Low-dose ACTH therapy for West syndrome: initial effects and long-term outcome.

BACKGROUND: Most Japanese pediatric neurologists attempt other treatments before using adrenocorticotropic hormone (ACTH) therapy for West syndrome (WS), and even then, they use only a low-dose synthetic ACTH to avoid serious adverse effects. In this multi-institutional study, the authors analyzed the initial effects, adverse effects, and long-term outcome in patients treated with low-dose synthetic ACTH in Japan. METHODS: The medical records of 138 patients with WS, who were treated with low-dose synthetic ACTH therapy for the first time at the authors' institutions between 1989 and 1998, were analyzed. RESULTS: At the end of ACTH therapy, excellent effect on seizures was noted in 106 of 138 (76%) patients, good effect in 23 (17%), and poor effect in 9 (7%). Initial effects on EEG were excellent in 53 of 138 (38%) patients, good in 76 (55%), and poor in 9 (7%). As for seizure prognosis at the time of follow-up, 51 of 99 (52%) patients were seizure-free, whereas 48 (48%) patients had seizures. Mental outcome was normal in 6 of 98 (6%) patients, mild mental retardation in 16 (16%), moderate mental retardation in 26 (27%), and severe mental retardation in 50 (51%). The initial effects of ACTH on seizures and long-term outcome were not dose dependent (daily dosage 0.005 to 0.032 mg/kg, 0.2 to 1.28 IU/kg; total dosage 0.1 to 0.87 mg/kg, 4 to 34.8 IU/kg). The severity of adverse effects correlated with total dosage of ACTH, and the severity of brain volume loss due to ACTH correlated well with the daily dosage and total dosage of ACTH. CONCLUSION: Low-dose synthetic ACTH therapy is as effective for the treatment of WS as the higher doses used in previous studies. The dosage of synthetic ACTH used in the treatment of WS can be decreased as much as possible to avoid serious adverse effects.

[A case of peculiar type of post-encephalitic/encephalopathic epilepsy: efficacy of bromide in the control of intractable seizures].

A 5-year-old boy with a peculiar type of post-encephalitic/encephalopathic epilepsy is reported. He had been healthy showing normal development before its onset. Five days after the onset of an upper respiratory infection, he had a severe generalized seizure, that evolved into intractable seizures. They were highly resistant to almost all anticonvulsants and occasionally resulted in status epilepticus. High-dose phenobarbital therapy successfully controlled the convulsions, but was discontinued because of drug-induced aplastic anemia. Alternative bromide therapy was markedly effective in controlling the seizures.

Possible participation of isolated epicardial cell clusters in the formation of chick embryonic epicardium.

The embryonic epicardium is formed by the spreading of cells derived from the extracardiac proepicardial organ over the myocardial surface after transfer to the dorsal side of the myocardium via a bridge of villous projections. Using whole-heart immunostaining for keratin, we found that the chronology and pattern of epicardial formation in the chick was basically identical to that reported previously in the quail. However, discrete epicardial islands were observed on the ventrolateral surface of the atrioventricular canal as well as in two previously reported areas. Closer examination by scanning electron microscopy demonstrated the presence of isolated, sparsely distributed epicardial cell clusters on both the dorsal and ventral surfaces of the myocardium. These cells showed a surface morphology similar to that of the epicardial cells at the advancing edge of the spreading epicardial sheet and possessed numerous well-developed filopodia, suggesting active motility. These clusters are probably seeded onto the myocardium by vesicular transport from proepicardial villi, and our findings suggest that the resulting small, localised patches of epicardial cells might accelerate, supplement and tune the epicardial formation mediated by radial spreading of the epicardial sheet in the chick embryonic heart.

[Acute disseminated encephalomyelitis in a 3-month-old infant].

Acute disseminated encephalomyelitis (ADEM) is a demyelinating disease showing multifocal central nervous system lesions due to an autoimmune disorder. We reported a 3-month-old girl with ADEM. One week after having a cold, she presented with somnolence, poor feeding and vomiting. When she was admitted three days after the onset, she could neither fix or follow objects with her eyes nor respond to sound. Her muscle tone was decreased. Cerebrospinal fluid examination revealed pleocytosis, elevated protein concentration and positive myelin basic protein. No oligoclonal band was detected. Diffuse monomorphic slow wave activity was noted on the electroencephalogram. Only wave I was present bilaterally on the auditory brainstem response. T2 weighted images of magnetic resonance imaging revealed multiple areas of high signal in the right posterior limb of the internal capsule, white matter of the cerebellum and brainstem. She was diagnosed as having ADEM, and underwent high dose gamma-globulin therapy. Corticosteroids were not given because of her high blood pressure. The clinical symptoms improved continuously before and after the administration. Two years after the onset, she showed normal growth and development without reoccurrence. The age at onset of childhood ADEM is usually 3 or 4 years. ADEM before one year of age is very rare. The demyelinating lesions of this case corresponded to the regions which normally become myelinated by 3 months. Although ADEM is usually treated with corticosteroids, high dose gamma 1-globulin therapy can be considered if patients are very young or have a high risk for corticosteroid, or respond poorly to corticosteroids.

A variant case of congenital bilateral perisylvian syndrome with asymmetric findings on neuroimaging and septum pellucidum defect.

We report a 17-year-old female patient with a variant form of congenital bilateral perisylvian syndrome (CBPS). She had pseudobulbar palsy, partial epilepsy and mild pyramidal symptoms predominantly in the left hand. Magnetic resonance imaging revealed asymmetric perisylvian and perirolandic polymicrogyric cortical dysplasia and septum pellucidum defect. The clinicoradiological findings for this patient met the criteria for CBPS. Moreover, they appeared to overlap those of congenital unilateral perisylvian syndrome. The findings in this case support the hypothesis that these two syndromes are parts of a continuous spectrum of one clinico-radiological syndrome.

Observation of the abluminal surface of the atrioventricular endothelium which undergoes transition into cardiac cushion mesenchymal cells in the chick embryo.

In the developing chick heart, endothelial cells in the atrioventricular canal (AV) undergo a series of morphological changes and transform into cushion mesenchymal cells. In the present scanning electron microscopic study, we examined the abluminal surface features of the AV endothelium through an artificial window in the myocardial wall. The AV endothelial cell at stages 12 or earlier had a smooth, flattened basal surface with only a few blebs. In the successive stages, the abluminal surface exhibited remarkable changes; 1) the number of blebs increased, 2) elongated microvillous projections emerged, and 3) a thick filopodium, or a migratory appendage developed. It appeared, however, that these changes do not occur synchronously within the entire AV endothelium but were initially observed mostly in the proximity of the endothelial "crease" which was a limited invagination of the endothelial sheet towards the underlying acellular matrix. In addition, even in the proximity of the crease, endothelial cells with flattened basal surfaces were also observed next to endothelial cells that showed apparent morphological indications of transition into mesenchymal cells. These findings suggest that AV endothelial cells are possibly heterogeneous in the competency of transformation into mesenchymal cells and such heterogeneity would be important for maintaining the continuity of the AV endothelium.

Regional excitatory and inhibitory amino acid concentrations in Noda epileptic rat (NER) brain.

We measured regional concentrations of excitatory and inhibitory amino acids in Noda epileptic rat (NER) brains to investigate the mechanisms responsible for spontaneous generalized seizures. Compared with Fisher 344 (F344) rats and F1 hybrid (female NER x male F344 rat) rats, NERs had significantly higher concentrations of glycine in the cerebellum. NERs and F1 hybrid rats had significantly lower concentrations of taurine in the cerebellum than did F344 rats. Although our findings do not explain sufficiently the mechanisms directly responsible for spontaneous seizures, they suggest that the cerebellum of NER may be in an excited state to dampen seizures, while the cerebellum of F1 hybrid rats may also be slightly excited to inhibit milder forms of seizures. Further studies, including microdialysis and receptor binding assays, will be required to elucidate these mechanisms.

A case of West syndrome well controlled by very short and low-dose ACTH therapy.

The case of a 5-month-old boy with tuberous sclerosis and West syndrome is reported. Tonic spasms were noted from the age of 4 months. High-dose pyridoxal phosphate could not control the seizures completely. Very short and low-dose adrenocorticotropic hormone (ACTH) therapy (i.e. 0.011 mg/kg per dose, 12 times in 20 days) controlled the seizures, while pyridoxal phosphate was on. Early tapering of ACTH was successfully done while abnormal electroencephalogram (EEG) findings remained. Although side effects such as hypertension and brain shrinkage were transiently observed, both the cognitive and seizure prognoses were excellent at the age of 3 years and 2 months. The good response to a small dosage of ACTH might be due to some responsiveness of the high-dose pyridoxal phosphate and the underlying cause of tuberous sclerosis with normal development before onset. The present case illustrates that the duration and dosage of ACTH therapy in West syndrome should be modified according to the individual's requirements.

Endothelial outgrowth and the subsequent cell transition in the culture of embryonic atrioventricular canal placed in an inverted polarity.

Endothelial cells in the atrioventricular (AV) segment of the developing chicken heart undergo a transition into mesenchymal cells. When the AV segment is explanted onto a hydrated collagen gel, endothelial cells grow out and reproduce in vivo cell transition regardless of the precise orientation of the explant on a gel. Our results showed that when the luminal side of an explant was placed towards a gel surface, the inverted polarity of endothelium was not adjusted by direct reorganization of polarity, but that the endothelium crawled down so as to settle on a gel surface in the correct original cell polarity. Subsequently, endothelial cells showed cytoplasmic hypertrophy, formed microvillous projections and then extended filopodial migratory appendages. These cellular changes were quite similar to those in vivo. However, the continuity of the endothelial layer was specifically disrupted in AV explant cultures. Such disruption was never observed in ventricle explant cultures in which endothelial-mesenchymal cell transition did not occur. The disintegration of AV endothelial outgrowth must be closely related to its capability to transform into mesenchymal cells and mitotic activity to keep a depository of endothelial cells.

Technetium-99m-HMPAO SPECT in patients with hemiconvulsions followed by Todd's paralysis.

We performed technetium-99m-hexamethylpropylene- amineoxime (Tc-HMPAO) single photon emission computed tomography in two patients with prolonged hemiconvulsions followed by transient hemiparesis (Todd's paralysis). In both cases, a prolonged post-ictal cerebral hyperperfusion state of approximately 24 h was observed, even after the neurological deficits had resolved. The cerebral hyperperfusion in both cases was of much longer duration than that in previously reported cases of single and uncomplicated focal seizures. The prolonged cerebral hyperperfusion might have been due to impairment of the cerebrovascular autoregulation in seizures followed by Todd's paralysis.

Visualization of sulfated glycoconjugates in the chicken embryonic heart by whole-mount alcian blue staining.

In the atrioventricular canal (AVC) and outflow tract (OT) of the developing heart, endothelial cells transform specifically to mesenchymal cells. The mesenchymal cells migrate into the underlying acellular matrix termed cardiac jelly and form endocardial cushion tissue. It is believed the that the highly hydrated nature of cardiac jelly is ascribed to sulfated glycoconjugates in the components of jelly matrix. In the present study, we have visualized the distribution and its temporal changes of sulfated glycoconjugates in the embryonic heart from stage 12 to 26 using whole mount alcian blue (AB) histochemistry. Atrial matrix was AB-negative in all the stages examined. Cardiac jelly in the AVC and OT were positive and the staining intensity increased as heart development proceeded, while AB-positive staining in the matrix of the ventricle became negative by stage 19. At stages later than 19, AB-positive matrix was localized in only the AVC and OT where endothelially-derived mesenchymal cells populated.

Regional excitatory and inhibitory amino acid concentrations in pentylenetetrazol kindling and kindled rat brain.

We determined regional concentrations of excitatory and inhibitory amino acids in pentylenetetrazol (PTZ) kindling and kindled rat brains in order to investigate the mechanisms responsible for the PTZ kindling process and kindled state. Compared with control rats, PTZ kindling rats had significantly higher concentrations of aspartate in the striatum and the temporal cortex 24 h after the 14th injection of PTZ. Glutamate and GABA concentrations were also significantly higher in the brainstem of PTZ kindling rats 24 h after the 14th injection of PTZ. These findings suggest that the striatum and temporal cortex may participate in a pathway for propagation of the PTZ kindling process, and that the brainstem may be a primary site of PTZ kindling epileptogenesis or a part of the pathways for propagation. On the other hand, the concentrations of amino acids in PTZ kindled rats and controls did not differ 4 weeks after the 14th injection. This suggests that the alterations we detected in amino acid metabolism are not related to retention of the PTZ kindled state, and that some other mechanism for it must exist.

Magnetic resonance imaging with fluid-attenuated inversion recovery pulse sequences in MELAS syndrome.

We report the brain magnetic resonance imaging findings in the case of a 5-year-old boy with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Fluid-attenuation inversion recovery (FLAIR) imaging revealed multifocal abnormal cortical signals which were difficult to see on conventional T1- and T2-weighted images. Although the patient was in an advanced clinical stage of disease and had severe cortical atrophy, FLAIR imaging demonstrated characteristic findings of MELAS.

[A quantitative study of regional cerebral blood flow in childhood using 123I-IMP-SPECT: with emphasis on age-related changes].

Single photon emission computed tomography (SPECT), using N-isopropyl-p-[123I] iodoamphetamine (123I-IMP) was used for quantitative analysis of regional cerebral blood flow (rCBF) on 26 individuals between 0 and 19 years of age. The rCBF showed age-related changes; it was low in early infancy, increased in late infancy through early childhood, and decreased and remained constant after puberty. The rCBF through cerebral cortex varied more greatly than through thalamus and cerebellum, and seemed to depend more closely on age. In the case of 4 months of age rCBF was very low at the frontal region and was very high at the occipital region. In more older cases, rCBF in the cerebral cortex was higher than in the thalamus. In childhood, rCBF was very inconsistent and showed a great inter-individual variance.

[Effect of the ketogenic diet for West syndrome into which early infantile epileptic encephalopathy with suppression-burst was evolved].

A male infant with early infantile epileptic encephalopathy (EIEE) was reported. Tonic spasms in series appeared since 1 month after birth and EEG showed a typical suppression-burst pattern. The patient was treated with a high-dose pyridoxal phosphate and thyrotropin-releasing hormone (TRH), but seizures were not controlled. ACTH was administered and the seizures disappeared transiently. The seizures reappeared during tapering ACTH and apparent cerebral shrinkage followed the ACTH therapy. Then, the patient who evolved into West syndrome was treated with ketogenic diet. The seizures disappeared immediately and EEG findings were improved. It is suggested that the ketogenic diet should be tried early for the treatment of EIEE.

Molecular genetic analysis of a female patient with pyruvate dehydrogenase deficiency: detection of a new mutation and differential expression of mutant gene product in cultured cells.

A new 18 bp insertion mutation in the gene for the alpha subunit of pyruvate dehydrogenase (E1 alpha) was found in a female patient with congenital lactic acidaemia. Cultured skin fibroblasts and Epstein-Barr virus-transformed lymphoblastoid cells from this patient showed decreased and normal pyruvate dehydrogenase complex (PDHC) activity, respectively. This 18 bp insertion was a de novo mutation, because it was not present in her parents. Although this female patient was heterozygous for the normal and the mutant alleles, 97% of cultured skin fibroblasts expressed the mutant allele, while 100% of cultured lymphoblastoid cells, 94% of peripheral blood lymphocytes and 98% of IL-2-activated T-cells expressed the normal allele. These results suggest that in this patient the X chromosome containing the normal allele was predominantly inactivated in fibroblasts and the X chromosome containing the mutant allele was predominantly inactivated in lymphocytes. The diagnosis of E1 alpha deficiency is usually established by measurement of PDHC activity and the level of immunoreactive proteins. However, these methods are not sufficient to diagnose the disorder in female patients with E1 alpha deficiency due to differential inactivation of the X chromosome. Therefore, it is necessary to develop a new method to firmly establish the diagnosis of E1 alpha deficiency.

GABA-gated chloride ion influx in brains of tremor rats.

We measured the GABA-gated chloride ion influx and GABA concentrations in the cerebral cortex and the hippocampus of young (5 weeks old) and older (15 weeks old) tremor rats. GABA-gated chloride ion influx in these tremor rats was significantly greater than in the controls of both the 5 week- and 15 week-old groups. GABA concentrations in the cerebral cortex and hippocampus of the tremor rats increased compared with controls of 5 weeks and decreased compared with controls of 15 weeks. These findings suggest that the GABAergic presynaptic neurons in the cortex and hippocampus of the tremor rat are disturbed with aging. This change may be related to the appearance of absence-like seizures in the rats. The increased GABA-gated chloride ion influx in tremor rats may be a compensatory mechanism against the genetically-determined seizure susceptibility of these rats. Furthermore, the increased GABA levels and GABA-gated chloride ion influx found in 5 week-old tremor rats may be related to the tremor movements.

Cloning and sequencing of the cDNA encoding a mouse tissue inhibitor of metalloproteinase-2.

A mouse cDNA encoding a tissue inhibitor of metalloproteinases (mTIMP-2) was cloned and the 1695-bp sequence was determined. While high homology was observed with the sequences encoding the human (hTIMP-2) and bovine (bTIMP-2) genes, mTIMP-2 contained a long 3'-nontranslated region not observed in the hTIMP-2 or bTIMP-2 genes.

One-step sandwich enzyme immunoassay for human laminin using monoclonal antibodies.

A one-step sandwich enzyme immunoassay (one step sandwich EIA) for human serum immunoreactive laminin was set up with a pair of monoclonal antibodies prepared against human placental laminin P1 fragment. The assay was characterized by carrying out two immunoreactions simultaneously, laminin P1 fragment reacting with both a monoclonal antibody as a solid phase and a horseradish peroxidase-labeled monoclonal antibody (Fab') against human laminin P1 fragment as conjugate. Sensitivity of the immunoassay was 0.01 ng/well (0.5 microgram/l), and linearity was obtained between 0.01-20 ng/well (0.5-1,000 micrograms/l). The levels of laminin in sera from normal individuals and patients with liver cirrhosis, hepatocellular carcinoma and primary biliary cirrhosis were 103 +/- 15 micrograms/l, 228 +/- 70 micrograms/l, 341 +/- 163 micrograms/l and 232 +/- 93 micrograms/l, respectively. Protein immunoblotting showed that the serum immunoreactive laminin measured by the assay was a fragment with rel mol mass of 200 kDa.