Bilateral cerebellar cysts and cerebral white matter lesions with cortical dysgenesis: Expanding the phenotype of LAMB1 gene mutations.

LAMB1 gene analysis should be considered for intellectually disabled patients with cerebellar cysts, white matter signal change, and cortical malformation. Muscular involvement is absent, in contrast to the α-dystroglycanopathy types of congenital muscular dystrophies.

Characterization of SPATA5-related encephalopathy in early childhood.

Mutations in SPATA5 have recently been shown to result in a phenotype of microcephaly, intellectual disability, seizures, and hearing loss in childhood. Our aim in this report is to delineate the SPATA5 syndrome as a clinical entity, including the facial appearance, neurophysiological, and neuroimaging findings. Using whole-exome sequencing and Sanger sequencing, we identified three children with SPATA5 mutations from two families. Two siblings carried compound heterozygous mutations, c.989_991del (p.Thr330del) and c.2130_2133del (p.Glu711Profs*21), and the third child had c.967T>A (p.Phe323Ile) and c.2146G>C (p.Ala716Pro) mutations. The three patients manifested microcephaly, psychomotor retardation, hypotonus or hypertonus, and bilateral hearing loss from early infancy. Common facies were a depressed nasal bridge/ridge, broad eyebrows, and retrognathia. Epileptic spasms or tonic seizures emerged at 6-12 months of age. Interictal electroencephalography showed multifocal spikes and bursts of asynchronous diffuse spike-wave complexes. Augmented amplitudes of visually evoked potentials were detected in two patients. Magnetic resonance imaging revealed hypomyelination, thin corpus callosum, and progressive cerebral atrophy. Blood copper levels were also elevated or close to the upper normal levels in these children. Clinical delineation of the SPATA5-related encephalopathy should improve diagnosis, facilitating further clinical and molecular investigation.

Fulminant sepsis-associated encephalopathy in two children: serial neuroimaging findings and clinical course.

We report on two children with sepsis-associated encephalopathy. They presented with fulminant neurological damage on clinical, neuroimaging, and neurophysiological findings. At onset, both went into deep coma after status epilepticus, resulting in near brain death. Both patients showed diffuse brain edema on CT and severe brain dysfunction on electroencephalography within a day of onset. Brain magnetic resonance (MR) imaging of one patient on day 2 showed restricted diffusion in the basal ganglia and the subcortical white matter of the frontal and occipital lobes. Brain edema aggravated and lasted for a few months despite a variety of treatments. MR imaging in the chronic phase revealed cracking lesions extending to the cerebral white matter, the cerebellum, and the brainstem. MR angiography showed diminished intracranial major arteries. These serial neuroradiological findings suggested severe brain damage resulting from fulminant elevation of intracranial pressure, which mimicked "brain death" or "respirator brain".

A nationwide survey of pediatric acquired demyelinating syndromes in Japan.

OBJECTIVE: To investigate the clinical and epidemiologic features of pediatric acquired demyelinating syndromes (ADS) of the CNS in Japan. METHODS: We conducted a nationwide survey and collected clinical data on children with ADS aged 15 years or younger, who visited hospitals between 2005 and 2007. RESULTS: Among 977 hospitals enrolled, 723 (74.0%) responded to our inquiries and reported a total of 439 patients as follows: 244 with acute disseminated encephalomyelitis (ADEM), 117 with multiple sclerosis (MS), 14 with neuromyelitis optica (NMO), and 64 with other ADS. We collected and analyzed detailed data from 204 cases, including those with ADEM (66), MS (58), and NMO (10). We observed the following: (1) the estimated annual incidence rate of pediatric ADEM in Japan was 0.40 per 100,000 children (95% confidence interval [CI], 0.34-0.46), with the lowest prevalence in the north; (2) the estimated prevalence rate of MS was 0.69 per 100,000 children (95% CI, 0.58-0.80), with the lowest prevalence in the south; (3) NMO in Japan was rare, with an estimated prevalence of 0.06 per 100,000 children (95% CI, 0.04-0.08); and (4) the sex ratio and mean age at onset varied by ADS type, and (5) male/female ratios correlated with ages at onset in each ADS group. CONCLUSIONS: Our results clarify the characteristic clinical features of pediatric ADS in the Japanese population.

Plasticity of central motor and sensory pathways in a case of unilateral extensive cortical dysplasia: investigation of magnetic resonance imaging, transcranial magnetic stimulation, and short-latency somatosensory evoked potentials.

We studied a 13-year-old girl with unilateral extensive cortical dysplasia who had mild hemiparesis with mirror movement and no sensory deficit. Transcranial focal magnetic stimulation (TMS) to the unaffected hemisphere elicited bilateral motor evoked potentials (MEPs) of the abductor pollicis brevis muscle (APB) with similar latency and amplitude. The scalp positions where the MEP amplitudes were highest were at the same site in the unaffected hemisphere for both APBs. TMS to the affected heimsphere showed no MEP for either APB. These data indicated that the APB response of the paretic side originated from the same motor cortex as for the contralateral APB, probably due to axonal sprouting. In the study of short-latency somatosensory evoked potentials, the cortical representation point of the paretic hand sensation was in the ipsilateral unaffected hemisphere; this point was located anterior to the cortical representation point of the contralateral hand sensation. We conclude that reorganization of primary motor and sensory cortex occurs when there is unilateral extensive brain damage in early gestation.

Normalization of creatine kinase level during arthritis in a patient with Becker muscular dystrophy.

A patient with Becker muscular dystrophy had transient arthritis. During the active illness his serum creatine kinase (CK) level normalized and serum levels of soluble interleukin 2 (IL-2) receptor, IL-6, IL-1 receptor antagonist, and soluble tumor necrosis factor receptor 2 were elevated. CK increased to his usual levels after arthritis remission whereas the levels of inflammatory cytokines and their inhibitors decreased.

Multiple epiphyseal dysplasia with small head, congenital nystagmus, hypoplasia of corpus callosum, and leukonychia totalis: a variant of Lowry-Wood syndrome?

We report on a boy with multiple epiphyseal dysplasia (MED), mild short stature, small head, mental retardation and congenital nystagmus associated with other visual problems. These manifestations were similar to those seen in Lowry-Wood syndrome (LWS). He also had hypoplasia of the corpus callosum and leukonychia totalis, which were not described in the previous cases.

Somatosensory evoked high-frequency oscillations recorded directly from the human cerebral cortex.

OBJECTIVE: To elucidate the generator sources of high-frequency oscillations of somatosensory evoked potentials (SEPs), we recorded somatosensory evoked high-frequency oscillations directly from the human cerebral cortex. SUBJECTS AND METHODS: Seven patients, 6 with intractable partial epilepsy and one with a brain tumor, were studied. With chronically implanted subdural electrodes, we recorded SEPs to median nerve stimulation in all patients, and also recorded SEPs to lip and posterior tibial nerve stimulation in one. High-frequency oscillations were recorded using a restricted bandpass filter (500-2000 Hz). RESULTS: For the median nerve oscillations, all oscillation potentials were maximum at the electrodes closest to the primary hand sensorimotor area. Most oscillations were distributed similar to or more diffusely than P20/N20. Some later oscillations after the peak of P20 or N20 were present in a very restricted cortical area similar to P25. We investigated the phase change of each oscillation potential around the central sulcus. One-third of the oscillations showed phase reversal around the central sulcus, while later oscillations elicited in a restricted cortical area did not. High-frequency oscillations to posterior tibial nerve and lip stimulation were also maximum in the sensorimotor areas. Most of the lip oscillations showed phase reversal around the central sulcus, but most of the posterior tibial nerve oscillations did not. CONCLUSION: High-frequency oscillations are generated near the primary sensorimotor area. There are at least two different generator mechanisms for the median nerve high-frequency oscillations. We suspect that most oscillations are derived from the terminal segments of thalamocortical radiations or from the primary sensorimotor cortex close to the generator of P20/N20, and some later oscillations from the superficial cortex close to the generator of P25.

Bilateral opercular syndrome caused by perinatal difficulties.

Four patients with pseudobulbar palsy, mental retardation and various degrees of speech disturbance associated with perinatal difficulties are described as having an acquired type of opercular syndrome. There were two patients with fetal bradycardia and three with subarachnoid haemorrhage and neonatal convulsion. Magnetic resonance imaging revealed cortical atrophy in the bilateral opercula with some signal abnormalities in the underlying white matter in common. Single photon emission computed tomography (SPECT) also confirmed the presence of hypoperfusion in the regions. Although the opercular syndrome is a clinical entity with a multitude of underlying pathologies, perinatal difficulties could be an important cause of the acquired type.

Facilitation of ipsilateral motor pathways during recovery from hemiplegia in two adolescent patients.

In two hemiplegic patients with acquired cerebral lesions, transcranial magnetic stimulation (TMS) was carried out to examine the contribution of the ipsilateral motor pathways to recovery from hemiplegia. A 13-year-old girl (patient 1) had acute hemiplegia due to a rupture of an arteriovenous malformation, and a 13-year-old boy (patient 2) had subacute hemiplegia due to a brain tumour. They showed complete upper limb palsy but recovered after therapy; patient 1 had slightly disabled motor function of the arm, and patient 2 recovered completely. Motor evoked potentials (MEPs) were recorded from the biceps brachii muscles on both sides. The MEPs of the paretic biceps were only elicited by TMS of the intact hemisphere at the beginning of recovery from hemiplegia, but not by TMS of the affected hemisphere. The MEP amplitudes increased and cortical representation areas for the paretic biceps by TMS were enlarged temporarily during recovery. They regressed in patient 1 and MEPs were not evoked at all in patient 2 after recovery. Conversely, MEPs were obtained by TMS of the affected hemisphere after recovery in both patients. These data indicate that ipsilateral motor pathways play a role in recovery from hemiplegia, especially at the beginning, and become inactivated when the contralateral motor pathways recover.

Nerve growth factor levels in cerebrospinal fluid from patients neurologic disorders.

Nerve growth factor levels were measured in the cerebrospinal fluid from 73 patients with neurologic disorders and non-neurologic acute illnesses by a two-site enzyme immunoassay. Elevated nerve growth factor levels in cerebrospinal fluid were demonstrated in 2 of 7 patients with bacterial meningitis, 7 of 14 patients with viral meningitis or encephalitis, and 1 with multiple sclerosis. Follow-up examinations of the 3 patients (1 with bacterial meningitis, 1 with viral meningitis, and 1 with multiple sclerosis) at convalescent stage showed diminished nerve growth factor levels in cerebrospinal fluid. None of the other patients showed elevation of nerve growth factor levels in cerebrospinal fluid. Nerve growth factor levels in cerebrospinal fluid were not correlated with cell numbers in patients with meningitis or encephalitis. No relationship was observed between nerve growth factor levels and outcome in patients with viral meningitis or encephalitis and bacterial meningitis. Nerve growth factor in cerebrospinal fluid may play a role in neuronal recovery or function as an immunomodulator in children with inflammatory and immune-mediated neurologic disorders.

Blink reflex in cerebral palsy: evaluation of late components in patients with normal auditory brainstem responses.

The electrically elicited blink reflex was examined and evaluated quantitatively in 60 controls and seven patients with cerebral palsy due to perinatal asphyxia who exhibited normal auditory brainstem responses. In the controls, the early component (R1) latency changed slightly from infancy to adulthood, and the late component (R2 and R2') latencies decreased to adult values by 4 to 6 years of age. The electromyographic activity of R2 and R2' increased later and became mature in the young adolescent period. Prolonged R2 latency and decreased R2 amplitude were observed more frequently than R1 abnormalities in the patients. The electromyographic activity of R2 in the patients was lower than that in control subjects more than 13 years old. Almost all patients showed bilateral cerebral atrophy and dilated lateral ventricles, but only one patient exhibited distinct pontine atrophy on cranial computed tomographic scan. These electrophysiologic abnormalities suggest that decreased excitability of interneurons of the reflex arc was present in the patients, particularly in older ones. The blink reflex test seems to be more sensitive than the auditory brainstem response for detecting brainstem dysfunction in patients with cerebral palsy due to neonatal asphyxia.

Intracranial calcifications, epilepsy, and optic atrophy associated with metaphyseal dysplasia: a case report.

A 15-year-old boy presenting with epilepsy, optic atrophy and intracranial calcifications was diagnosed as having metaphyseal dysplasia by bone X-ray examinations. The patient had no laboratory data suggesting other metabolic or endocrinologic disorders. In addition, CT scans showed unique intracranial calcifications of the corpus callosum and periventricular and subcortical white matter, which were distinct from those of previously reported disorders. This case may represent a unique subset or a new type of metaphyseal dysplasia associated with intracranial calcifications and central nervous system symptoms.

Sensorineural deafness in siblings with adenosine deaminase deficiency.

Two siblings with adenosine deaminase deficiency were successfully treated with allogeneic bone marrow transplantation without conditioning. Although the patients were free from infections after immunologic reconstitution, both showed sensorineural deafness at 1 year of age. Because there were no structural abnormalities in the inner and middle ears, no evidence of prenatal infections of rubella, cytomegalovirus or toxoplasma, and no postnatal infection of mumps in the siblings, sensorineural deafness might be one of the neurologic problems associated with adenosine deaminase deficiency.

Epileptic negative myoclonus induced by carbamazepine in a child with BECTS. Benign childhood epilepsy with centrotemporal spikes.

A 7-year-old female with benign childhood epilepsy with centrotemporal spikes developed epileptic negative myoclonus (ENM) seizures during carbamazepine (CBZ) treatment. She had experienced nocturnal partial seizures since 5 years of age. Interictal electroencephalography demonstrated typical rolandic discharges. Valproate was first initiated at 6 years of age, but the seizures were uncontrollable. Carbamazepine was added and valproate withdrawn. The frequency of partial seizures did not decrease. Moreover, she had brief episodes of tone loss in each or both arms and eye blinking several weeks after CBZ introduction. Unilateral loss of arm tone corresponded to spike-and-wave discharges in the contralateral centrotemporal region, and a loss of tone in arms was associated with bilateral synchronous discharges. Eye blinking was also related to bilateral synchronous discharges and classified as a myoclonic seizure. The ENM and myoclonic seizures disappeared soon after CBZ withdrawal. Therefore the authors concluded that CBZ induced the ENM and myoclonic seizures in this patient. CBZ sometimes induces generalized seizures in the treatment of partial epilepsy and generalized epilepsy. CBZ-induced ENM seizures should be considered when a brief lapse of tone appears during CBZ treatment.

Neuroleptic malignant syndrome and methylphenidate.

A 1-year-old female presented with neuroleptic malignant syndrome probably caused by methylphenidate. She had defects in the supratentorial brain including the basal ganglia and the striatum (multicystic encephalomalacia) due to severe perinatal hypoxic-ischemic encephalopathy, which was considered to be a possible predisposing factor causing neuroleptic malignant syndrome. A dopaminergic blockade mechanism generally is accepted as the pathogenesis of this syndrome. However, methylphenidate is a dopamine agonist via the inhibition of uptake of dopamine, and therefore dopaminergic systems in the brainstem (mainly the midbrain) and the spinal cord were unlikely to participate in the onset of this syndrome. A relative gamma-aminobutyric acid-ergic deficiency might occur because diazepam, a gamma-aminobutyric acid-mimetic agent, was strikingly effective. This is the first reported patient with neuroleptic malignant syndrome probably caused by methylphenidate.

Mitochondrial encephalomyopathy with 15915 mutation: clinical report.

A 16-year-old boy with mitochondrial encephalomyopathy had seizures, short stature, muscle weakness, progressive hearing loss, mental retardation, and myoclonus. His cranial computed tomography showed progressive calcification in the basal ganglia and cerebral atrophy. Muscle biopsy revealed many ragged-red fibers with variable cytochrome c oxidase activity and some strongly succinate dehydrogenase-reactive blood vessels. Sequence analysis of the entire mitochondrial DNA revealed a novel point mutation in the tRNA-Thr gene at nucleotide pair 15915. Serum lactate levels were decreased by high-dose coenzyme Q10 (CoQ10) therapy. The spectral power density, a parameter of background activity on electroencephalography, was markedly improved after additional administration of idebenone. After initiation of combined CoQ10 and idebenone therapy, the clinical abnormalities did not progress for 16 months.

Successful treatment of progressive myoclonus epilepsy with TRH.

Thyrotropin-releasing hormone (TRH) is sometimes used for the treatment of neurologic disorders such as intractable epilepsy and spinocerebellar degeneration. A 14-year-old girl with progressive myoclonus epilepsy was treated with intravenous TRH for 12 months. Clinical symptoms, such as cortical myoclonus and cerebellar signs, were improved, and P25-N33 amplitudes of somatosensory-evoked potentials decreased after TRH therapy. P100 amplitudes on flash visual-evoked potentials and photosensitivity on electroencephalograms also decreased but only temporarily. Changes in neurophysiologic findings after TRH therapy indicate that TRH inhibits hyperexcitability in the sensorimotor cortex and the visual cortex. Therefore, intravenous TRH therapy is recommended as an alternative therapy in the treatment of progressive myoclonus epilepsy.

Excitability recovery curves of blink reflexes in patients with athetotic cerebral palsy.

We evaluated the brainstem function or its excitability by the blink reflex evoked with the electrical stimulation to the supraorbital nerve in 10 patients with athetotic cerebral palsy compared with 10 normal subjects and 7 spastic type patients. There were no differences in stimulus intensity, latency of R1 and R2 components, and duration and area of EMG activity of the R2 component of the blink reflex elicited by single stimulation among the two patients' groups and normal subjects. R1 recovery cycle to paired stimuli in the athetotic group showed a facilitation of the test responses by the conditioning stimuli at 100 and 200 ms intervals, but were not significantly different from those in the normals. On the other hand, the R2 recovery curve in the athetotic group showed a significant hyperexcitability at all intervals from 100 to 600 ms compared to the normals. Our results from the R2 hyperexcitable recovery to paired stimuli are indicative of increased brainstem interneuronal excitability in athetotic patients and similar to the results reported in the disorders of the basal ganglia, i.e. Parkinson's disease, dystonia and blepharospasm. We suggest that this hyperexcitability might be caused by abnormal input possibly from the basal ganglia upon these brainstem interneurons.