recommendations for the management of IS. Methods The Cochrane and Medline (1966-July 2014) databases were searched. Literature known to the guideline working group and identified through citations was also considered. The results of previously published guidelines were taken into account in our analysis. Rating the level of evidence followed the Scottish Intercollegiate Guidelines Network. Recommendations If IS are suspected, electroencephalogram (EEG) should be performed within a few days and, if confirmed, treatment should be initiated immediately. Response to first-line treatments should be evaluated clinically and electroencephalographically after 14 days.Adrenocorticotropic hormone, corticosteroids, and vigabatrin are the first-line drugs for the treatment of IS. In children with tuberous sclerosis complex, vigabatrin is the treatment of first choice. Ketogenic diet, sulthiame, topiramate, valproate, zonisamide, and benzodiazepines can be used when first-line drugs have proved ineffective. Children refractory to drug therapy should be evaluated for epilepsy surgery, especially if focal brain lesions are present.Regular follow-up controls, including EEG (preferably sleep EEG) and standardized developmental assessment are recommended.

Inverted formin 2-related Charcot-Marie-Tooth disease: extension of the mutational spectrum and pathological findings in Schwann cells and axons.

Mutations in the gene encoding inverted formin FH2 and WH2 domain-containing protein (INF2), a Cdc42 effector involved in the regulation of actin dynamics, cause focal segmental glomerulosclerosis (FSGS) and intermediate Charcot-Marie-Tooth neuropathy combined with FSGS (FSGS-CMT). Here, we report on six patients from four families with sensorimotor polyneuropathy and FSGS. Nerve conduction velocities were moderately slowed, and amplitudes of sensory and motor potentials were decreased. One patient had internal hydrocephalus and was intellectually disabled. Molecular genetic testing revealed two known and two novel missense mutations in the second and fourth exons of the INF2 gene. Investigations of one nerve biopsy confirmed the diagnosis of intermediate-type CMT and revealed occasional abnormal in- and outfoldings of myelin sheaths and expansions of the endoplasmic reticulum in axons and Schwann cells. While earlier reports suggested that mutations causing FSGS-CMT are restricted to exons 2 and 3 of the INF2 gene, we found one CMT-FSGS causing mutation (p.Glu184Lys) in exon 4 extending the critical region of INF2 for rapid CMT-FSGS molecular genetic diagnosis. Study of a nerve biopsy showed abnormalities that might be related to the known role of the INF2-binding partner CDC42 in myelination.

Differential Analysis of Bone Density in Children and Adolescents with Neuromuscular Disorders and Cerebral Palsy.

Determinants that affect bone density in disabled children and adolescents with neuromuscular disorders have not been differentially investigated well. We performed dual-energy X-ray absorptiometry of the lumbar spine in three groups (Duchenne muscular dystrophy, n = 16; other neuromuscular diseases, n = 11; and cerebral palsy, n = 18) providing height-age- and sex-adjusted z scores. Mobility was assessed by functional tests. Seven Duchenne patients were taking glucocorticoids; two reported previous treatment. We documented vitamin D blood levels and markers of bone turnover. Many patients presented low bone density for height-age (mean z score = - 0.86 ± 1.47). Areal bone density increased with age in the cerebral palsy and "other neuromuscular disease" groups, however, the Duchenne group demonstrated a decrease of z scores (r = - 0.622, p = 0.010). Tanner stage, body mass index, and mobility were independent variables affecting bone density. Vitamin D levels were low, but similar to those reported in healthy children. We conclude that bone mineral density in disabled children is mainly determined by their level of physical maturity, thriving, and mobility.

Decompressive craniectomy after severe traumatic brain injury in children: complications and outcome.

Decompressive craniectomy (DC) is a controversially discussed neurosurgical procedure to reduce elevated intracranial pressure after severe traumatic brain injury (TBI). In contrast to adults, several studies could show a benefit for the pediatric population, but still DC is considered as an emergency procedure only. The aim of our study was to identify secondary complications and long-term sequelae of the procedure. All children presenting to the University Medical Center Freiburg between 2005 and 2013 who underwent DC after severe TBI were retrospectively reviewed with respect to complications and outcome. Twelve children were included with a mean Glasgow Coma Scale of 4.5 ± 1.7. The most frequent complications after TBI and DC were formation of hygroma (83%), aseptic bone resorption of the reimplanted bone flap (50%), posttraumatic hydrocephalus (42%), secondary infection or dysfunction of ventriculoperitoneal shunt (25%) or cranioplasty (33%), and epilepsy (33%). Because of these complications, 75% of patients required further surgery in addition to cranioplasty with up to eight interventions. At follow-up, mean Glasgow Outcome Scale was 3.3 ± 1.2. Within our patient population, we demonstrated high incidence of complications after DC, leading to further surgical procedures and longer hospitalization. These potential complications have to be considered in any decision about DC as an emergency procedure.

A Multinational Survey on Actual Diagnostics and Treatment of Subacute Sclerosing Panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a chronic infection of the central nervous system caused by the measles virus (MV). Its prevalence remains high in resource poor countries and is likely to increase in the Northern Europe as vaccination rates decrease. Clinical knowledge of this devastating condition, however, is limited. We therefore conducted this multinational survey summarizing experience obtained from more than 500 patients treated by 24 physicians in seven countries. SSPE should be considered in all patients presenting with otherwise unexplained acquired neurological symptoms. In most patients, the diagnosis will be established by the combination of typical clinical symptoms (characteristic repetitive myoclonic jerks), a strong intrathecal synthesis of antibodies to MV and typical electroencephalogram findings (Radermecker complexes). Whereas the therapeutic use of different antiviral (amantadine, ribavirin) and immunomodulatory drugs (isoprinosine, interferons) and of immunoglobulins has been reported repeatedly, optimum application regimen of these drugs has not been established. This is partly due to the absence of common diagnostic and clinical standards focusing on neurological and psychosocial aspects. Carbamazepine, levetiracetam, and clobazam are the drugs most frequently used to control myoclonic jerks. We have established a consensus on essential laboratory and clinical parameters that should facilitate collaborative studies. Those are urgently needed to improve outcome.

ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies.

Dystroglycanopathies are a clinically and genetically diverse group of recessively inherited conditions ranging from the most severe of the congenital muscular dystrophies, Walker-Warburg syndrome, to mild forms of adult-onset limb-girdle muscular dystrophy. Their hallmark is a reduction in the functional glycosylation of α-dystroglycan, which can be detected in muscle biopsies. An important part of this glycosylation is a unique O-mannosylation, essential for the interaction of α-dystroglycan with extracellular matrix proteins such as laminin-α2. Mutations in eight genes coding for proteins in the glycosylation pathway are responsible for ∼50% of dystroglycanopathy cases. Despite multiple efforts using traditional positional cloning, the causative genes for unsolved dystroglycanopathy cases have escaped discovery for several years. In a recent collaborative study, we discovered that loss-of-function recessive mutations in a novel gene, called isoprenoid synthase domain containing (ISPD), are a relatively common cause of Walker-Warburg syndrome. In this article, we report the involvement of the ISPD gene in milder dystroglycanopathy phenotypes ranging from congenital muscular dystrophy to limb-girdle muscular dystrophy and identified allelic ISPD variants in nine cases belonging to seven families. In two ambulant cases, there was evidence of structural brain involvement, whereas in seven, the clinical manifestation was restricted to a dystrophic skeletal muscle phenotype. Although the function of ISPD in mammals is not yet known, mutations in this gene clearly lead to a reduction in the functional glycosylation of α-dystroglycan, which not only causes the severe Walker-Warburg syndrome but is also a common cause of the milder forms of dystroglycanopathy.

High frequency oscillations mirror disease activity in patients with focal cortical dysplasia.

PURPOSE: The study analyzes the occurrence of high frequency oscillations in different types of focal cortical dysplasia in 22 patients with refractory epilepsy. High frequency oscillations are biomarkers for epileptic tissue, but it is unknown whether they can reflect increasingly dysplastic tissue changes as well as epileptic disease activity. METHODS: High frequency oscillations (80-450 Hz) were visually marked by two independent reviewers in all channels of intracranial implanted grid, strips, and depth electrodes in patients with focal cortical dysplasia and refractory epilepsy. Rates of high frequency oscillations in patients with pathologically confirmed focal cortical dysplasia of Palmini type 1a and b were compared with those in type 2a and b. KEY FINDINGS: Patients with focal cortical dysplasia type 2 had significantly more seizures than those with type 1 (p < 0.001). Rates of high frequency oscillations were significantly higher in patients with focal cortical dysplasia type 2 versus type 1 (p < 0.001). In addition, it could be confirmed that rates of high frequency oscillations were significantly higher in presumed epileptogenic areas than outside (p < 0.001). SIGNIFICANCE: Activity of high frequency oscillations mirrors the higher epileptogenicity of focal cortical dysplasia type 2 lesions compared to type 1 lesions. Therefore, rates of high frequency oscillations can reflect disease activity of a lesion. This has implications for the use of high frequency oscillations as biomarkers for epileptogenic areas, because a detailed analysis of their rates may be necessary to use high frequency oscillations as a predictive tool in epilepsy surgery.

Seizure control and developmental trajectories after hemispherotomy for refractory epilepsy in childhood and adolescence.

PURPOSE: To evaluate the seizure control and developmental outcomes after hemispherotomy for refractory epilepsy in childhood and to identify their predictive factors. METHODS: We retrospectively studied the clinical courses and outcomes of 52 children with refractory epilepsy who underwent hemispherotomy in the Epilepsy Center Freiburg between 2002 and 2011. KEY FINDINGS: Mean age at epilepsy onset was 1.8 years (range 0-8 years) and mean age at surgery was 6.7 years (range 6 months-18 years). The underlying etiology was congenital in 22 (42%) children, acquired in 24 (46%), and progressive in 6 (12%). At final follow-up of 1-9.8 years (mean 3.3), 43 children (83%) were seizure-free. Seizure outcome was not correlated to etiology, with the exception of hemimegalencephaly that was linked to poor seizure control. Presurgical development was impaired in all but one child. Postsurgical development highly correlated with presurgical development. Patients with acquired or progressive etiology, later epilepsy onset, and subsequent later surgery exhibited higher presurgical developmental status that substantially determined postoperative developmental outcome. Improved postsurgical development was determined by acquired etiology and seizure freedom off antiepileptic drugs. SIGNIFICANCE: In our study, most of the selected children and adolescents achieved seizure freedom, including those with congenital etiology. Developmental outcomes, however, were superior in patients with acquired etiology and older age at surgery, underscoring that it is never too late to reap the benefits of this procedure in terms of both epilepsy and development.