What are the predominant predictors of seizure relapse following discontinuation of anti-seizure medication in epileptic children?

OBJECTIVE: The aim of the study was to identify the predominant predictors of seizure relapse following discontinuation of ASM in epileptic children. METHODS: The study cohort consisted of 403 epileptic children who had a withdrawal process of ASM (monotherapy: 344; dual therapy or polytherapy: 59) after at least a 2-year seizure-free period. Patients were categorized if they had a well-defined epileptic syndrome. Epileptic children with ongoing ketogenic diet, vagal nerve stimulation, or surgery were excluded from the cohort due to the additional withdrawal process related to other therapy modalities. RESULTS: The cohort's seizure relapse rate was 12.7% (51/403). The highest rates of seizure relapse were defined for genetic etiology at 25% and structural etiology at 14.9%. An epilepsy syndrome was defined in 183 of 403 children (45.4%). There was no difference in the seizure relapse rate between the subgroups of well-defined epileptic syndromes; 13.8% for self-limited focal epileptic syndromes, 11.7% for developmental and epileptic encephalopathies, and 7.1% for generalized epileptic syndromes. Five predictors were defined as the most powerful predictors of seizure relapse in univariate analysis: age at epilepsy diagnosis >2 years (hazard ratio [HR]: 1.480; 95% confidence interval [CI]: 1.134-1.933), defined etiology (HR: 1.304; 95% CI: 1.003-1.696), focal seizure (HR: 1.499; 95% CI: 1.209-1.859), ≤3 months duration of the withdrawal process (HR: 1.654; 95% CI: 1.322-2.070), and a history of neonatal encephalopathy with or without seizures (HR: 3.140; 95% CI: 2.393-4.122). In multivariate analysis, the main predictor of seizure relapse was a history of neonatal encephalopathy with or without seizures (HR: 2.823; 95% CI: 2.067-3.854). SIGNIFICANCE: The duration of seizure freedom before discontinuation of ASM was not a predominant risk factor for seizure relapse: 2-3 years versus >3 years. The predictive values of five predictors of seizure relapse rate should be evaluated for patients with different epilepsy subgroups.

Cerebral folate transporter deficiency: a potentially treatable neurometabolic disorder.

Cerebral folate deficiency (CFD) syndrome is a rare treatable neurometabolic disorder with low levels of the active form of folaten in cerebrospinal fluid (CSF) arising from different causes such as FOLR1 gene mutations or autoantibodies against the folate receptor-alpha (FR) protein that can block folate transport across the choroid plexus. It is characterized by late infantile onset refractory seizures, ataxia, movement disorder, and unexplained global developmental delay. Here, we report a patient diagnosed with autistic spectrum disorder, followed by refractory myoclonic-atonic seizures, ataxia, and loss of motor skills over time. A homozygous missense (c.665A > G) mutation in FOLR1 gene and extremely low CSF 5-methyltetrahydrofolate level led to the diagnosis of CFD. Although she was initiated on combined oral and intravenous high doses of folinic acid treatment at 6 years of age, mild improvement was achieved in terms of epileptic seizures and motor skills. It is important that CFD should be kept in mind in cases with refractory myoclonic-atonic seizure and folinic acid treatment should be started as soon as possible.

A Rare Case of Peripheral Nerve Hyperexcitability in Childhood: Isaacs Syndrome.

Isaacs syndrome is rare disorder with peripheral nerve hyperexcitability syndromes with acquired neuromyotonia in childhood. We present a 13-year-old girl with muscle stiffness and neuromyotonia diagnosed Isaac syndrome with spontaneous discharge potentials on motor unit in electromyography and the diagnosis supported by the presence of antinuclear antibodies. A successful treatment was obtained using low-dose carbamazepine. Cause of Isaacs syndrome is unknown, generally thought to be an autoimmune etiology with voltage-gated potassium channelopathy; it sometimes occurs as a paraneoplastic syndrome. Early use of electromyography has critical role in the differential diagnosis with certain muscle disorders and peripheral nerve hyperexcitability syndromes.

Dropped head related lamin A/C associated congenital muscular dystrophy case; previously defined as emerydreifuss muscular dystrophy.

Dropped head syndrome can be seen in many neuromuscular diseases. However, there are very few diseases in which neck extensors are weak among neuromuscular diseases. A 7 years old boy who had weakness of the neck extensor muscles, creatinine kinase elevation and dystrophy findings in biopsy followed up with the preliminary diagnosis of muscular dystrophy is presented. We detected p.N456K (c.1368C > A) heterozygote mutation by the gene sequencing in the Lamin A/C associated (LMNA) gene. This mutation was previously reported as Emery-Dreifuss muscular dystrophy.

A rare cause of brachial plexopathy: hereditary neuralgic amyotrophy.

Neuralgic amyotrophy is characterized by recurrent, painful, unilateral neuropathy involving mainly the upper brachial plexus followed by muscle weakness and muscle wasting. There are two forms: idiopathic and hereditary. Hereditary neuralgic amyotrophy is an autosomal dominant disease that is often linked to a mutation of SEPT9, a gene of the Septin family. The phenotypic spectrum of the disease may include hypotelorism, cleft palate, and other minor dysmorphisms. The age of onset is from infancy to adulthood. Hereditary neuralgic amyotrophy can be triggered by external stimuli such as infections, vaccinations, cold, stress, surgery, and strenuous exercise. Here, we report a six-year-old girl who was found to have mutation in the SEPT9 gene when she presented with recurrent attacks of painful brachial plexopathy following vaccinations, and was diagnosed as having hereditary neuralgic amyotrophy.

Ictal urinary urge: localization and lateralization value in a pediatric case.

BACKGROUND: Ictal urinary urge is a rare autonomic symptom usually lateralizing to the non-dominant hemisphere and localizing to the temporal lobe. CASE REPORT: A 12-year-old boy was referred with desire to void and contraction of the left arm. The history of the case revealed tickling and an unpleasant rising feeling in the stomach and sense of fear lasting for 1 year. He had been evaluated and treated several times with the diagnosis of gastroesophageal reflux and cystitis. His cranial MRI displayed an intra-axial mass formation on the right temporal lobe. Pathological findings were consistent with a low-grade glial mass. CONCLUSION: Ictal urinary urge has a considerable value both for localization and lateralization of seizures.

Concomitant alpha- and gamma-sarcoglycan deficiencies in a Turkish boy with a novel deletion in the alpha-sarcoglycan gene.

Limb-girdle muscular dystrophy type 2D (LGMD-2D) is caused by autosomal recessive defects in the alpha-sarcoglycan gene located on chromosome 17q21. In this study, we present a child with alpha-sarcoglycanopathy and describe a novel deletion in the alpha-sarcoglycan gene. A 5-year-old boy had a very high serum creatinine phosphokinase level, which was determined incidentally, and a negative molecular test for the dystrophin gene. Muscle biopsy showed dystrophic features. Immunohistochemistry showed that there was diminished expression of alpha- and gamma-sarcoglycans. DNA analysis revealed a novel 7 bp homozygous deletion in exon 3 of the alpha-sarcoglycan gene. His parents were consanguineous heterozygous carriers of the same deletion. We believe this is the first confirmed case of primary alpha-sarcoglycanopathy with a novel deletion in Turkey. In addition, this study demonstrated that both muscle biopsy and DNA analysis remain important methods for the differential diagnosis of muscular dystrophies because dystrophinopathies and sarcoglycanopathies are so similar.

Acute transverse myelitis complicating breakthrough varicella infection.

We report a 10-year-old girl who presented with acute transverse myelitis after breakthrough varicella infection. The diagnosis was based on the development of motor weakness, paraparesis and bladder dysfunction, spinal magnetic resonance imaging findings and detection of anti-varicella zoster virus IgG antibody in the cerebrospinal fluid. This case report highlights that breakthrough varicella can result in serious complications such as acute transverse myelitis.

Early-onset acquired myasthenia gravis secondary to anti-muscle-specific kinase autoantibodies.

Autoimmune myasthenia gravis is rarely seen during infancy. Similar to adults, 85% to 90% of generalized pediatric myasthenia gravis cases have acetylcholine receptor antibodies. Approximately 30% of the remaining cases have antibodies against muscle-specific kinase. Information on the clinical course, treatment alternatives, and prognosis of pediatric muscle-specific kinase antibody-positive myasthenia gravis is limited because of the small number of cases. Here, we present a 14-month-old girl with muscle-specific kinase antibody-positive myasthenia gravis as one of the youngest patients described so far in the literature.

Novel mutations consolidate KCTD7 as a progressive myoclonus epilepsy gene.

BACKGROUND: The progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous disorders characterised by myoclonus, epilepsy, and neurological deterioration. This study aimed to identify the underlying gene(s) in childhood onset PME patients with unknown molecular genetic background. METHODS: Homozygosity mapping was applied on genome-wide single nucleotide polymorphism data of 18 Turkish patients. The potassium channel tetramerisation domain-containing 7 (KCTD7) gene, previously associated with PME in a single inbred family, was screened for mutations. The spatiotemporal expression of KCTD7 was assessed in cellular cultures and mouse brain tissue. RESULTS: Overlapping homozygosity in 8/18 patients defined a 1.5 Mb segment on 7q11.21 as the major candidate locus. Screening of the positional candidate gene KCTD7 revealed homozygous missense mutations in two of the eight cases. Screening of KCTD7 in a further 132 PME patients revealed four additional mutations (two missense, one in-frame deletion, and one frameshift-causing) in five families. Eight patients presented with myoclonus and epilepsy and one with ataxia, the mean age of onset being 19 months. Within 2 years after onset, progressive loss of mental and motor skills ensued leading to severe dementia and motor handicap. KCTD7 showed cytosolic localisation and predominant neuronal expression, with widespread expression throughout the brain. None of three polypeptides carrying patient missense mutations affected the subcellular distribution of KCTD7. DISCUSSION: These data confirm the causality of KCTD7 defects in PME, and imply that KCTD7 mutation screening should be considered in PME patients with onset around 2 years of age followed by rapid mental and motor deterioration.

Video/EEG recording of myoclonic absences in GLUT1 deficiency syndrome with a hot-spot R126C mutation in the SLC2A1 gene.

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is an inborn error of brain energy metabolism characterized by impaired glucose transport into the brain. A classic phenotype comprising epilepsy, mental retardation, an often paroxysmal disorder, and several subtypes has been described. Although typical absences are frequent in GLUT1DS, myoclonic absence seizures are rarely reported. Here we describe a novel Turkish patient with a hot-spot mutation (R126C) in the SLC2A1 gene who presented with unusual myoclonic absence epilepsy and paroxysmal shivering. The case is discussed in view of eight other cases carrying the R126C mutation.

Recurrent pseudotumor cerebri in childhood: a case of neuro-Behçet disease complicated with thrombotic risk factors.

Pseudotumor cerebri with or without venous sinus thrombosis is a rare clinical presentation of Behçet disease in childhood. We present here a case of childhood pseudotumor cerebri without a previous diagnosis of Behçet disease. The detailed history and physical examination of the case led to the diagnosis of neuro-Behçet disease. The investigation of predisposition to thrombosis revealed heterozygous factor V Leiden mutation along with the high lipoprotein(a) level. The symptoms resolved dramatically by treatment with the combination of immunosuppression and anticoagulation with regard to the detected factor V Leiden mutation and high lipoprotein(a) level. After a symptom-free period of 9 months, the cerebral vein thrombosis recurred. We present this case to draw attention to this rare cause of pseudotumor cerebri in childhood and to emphasize the importance of additional thrombotic risk factors regarding the potential recurrence of thrombotic events in Behçet disease.

A rare cause of recurrent stroke in childhood: left atrial rhabdomyosarcoma.

UNLABELLED: We present a case of recurrent stroke secondary to cardiac rhabdomyosarcoma. The detected prothrombotic mutations at the first attack had seemed to be the main cause, but the echocardiography performed at the recurrence revealed the actual underlying cause of stroke. CONCLUSION: The aetiological investigation into childhood stroke should absolutely include echocardiography regardless of the presence of other risk factors.

Central core disease: atypical case with respiratory insufficiency in an intensive care unit.

Central core disease is a rare congenital myopathy characterized by formation of typical cores in myofibrils. We report an atypical case of central core disease with respiratory insufficiency in the late stage of congenital myopathy. A 13-year-old girl was admitted to the intensive care unit with the diagnosis of respiratory distress syndrome. Ventilatory support was initiated. After 2 weeks of follow-up, the Division of Pediatric Neurology was consulted owing to the failure to wean her from the ventilator. Clinical and electromyographic features were in favor of primary muscle disease. Muscle biopsy revealed typical cores in type 1 muscle fibers, which were diagnostic for central core disease. This case was presented to emphasize that patients with respiratory distress who cannot be weaned from the ventilator should be evaluated for central core disease with an atypical presentation.

Cerebrospinal fluid interleukin-6 levels in patients with West syndrome.

Elevated cytokine response has been reported in patients with epileptic seizures. The objective of this study was to investigate the possible role of interleukin-6 (IL-6) in the pathogenesis of infantile spasms in West syndrome (WS). We measured IL-6 levels in cerebrospinal fluid (CSF) obtained from the newly diagnosed patients with WS. Twelve patients with WS (Group I) were classified as symptomatic WS (Group IA) in eight and as cryptogenic WS (Group IB) in four. The results were compared with control groups including patients with tonic-clonic seizures associated with two different kind of inflammation of central nervous system; Group IIA (infection): bacterial meningitis/encephalitis and Group IIB (trauma): post-traumatic seizures. There was no statistically significant difference between the mean values of CSF IL-6 levels in patients with WS (2.95 +/- 2.31 pg/ml) and those of subgroups of WS (Group IA: 2.26 +/- 2.01 pg/ml and Group IB: 4.33 +/- 2.52 pg/ml). Both control groups had highly increased IL-6 levels in CSF (Group IIA: 193.05 +/- 185.52 pg/ml and Group IIB: 112.74 +/- 167.44 pg/ml) than those of the patients with WS. Elevated IL-6 response in patients with tonic-clonic seizures associated with inflammation of central nervous system might be due to the seizures themselves or related to the underling etiology (infection or trauma). However, no elevated IL-6 response was found in patients with infantile spasms.

T-cell subsets and interleukin-6 response in Rasmussen's encephalitis.

To evaluate the immunopathogenesis in Rasmussen's encephalitis, peripheral lymphocyte subsets and interleukin-6 analysis were performed in three patients. Magnetic resonance spectroscopy and diffusion-weighted magnetic resonance imaging were performed to assess neuronal injury in the affected hemisphere. Before initiation of immune therapy, percentage of cytotoxic T cells was found to be increased in peripheral blood obtained from patients compared with a group of age-matched normal control subjects. During follow-up, percentage of cytotoxic T cells returned to the normal ranges only in one patient who had an early functional hemispherectomy. All three patients had significantly increased interleukin-6 concentration in cerebrospinal fluid and serum compared with the mean values of patients with acute viral encephalitis. The magnitude of interleukin-6 response in the patients correlated with the neuronal loss and atrophy on magnetic resonance spectroscopy and diffusion-weighted magnetic resonance imaging studies. The patient, who had a fulminant course and an early hemispherectomy, had higher interleukin-6 concentration in cerebrospinal fluid and serum than those of the other two. Detection of an increased percentage of cytotoxic T cells in peripheral blood supports the presence of a T cell-mediated inflammatory pathogenesis in Rasmussen's encephalitis. However, elevated interleukin-6 response might reflect the magnitude of the inflammatory process in the affected hemisphere.

Correlative value of magnetic resonance imaging for neurodevelopmental outcome in periventricular leukomalacia.

The aim of this study was to evaluate the correlative value of magnetic resonance imaging (MRI) in children with periventricular leukomalacia (PVL) for neurodevelopmental outcome. MRI examinations of 89 children (46 males, 43 females) with PVL (median age 4y, range 1 to 14y) were reevaluated. PVL was graded as follows: grade I, unilateral or bilateral areas of periventricular hyperintensity (1-3); grade II, hyperintensity more than 3; grade III, hyperintense lesions more than 3 and ventricular wall irregularity; grade IV, diffuse PVL and ventricular dilatation. Localizations of PVL and brain abnormalities associated with PVL were also noted. Assignment to PVL grades on MRI was as follows: PVL I (n=22), PVL II (n=18), PVL III (n=30), and PVL IV (n=19). Cerebral palsy was slightly less common in children with PVL I and II compared with PVL III to IV. Motor function was normal in 50% of children with PVL grade I, but severely impaired in 73.7% of children with PVL grade IV. Results of visual function were normal in all with PVL I, but pathological in 42.1% of patients with PVL IV. Developmental tests were appropriate for age in 75% of patients with PVL I, but significantly delayed in all patients with PVL IV. Thinning of the corpus callosum and presence of cortical atrophy were also correlated with neurological outcome. Significant risk factors associated with developmental delay were asphyxia at birth (odds ratio [OR] 4.3), PVL localization numbers over 3 (OR 4.4), PVL III to IV (OR 15), thinning of corpus callosum, and cortical atrophy.

Value of biochemical markers for outcome in term infants with asphyxia.

The aim of this study was to define the predictive values of serum and cerebrospinal fluid concentrations of interleukin-6 and neuron-specific enolase and urinary uric acid/creatinine ratio for outcome in term infants with perinatal asphyxia. All biochemical markers were measured simultaneously within the 24-72 hours of life in 21 infants. The infants were monitored with a standardized neurologic and developmental evaluation protocol over the 2 years of life. The overall outcome at 2 years of age was categorized as "favorable" or "adverse". According to Sarnat and Sarnat classification, 12 infants had mild encephalopathy and 9 infants had moderate to severe encephalopathy. Seven of 9 (78%) infants with moderate to severe encephalopathy had adverse outcome. However, all infants with mild encephalopathy had favorable outcome. Interleukin-6 and neuron specific enolase levels in cerebrospinal fluid and serum interleukin-6 levels were significantly correlated with the degree of encephalopathy, as well as the outcome. Interleukin-6 in cerebrospinal fluid (cutoff value, 25.9 pg/mL) had the highest predictive value among the biochemical markers. The predictive factors identified in this study should be examined for their ability in a fresh clinical sample in the neonatal intensive care unit before these markers can be applied to the routine clinical of infants with perinatal asphyxia.

Lymphocyte subsets in Bell's palsy: immune pathogenesis and outcome prediction.

The aim of this prospective study is to define the prognostic significance of lymphocyte subset analysis in children with Bell's palsy. Lymphocyte subgroup analysis in peripheral blood was performed in 17 children with Bell's palsy by using flow cytometry. Before a standard protocol of corticosteroid treatment, patients were categorized into two groups for facial nerve impairment on the basis of the clinical findings: Group 1 (mild to moderate impairment), 7 patients; and Group 2 (severe impairment), 10 patients. Outcome of the patients was evaluated at the end of 3 months follow-up and categorized as satisfactory recovery (n = 12) or unsatisfactory recovery (n = 5). Decreased percentages of B cells (CD19) and T helper/inducer (CD4) subsets were measured in patients with Bell's palsy compared with age-matched healthy control patients. Patients with severe impairment had significantly lower percentages of CD4 and CD19 subsets, whereas patients with mild to moderate impairment had only decreased percentage of CD19 subsets. There was no statistically significant difference in the percentage of lymphocyte subsets between the patients with satisfactory and unsatisfactory recovery. These results provide additional support for cell-mediated immunopathogenesis in patients with Bell's palsy, without any prognostic significance for the outcome.