Tatton-Brown-Rahman syndrome due to 2p23 microdeletion.

Tatton-Brown-Rahman syndrome is a new overgrowth syndrome due to DNMT3A (DNA cytosine 5 methyltransferase 3A) mutations. Mutation carriers show a distinctive facial appearance, intellectual disability, and increased height. We report a patient with overgrowth who showed submicroscopic deletion of chromosome 2p23 including DNMT3A. The deletion was detected by array-CGH. He showed moderate ID and distinctive facial gestalt. His clinical features were consistent with those of Tatton-Brown-Rahman syndrome. We suggest that 2p23 microdeletion including DNMT3A may cause similar symptoms in patients with DNMT3A mutations and should be considered in patients with overgrowth.

Parents'opinions of the changes in their children's epilepsy treatment during the transition from childhood to adulthood.

Objective: Patients with childhood-onset epilepsy often need continued epilepsy treatment into adulthood. We investigated parents' opinions of the changes in their children's epilepsy treatment during the transition from childhood to adulthood using questionnaires and formulated agendas to build the appropriate medical treatment system for epilepsy. Methods: We distributed questionnaires to parents of patients with epilepsy who were 12 to 18 years old. Results: We distributed 176 questionnaires, and analyzed 79 (45%) questionnaires. Most parents (59%) wanted their child to continue treatment for epilepsy in the pediatrics department because of confidence in the current treatment environment. Most parents (73%) were anxious about their child not being treated in the pediatrics department during future epilepsy medical treatments because of concerns about whether a proper handover from the pediatrics department to other departments is possible. No parent was recommended the departmental transition by the primary pediatrician to other courses for future epilepsy treatment, while 19% of par-ents had a sense of incongruity regarding epilepsy treatment at the current pediatrics department. Parents who were anxious about future epilepsy treatments had significantly fewer general-school students than parents without anxiety. In addition, their children had more seizures than children of parents who were not anxious. Furthermore, they wanted their child to continue treatment for epilepsy in the pediatrics department more than the parents without anxiety. Conclusions: Approximately 70% of the parents were anxious about obtaining future epilepsy treatment in clinical departments other than the pediatrics department. To build a satisfactory medical treatment system for patients with epilepsy having different backgrounds and requiring continued treatment in adulthood, it is important to create a cooperating network consisting of pediatricians, neurologists, neurosurgeons, psychiatrists, and epileptologists.

Predictive value of EEG findings at control of epileptic spasms for seizure relapse in patients with West syndrome.

PURPOSE: To evaluate the prognostic importance of electroencephalography (EEG) findings at cessation of epileptic spasms for seizure outcome. METHODS: We reviewed 71 children with West syndrome (cryptogenic 14) who had obtained control of epileptic spasms with initial treatment (adrenocorticotropic hormone (ACTH) 37, high-dose vitamin B6 2, and antiepileptic drugs 32). According to the EEG findings at control of epileptic spasms, the subjects were divided into three groups: normal group (no epileptic activity, n=12), abnormal group (residual epileptic activity without hypsarrhythmia, n=53), and hypsarrhythmic group (persisting hypsarrhythmia, n=6). RESULTS: Overall, 47 (66%) of the 71 patients (cryptogenic 4) had experienced relapses of seizures (epileptic spasms 23 and focal seizure 24) after initial control of epileptic spasms. Within symptomatic cases, seizure relapse rate varied widely from 0% (Down syndrome) to 100% (tuberous sclerosis), depending on underlying causes. Seizure relapse depended on the EEG findings at control of epileptic spasms. The normal group had a significantly lower seizure relapse rate (17%) in comparison with the abnormal group (75%), the hypsarrhythmic group (83%), and the epileptiform (abnormal plus hypsarrhythmic, 76%) group. No significant difference in seizure relapse rate was observed between non-hypsarrhythmic (normal plus abnormal, 65%) and hypsarrhythmic groups. At the last follow-up, normal group children also showed a favorable seizure prognosis (seizure control 100%). CONCLUSIONS: A favorable seizure prognosis is associated with the disappearance of epileptic activity, but not the resolution of hypsarrhythmic pattern on EEG at control of epileptic spasms. We suggest that effective treatment for West syndrome should produce both cessation of epileptic spasms and disappearance of epileptic activity on EEG.

The grasp reflex and moro reflex in infants: hierarchy of primitive reflex responses.

The plantar grasp reflex is of great clinical significance, especially in terms of the detection of spasticity. The palmar grasp reflex also has diagnostic significance. This grasp reflex of the hands and feet is mediated by a spinal reflex mechanism, which appears to be under the regulatory control of nonprimary motor areas through the spinal interneurons. This reflex in human infants can be regarded as a rudiment of phylogenetic function. The absence of the Moro reflex during the neonatal period and early infancy is highly diagnostic, indicating a variety of compromised conditions. The center of the reflex is probably in the lower region of the pons to the medulla. The phylogenetic meaning of the reflex remains unclear. However, the hierarchical interrelation among these primitive reflexes seems to be essential for the arboreal life of monkey newborns, and the possible role of the Moro reflex in these newborns was discussed in relation to the interrelationship.

Diagnostic accuracy of blood and CSF lactate in identifying children with mitochondrial diseases affecting the central nervous system.

OBJECTIVE: To determine the diagnostic accuracy of blood and cerebrospinal fluid (CSF) lactate and pyruvate concentrations in identifying children with mitochondrial diseases (MD) affecting the central nervous system (CNS). METHODS: We studied lactate and pyruvate concentrations in paired samples of blood and CSF collected concurrently from 17 patients with MD (Leigh encephalomyelopathy 10, MELAS 5, Pearson disease 1, PDH deficiency 1) and those from control patients (n=49). RESULTS: Although blood and CSF variables (lactate, pyruvate concentrations and lactate/pyruvate ratio) were significantly higher in the mitochondrial group than in the control group, there was considerable overlap of individual values between these two groups. The maximum value of the area under the receiver operating characteristic curve (AUC) was observed for the CSF lactate concentration (0.994, optimal cut-off value 19.9 mg/dl, sensitivity 0.941 and specificity 1.00), followed by the CSF pyruvate level (0.983). There was an inverse relationship between blood lactate and lactate CSF/blood ratio. For blood lactate concentrations between 20 and 40 mg/dl, a significant difference was also noted in the lactate CSF/blood ratio between the two groups (AUC 1.0, optimal cut-off value 0.91, sensitivity 1.0 and specificity 1.0). CONCLUSIONS: Our study suggests that that CSF lactate level>19.9 mg/dl is the most reliable variable for identifying patients with MD affecting the CNS. When blood lactate concentrations are marginally elevated (20-40 mg/dl), lactate CSF/blood ratio>0.91 may also provide diagnostic information.

MRI findings and steroid therapy for neuralgic amyotrophy in children.

Neuralgic amyotrophy is not uncommon in adults but is relatively rare in children. We recently encountered 2 cases of neuralgic amyotrophy in children. Patient 1 was a 7-year-old girl who developed a right leg paralysis after an epileptic seizure. Lumbar plexus T(2)-weighted magnetic resonance imaging (MRI) revealed a hyperintense and thickened portion extending from the root to the knee region of the right sciatic nerve, and T(1)-weighted conventional spin echo with gadolinium administration revealed enhancement. Patient 2 was a 4-year-old boy who experienced a sudden onset of severe right arm pain and paralysis. T(2)-weighted MRI with a short tau inversion recovery revealed a slightly thickened and high intensity region at the right C(6)-C(8) level. After high-dose methylprednisolone pulse therapy was performed in each case, patient 1 experienced complete recovery, whereas patient 2 experienced only amelioration of pain. A diagnosis of neuralgic amyotrophy in children was facilitated by an MRI study (T(2) weighed with short tau inversion recovery and T(1) weighted with gadolinium enhancement), and early steroid therapy might have improved the condition of these children.

[Changes of brain edema after initiation of mild hypothermia therapy in children].

To determine the effects of mild hypothermia therapy (34 degrees C) for brain edema caused by hypoxic ischemic encephalopathy (HIE) or acute encephalitis/encephalopathy, we reviewed the charts and serial brain CT images in six children (males 3, average age 1.6 years) treated with mild hypothermia therapy between November 2006 and April 2009. Both of the two children with HIE after cardiopulmonary arrest did not show any deterioration of brain edema after the initiation of hypothermia therapy. However, two of four non-HIE patients (acute encephalitis/encephalopathy 3 cases and metabolic encephalopathy plus HIE 1 case) showed progressive brain edema during the cooling phase and re-warming phase, respectively. There were no differences between patients with and those without progressive brain edema with regard to the interval until initiation of mild hypothermia therapy, duration of cooling phase, duration of re-warming phase, or peak serum NSE (neuron-specific enolase) levels. However, two children with progressive brain edema showed a delayed NSE peak time (15 and 13 days after onset, respectively), compared with those without progressive brain edema (2-6 days after onset). Our study suggests that serial measurement of serum NSE might be useful marker for adjusting the methods of hypothermia therapy according to neuropathology. Further study is necessary to establish optimal hypothermia therapy especially in children with acute encephalitis/ encephalopathy.

[Successful treatment with additional plasmapheresis for the exacerbation of acute neurological symptoms in a girl with multiple sclerosis].

Few studies have indicated the efficacy of plasmapheresis in children with multiple sclerosis (MS). We report a 10-year-old girl with MS who was successfully treated with plasmapheresis. She experienced the first episode (vomiting and unconsciousness) at the age of eight years. After two years and six months remission period, she had a relapse with left hemiplegia. Her symptoms did not respond to high-dose intravenous methylprednisolone or immunoglobulin therapies, and rapidly deteriorated. After bulbar palsy was observed, plasmapheresis (total : every two days, seven times) was initiated at the 17th day during the relapse. Neurological symptoms improved remarkably after the second trial of plasmapheresis. There were no complications associated with plasmapheresis. Plasmapheresis may be effective as an additional therapy for exacerbation of acute neurological symptoms in children with MS.

Early infantile manifestations of incontinentia pigmenti mimicking acute encephalopathy.

OBJECTIVE: We retrospectively reviewed six patients with incontinentia pigmenti (IP) who had encephalopathic manifestations during early infancy. METHODS: We enrolled six patients who met the following criteria from the mailing list of the Annual Zao Conference: (1) diagnosis of IP; (2) encephalopathic manifestations with reduced consciousness and clusters of seizures by 6 months of age; and (3) no evidence of central nervous system infection or metabolic derangement. RESULTS: The onset of the encephalopathic events was within the first 2 months of life in all but one patient. All had clusters of focal clonic seizures. The duration of seizures was typically 5 min. The seizures ceased within 5 days in all patients. Various degrees of reduced consciousness were observed in association with the frequent seizures. Diffusion-weighted imaging during the acute phase showed reduced water diffusion in the subcortical white matter, corpus callosum, basal ganglia, thalami, and internal capsule in two patients. Scattered subcortical white matter lesions were observed on fluid-attenuated inversion-recovery images in two patients. CONCLUSIONS: The encephalopathic manifestations in patients with incontinentia pigmenti were characterized by seizure clusters and reduced consciousness, albeit of relatively short duration. Magnetic resonance imaging abnormalities were predominant in the subcortical areas in most patients.

Clinicopathological features of acute autonomic and sensory neuropathy.

Acute autonomic and sensory neuropathy is a rare disorder that has been only anecdotally reported. We characterized the clinical, electrophysiological, pathological and prognostic features of 21 patients with acute autonomic and sensory neuropathy. An antecedent event, mostly an upper respiratory tract or gastrointestinal tract infection, was reported in two-thirds of patients. Profound autonomic failure with various degrees of sensory impairment characterized the neuropathic features in all patients. The initial symptoms were those related to autonomic disturbance or superficial sensory impairment in all patients, while deep sensory impairment accompanied by sensory ataxia subsequently appeared in 12 patients. The severity of sensory ataxia tended to become worse as the duration from the onset to the peak phase of neuropathy became longer (P<0.001). The distribution of sensory manifestations included the proximal regions of the limbs, face, scalp and trunk in most patients. It tended to be asymmetrical and segmental, rather than presenting as a symmetric polyneuropathy. Pain of the involved region was a common and serious symptom. In addition to autonomic and sensory symptoms, coughing episodes, psychiatric symptoms, sleep apnoea and aspiration, pneumonia made it difficult to manage the clinical condition. Nerve conduction studies revealed the reduction of sensory nerve action potentials in patients with sensory ataxia, while it was relatively preserved in patients without sensory ataxia. Magnetic resonance imaging of the spinal cord revealed a high-intensity area in the posterior column on T(2)*-weighted gradient echo image in patients with sensory ataxia but not in those without it. Sural nerve biopsy revealed small-fibre predominant axonal loss without evidence of nerve regeneration. In an autopsy case with impairment of both superficial and deep sensations, we observed severe neuronal cell loss in the thoracic sympathetic and dorsal root ganglia, and Auerbach's plexus with well preserved anterior hone cells. Myelinated fibres in the anterior spinal root were preserved, while those in the posterior spinal root and the posterior column of the spinal cord were depleted. Although recovery of sensory impairment was poor, autonomic dysfunction was ameliorated to some degree within several months in most patients. In conclusion, an immune-mediated mechanism may be associated with acute autonomic and sensory neuropathy. Small neuronal cells in the autonomic and sensory ganglia may be affected in the initial phase, and subsequently, large neuronal cells in the sensory ganglia are damaged.

12q interstitial deletion with bilateral cleft lip and palate: case report and literature review.

The authors report the case of a Japanese girl with interstitial deletion of chromosome 12q15-q21.2 who had multiple congenital anomalies including bilateral cleft lip and palate (BCLP) with intrauterine onset of growth retardation and severe psychomotor developmental delay. Only two other patients with a similar deletion have been reported previously. However, these two patients showed such different clinical features that defining the karyotype-phenotype correlation has remained unfeasible. The additional case presented here reveals that two of the three cases with an overlapping deletion in 12q show the phenotype of BCLP, suggesting the correlation between this area of gene deletion and cleft lip and palate.

Epilepsy in patients with congenital cytomegalovirus infection.

Patients with congenital cytomegalovirus (CMV) infection were at high risk for postnatal seizures, but little is known about epilepsy associated with congenital CMV infection. To define the features of epilepsy, we retrospectively reviewed the clinical, laboratory and neuroradiographic findings in 19 children (male 9) with congenital CMV infection. Seven (37%) patients had developed epilepsy (partial seizure 5 and epileptic spasms 2) at a mean age of 20 months (range 2-37 months). During the clinical course, West syndrome occurred in only three patients. The most common seizure type in our series was partial seizure. At the time of last follow-up (mean 96 months), seizures remained uncontrolled in six patients. Neonatal clinical manifestations (gestational age, gender distribution, birth asphyxia or symptoms at birth) were not predictive of the development of epilepsy. On the contrary, some neuroradiographic findings (ventricular dilatation and migration disorder) were significantly associated with the development of epilepsy.

[Usefulness of L-arginine infusion for status epilepticus in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes].

We encountered an 11-year-old girl with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) who developed occipital lobe epilepsy at the age of 7 years and 4 months. Thereafter she had repeated status epilepticus associated with stroke-like episodes. Status epilepticus consisted of repetitive complex partial seizures with or without secondarily generalized tonic clonic seizures. The seizures did not respond to conventional anticonvulsive drugs, including diazepam, midazolam, phenytoin, lidocaine, chloral hydrate, and thiamylal sodium, and lasted for several hours (mean 9.5 hours). At the age of 11 years, intravenous infusion of L-arginine (0.5 g/kg body weight) was first given five hours after the onset of status epilepticus. The seizures and electroencephalographic abnormalities improved dramatically. After the introduction of L-arginine, in addition to shortened duration of status epilepticus (mean 3 hours), clinical recovery from the status epilepticus was prompt, and the average hospitalization periods could be shortened. There were no obvious adverse effects, including vomiting, hypotension, and urticaria. Our experience suggests that early intravenous administration of L-arginine may be useful in the treatment of status epilepticus associated with stroke-like episode in patients with MELAS.

Neurodevelopmental outcome in children with intraventricular hemorrhage.

To clarify the neurodevelopmental outcome in children with intraventricular hemorrhage, a follow-up study was performed for a consecutive group of 335 subjects in one tertiary center born between 1981 and 1999. Their mean gestation and birth weight were 28.1 weeks and 1162.2 gm, respectively. The follow-up period ranged from 3 to 20 years (mean: 7.5 years). The neurodevelopmental outcomes were normal in 188 (56.1%), cerebral palsy in 75 (22.4%), mental retardation in 34 (10.2%), and borderline intelligence in 38 (11.3%). There were statistically significant differences in the outcomes among the groups with different grades of intraventricular hemorrhage. Approximately 70% of the children with intraventricular hemorrhage grade 1 were normal, whereas only 15.4% of the children with intraventricular hemorrhage grade 4 were normal. Cerebral palsy was associated with as high as 71.2% in the patients with intraventricular hemorrhage grade 4. The overall incidence of epilepsy was 39/335 (11.6%). This study has not demonstrated clear improvement of the outcome in children with intraventricular hemorrhage between the 1980s and 1990s.

Neurodevelopmental outcome in children with posthemorrhagic hydrocephalus.

To determine the factors affecting the neurodevelopmental outcome in children with posthemorrhagic hydrocephalus, 78 children with intraventricular hemorrhage grade 3 or 4 were analyzed concerning the outcome in relation to the grade of intraventricular hemorrhage and intervention (surgical, medical, or no intervention) by means of a follow-up study. The mean age of the subjects at the last follow-up was 9.8 years. In children with intraventricular hemorrhage grade 4 with parenchymal hemorrhage, the outcomes in the group not requiring intervention were better than those in the groups requiring intervention, whereas in children with intraventricular hemorrhage grade 3 without parenchymal hemorrhage, there were no differences in the outcomes among the three groups with and without intervention. For the subjects who had undergone the same intervention, the outcomes in children with intraventricular hemorrhage grade 4 were worse than those in children with intraventricular hemorrhage grade 3. The outcomes in the children with surgical intervention only correlated with the grade of intraventricular hemorrhage. From these findings, we concluded that the outcomes in children with posthemorrhagic hydrocephalus were far more affected by the existence or extent of parenchymal hemorrhage than by the hydrocephalic process, which was suggested to be effectively controlled by the intervention.

[Clinical efficacy of shortened ACTH therapy --an individualized method for minimization of adverse effects--Part 1. The short-term outcome].

To minimize adverse effects and to get good efficacy of ACTH therapy against West syndrome, we tried a new 2-steps therapeutic protocol consisting of the shortened ACTH therapy and the additional ACTH therapy. In a prospective multi-institutional study, 20 patients with newly diagnosed West syndrome who had failed to respond to high-dose vitamin B6 and zonisamide were treated by this shortened ACTH therapy. Synthetic corticotropin (ACTH-Z 0.025 mg/kg/dose, max 0.25 mg) was administrated intramuscularly seven times on every other day for 14 days. At 1 month after discontinuing corticotropin, spasms and hypsarrhythmia disappeared in 10/20 (50%) and 13/17 (59%) patients respectively. Subsequently, 9 out of the 10 patients with persistent spasms received additional therapy for 1 or 2 weeks with daily intramuscular ACTH-Z, which was tapered off over a few weeks. Including the additional ACTH therapy, the disappearance of spasms and hypsarrhythmia were found in 13 patients (65%) and 13 patients (76%). Adverse effects during the shortened ACTH therapy were fewer than additional ACTH therapy but not statistically significant. Severe adverse effects were not observed in both ACTH therapy. In the 2-steps therapeutic protocol according to the response to ACTH, favorable results were obtained in seizure control, EEG findings and the degree of adverse effects.

[A neonatal case of anterior spinal artery syndrome presenting with bilateral arm paresis].

Anterior spinal artery syndrome is rare in children, especially in neonates. We present a girl with hydrops fetalis and hypothyroidism who developed flaccid paresis of both arms in the neonatal period (around day 25). MRI of the spine performed on day 52 revealed atrophic changes at C5-Th1 without Gd-DTPA-induced enhancement. Nerve conduction studies were also helpful in the diagnosis;in the upper limbs, motor potential was not elicited, while sensory nerve conduction velocity was normal. These clinical and laboratory findings suggested an atypical case of anterior spinal artery syndrome.

Epilepsy in Wolf-Hirschhorn syndrome (4p-).

PURPOSE: We investigated the evolution of epilepsy, seizure types, and effective drugs in Wolf-Hirschhorn syndrome, which is a malformation syndrome often with refractory seizures and status epilepticus. METHODS: We reviewed 11 cases of Wolf-Hirschhorn syndrome (age range, 2-25 years; SD, 7.2 years) and who were treated in Osaka University or Osaka Medical Center of Research Institute for Maternal and Child Health. RESULTS: In all patients, febrile or afebrile convulsions had developed. Epileptic seizures included alternative hemiconvulsions, generalized tonic-clonic seizures, focal clonic seizures, tonic seizures, and epileptic spasms. Seizures were often induced by a high fever or a hot bath. Status epilepticus occurred in all patients, including one patient who died at the first status epilepticus. In some cases, intratracheal intubation was needed because of respiratory insufficiency. The effective antiepileptic drugs for long-term use were sodium bromide (four of four), followed by clorazepate (CLP; one of two), and nitrazepam (NZP; two of four). Sodium bromide was particularly effective for preventing status epilepticus. The mean age of last status epilepticus in patients receiving sodium bromide (1 year 8 months) was significantly younger than that in those not treated with sodium bromide (3 year 4 months). CONCLUSIONS: We identified that, in most patients of Wolf-Hirschhorn syndrome, the frequency of both seizures and status epilepticus decreased gradually after age 5 years. However, during infancy, status epilepticus sometimes resulted in permanent disability or even death. We propose that sodium bromide should be used as the initial treatment for the prevention of the development of status epilepticus associated with Wolf-Hirschhorn syndrome.

[An autopsy case of cryptococcal meningoencephalitis: correlation of MRI and pathologic findings].

A comparative study of MRI and pathology was performed on a case of cryptococcal meningoencephalitis. An 11-year-old female presented with confusion and vomiting. On admission, CSF examination revealed spherical fungal cells with mild pleocytosis, decreased glucose and elevated protein level. MRI showed multiple punctate lesions in the basal ganglia with high intensity on T2-weighted image, while enhanced MRI revealed diffuse meningeal involvement. Post-mortem examination disclosed that the T2-weighted lesions found in the basal ganglia were aggregated small cystic lesions consisting of a cryptococcal invasion of Virchow-Robin spaces, termed "soap bubble lesions", characteristic findings of cryptococcal meningoencephalitis. Thus MRI findings of the basal ganglia and meninges may help to diagnose cryptococcal meningoencephalitis.