SPECT findings in mitochondrial encephalomyopathy.

UNLABELLED: We investigated the alterations in regional cerebral blood flow (rCBF) in mitochondrial encephalomyopathy (MEM), using [123I]N-isopropyl-p-iodoamphetamine (IMP) or 99mTc-hexamethyl propyleneamine oxime SPECT in 10 MEM patients. METHODS: Four of the patients had MEM with lactic acidosis and strokelike episodes (MELAS), 2 had Kearns-Sayre syndrome (KSS), 1 had myoclonic epilepsy with ragged red fibers (MERRF) and 3 had cytochrome C oxidase deficiency (CCOD). Cerebral perfusion reserve was obtained from 6 patients (3 MELAS, 1 MERRF, 1 KSS, 1 CCOD) for a comparative analysis using the split-dose 123I-IMP SPECT method before and after the injection of acetazolamide. RESULTS: All patients with MELAS showed focal hypoperfusion in the parietal and/or occipital lobes. Follow-up studies (3 MELAS patients) revealed extension or improvement in the abnormal perfusion. The hypoperfused lesions were correlated with abnormal CT/MRI findings. Perfusion was normal in 1 MERRF, 2 KSS and 3 CCOD patients, whereas CT/MRI findings in 1 MERRF, 1 KSS and 1 CCOD patient were abnormal. The cerebral perfusion reserve in 3 MELAS patients was decreased significantly compared with that in patients with other types of MEM (MELAS 7.4%, other MEM 33.8%; p < 0.05). CONCLUSION: The rCBF was altered specifically in patients with MELAS, suggesting that brain perfusion SPECT will be useful in diagnosing and assessing such patients. The decreased cerebral perfusion reserve in patients with MELAS may represent an important feature of the pathogenesis of the strokelike episodes. The SPECT findings of patients with other types of MEM (MERRF, KSS and CCOD) were normal.

Regional cortical dysplasia associated with suspected hypomelanosis of Ito.

A 15-year-old girl with epilepsy, whose skin lesions were reminiscent of hypomelanosis of Ito, is reported. She manifested hypopigmented linear streaks on her upper and lower limbs. Brain magnetic resonance imaging examinations demonstrated poor differentiation of cerebral gray and white matter of her left occipital lobe, with accompanying gliosis. This region also revealed narrowing of sulci, considered to be mass effect. In this region, almost continuous spike discharges were evident on electroencephalograms, and low-perfusion status was observed on single photon emission computed tomography at rest. She also manifested right lower homonymous quadrant anopsia, which may have its origin in the lesion detected, which appeared to be a migration disorder of neuroblasts in our patient, suggesting that the spectrum of hypomelanosis of Ito might be involved.

[Outcome of initial treatment with high-dose vitamin B6, valproate sodium or clonazepam in West syndrome].

We reviewed the outcome (seizures and development) of 25 cases with West syndrome in which antiepileptic drugs (valproate sodium, clonazepam) or high doses of vitamin B6, instead of ACTH therapy, were administered for the initial treatment. Five of 9 cryptogenic cases (56%) and 4 of 16 symptomatic cases (25%) showed complete cessation of spasms. In cryptogenic cases, response to vitamin B6, valproate sodium or clonazepam was not predicted by clinical features (age of onset, seizure type, initial EEG finding or treatment lag). On the other hand, response to these drugs was correlated with some clinical findings in symptomatic cases; all infants with neurocutaneous syndrome (tuberous sclerosis, neurofibromatosis type 1) had controlled infantile spasms, while none of patients with severe neonatal asphyxia or with prior other seizures responded. Twenty of 25 patients have been followed-up. The average age at follow-up was 5 years and 8 months. Prognosis of both cryptogenic and symptomatic "responders" was favorable; all had seizures controlled, and 50% had normal psychomotor development or only mild impairment (DQ > 70). Symptomatic "nonresponders" had the worst prognosis. Our results suggest that choice of drug in the initial treatment of West syndrome should be determined by clinical features (especially etiology).

A transcranial doppler ultrasonography study of cerebrovascular CO2 reactivity in mitochondrial encephalomyopathy.

BACKGROUND AND PURPOSE: To elucidate the pathogenic role of vascular involvement such as mitochondrial angiopathy in patients with mitochondrial encephalomyopathy (MEM). we used the transcranial Doppler sonography (TCD) method to detect impairment of cerebrovascular CO2 reactivity. METHODS: The cerebral perfusion reserve in 13 MEM patients, including 6 with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) was studied by TCD for different CO2 partial pressures. For the parameter of mean flow velocity, the mean spatial Doppler frequency (fm) was obtained from the right and left middle cerebral arteries and basilar artery under conditions of normocapnia, hypercapnia, and hypocapnia in cases in which hyperventilation was possible. By fitting the obtained fm and the end-tidal CO2 partial pressure (PETCO2) to the exponential formula fm = a x e(K < PETCO2), where a is the theoretical fm at a PETCO2 of 0 mm Hg, the parameter K, an index of CO2 reactivity, was calculated. RESULTS: The K value was lower than control values at at least one site of the middle cerebral arteries and basilar artery of all patients with MELAS as well as the other MEM patients except for one patient with myoclonic epilepsy with ragged-red fiber and one with Kearns-Sayer syndrome. CONCLUSIONS: Our results suggest that there is a high incidence of impairment of cerebrovascular CO2 reactivity in MEM patients. Moreover, the noninvasive TCD method was found useful for evaluation of cerebral hemodynamics in MEM patients.

Manganese deposition in the brain during long-term total parenteral nutrition.

BACKGROUND: Manganese deposition was suspected in a pediatric patient who received long-term total parenteral nutrition. T1-weighted magnetic resonance images revealed high intensity areas in the globus pallidus. This study was designed to clarify if these abnormal findings were related to manganese deposition and clinical neurological manifestations. METHODS: Whole-blood manganese concentrations were measured during manganese supplementation to total parenteral nutrition and after 5 months without manganese. Magnetic resonance images were also examined on each occasion and compared with the blood level of manganese. RESULTS: The whole-blood manganese level during supplementation was 135 micrograms/L (normal range 14.6 +/- 4.7 micrograms/L), whereas the level was 20 micrograms/L after a manganese-free period of 5 months. Accompanied with normalization of manganese level, abnormal high intensity lesions in the globus pallidus on T1-weighted images also disappeared. No neurological manifestation related to the high manganese level was recognized. CONCLUSIONS: It is probable that the high manganese level was elicited by manganese supplementation to total parenteral nutrition. This high manganese condition was confirmed by the measurement of whole-blood manganese level, which was associated with the abnormal high intensity lesions on T1-weighted magnetic resonance images.

Interaction between valproate formulation and phenytoin concentrations.

Changes in phenytoin concentrations caused by switching valproate formulations with different absorption rates were retrospectively investigated in eleven epileptic patients receiving treatment with both drugs. Total plasma phenytoin concentrations were measured before and after a standard tablet of valproate was replaced by the same dose as a slow-release tablet. The mean plasma phenytoin level rose significantly from 14.4 to 18.7 micrograms.ml-1. Nine of eleven patients had markedly increased phenytoin levels (by 21 to 72%), and two developed toxic symptoms. The results indicate that changing valproate formulations can cause major alterations in the plasma concentration of co-administered phenytoin.

[A case of pontine hematoma with Foville's syndrome in childhood].

We reported a surviving case of 6-year-old boy with pontine hematoma. He complained of headache as an initial symptom and developed progressively Foville's syndrome with impairments of the IX-XII cranial nerves. Although brainstem tumor was suspected initially using CT scan, MRI revealed the existence of hematoma in the ventromedial pons. During the first 4 months of his clinical course, Gd-DTPA did not demonstrate any enhancement in that lesion. However, hemangiomatous lesion was suspected by subsequent serial MRIs with positive Gd-DTPA enhancement. Using conservative treatment including oral corticosteroids, all the neurological deficits disappeared in several months and he did not show any recurrence of clinical signs for 3 years. It was suggested that MRI was very useful in the differential diagnosis and the follow-up of hematoma in the posterior fossa.

Central nervous system abnormalities in chromosome deletion at 11q23.

Two Japanese pediatric patients with terminal deletion of the long arm of chromosome 11 are described. Both had the morphological abnormalities of the 11q deletion syndrome, such as prominent epicanthal folds, broad flat nasal bridge with short, upturned nose, short philtrum with carp-shaped mouth, cardiac anomalies and nonprogressive moderate psychomotor developmental delay. Patient 1 is the first case to be reported with 11q deletion with serial magnetic resonance (MR) examinations of cerebral white matter. The initial MR imaging studies demonstrated multiple areas of T1 and T2 prolongation in the cerebral white matter in both patients at the ages of 2 5/12 and 2 1/12 years, respectively. A second MR imaging, performed 1 year after the first in Patient 1, demonstrated slight improvement of the lesions. Neither patient showed clinical deterioration. These results suggest that the lesions were caused by delayed myelination, rather than by demyelination. It is suggested that an unknown factor which is important for myelination is located on the long arm of chromosome 11: perhaps the neural cell adhesion molecule (NCAM).

MR diffusion imaging in Pelizaeus-Merzbacher disease.

A case of classical type Pelizaeus-Merzbacher disease was reported. This patient exhibited marked motor and mental developmental delay, and nystagmus, with a positive familial history. Electrophysiological studies, such as on brainstem auditory evoked potentials, blink reflex and somatosensory evoked potentials, suggested marked disturbance of nerve conduction in CNS. T2-weighted magnetic resonance (MR) images revealed non-progressive diffuse T2 prolongation of cerebral white matter after a 2-year interval, indicating congenital hypomyelination in CNS. A newly developed magnetic resonance diffusion imaging method demonstrated the existence of diffusional anisotropy in the corpus callosum, internal capsule, and white matter of the frontal lobe. Although the diffusional anisotropy was considered to depend on the well-developed multiple layers of myelin around the axons, the imaging data of this patient demonstrated that the diffusional anisotropy did not necessarily depend on those multiple layers. These results may indicate the potential usefulness of MR diffusion imaging, combined with electrophysiological studies and conventional MR imaging, for analyzing the lesions of the cerebral white matter.

Evaluation of myelination by means of the T2 value on magnetic resonance imaging.

The progress of myelination in the cerebrum was evaluated by visual inspection, and magnetic resonance (MR) imaging and the transverse relaxation time (T2) was calculated from double echo images. Twenty-three pediatric cases, who did not show intracranial organic changes on MR examination, were included. The T2 values in the corpus callosum (CC), frontal deep white matter (FWM), occipital deep white matter (OWM) and centrum semiovale (CS) were calculated, and the changes in these values with age were followed. During the first year of life, a rapid decrease in the T2 value was seen, followed by a more gradual decrease. The T2 value seemed to reach the adult level between 2 and 3 years of life in all areas examined. The T2 values between 2 and 16 years in CC, FWM, OWM and CS were 59.7 +/- 3.6, 64.5 +/- 5.2, 69.8 +/- 4.8 and 66.3 +/- 3.3 ms (mean +/- S.D.), respectively. The T2 values in patients with clinically diagnosed Pelizaeus-Merzbacher disease (PMD) and late onset Krabbe disease were also calculated. In PMD, non-progressive prolongation of the T2 value was observed in all areas. In late onset Krabbe disease, on the other hand, progressive prolongation of the T2 values was mainly demonstrated in OWM and the posterior part of CS. These results suggest that the T2 value in the cerebral white matter allows more objective judgement than visual inspection, and makes it possible to clarify the mechanism underlying abnormal myelination, i.e. progressive or not.

[A girl presenting clinical course and neuroimagings on MRI compatible with Pelizaeus-Merzbacher disease].

A 5-year-old girl who showed congenital nystagmus and mental and motor developmental delay, is described. Auditory brainstem responses (ABR) revealed wave I at normal latency, but all of the following waves were absent. In T2-weighted images, magnetic resonance imaging (MRI) demonstrated diffuse high intensity area of cerebral white matter, suggesting extensive dysmyelination or demyelination. She has not shown any deterioration through her clinical course. Subsequent MRI examinations did not demonstrate a progressive disorder. These findings suggest the possibility of Pelizaeus-Merzbacher (P-M) disease in this patient, which is a rare form of sudanophilic leukodystrophy, transmitted by an X-linked recessive mutant gene. It is reported that the proteolipid protein, one of the major proteins of myelin, was absent in classical type P-M disease, resulting in dysmyelination. Because chromosomal study showed the normal female karyotype and no family history of a similar disease was found in this case, it might be different from classical P-M disease. Since P-M disease may be heterogeneous, more detailed chromosomal analysis in each case of congenital hypomyelination will give a clue to clarify the pathogenesis of P-M disease and other disorders showing failure in myelination.

Purification and characterization of glutathione S-transferase isozymes in dog lens.

1. Two isozymes of glutathione S-transferase (GST-dl1 and GST-dl2) were purified to homogeneity from dog lens. 2. The subunit size and the isoelectric point were determined to be 24,000 and > pI 9.5 for GST-dl1 and 22,000 and pI 8.1 for GST-dl2. 3. It was judged that GST-dl1 is a class alpha enzyme and GST-dl2 belongs to class pi on the basis of their immunological properties and N-terminal amino acid sequences. 4. The expression pattern of glutathione S-transferase isoenzymes in dog lens is different from that in pig, rat and bovine lenses.

Glutathione S-transferase isozymes in rat lens.

Rat lens contains two classes of glutathione S-transferase (GST) isozymes; one is class mu, Yb1-Yb1, and the other is class pi, Yp-Yp, judged from their molecular weights, immunological properties and N-terminal amino acid sequences. The expression pattern of GST isozymes in the rat lens is different from that in pig and bovine lenses which have only class pi and class mu isozymes, respectively.

The moment of intraventricular hemorrhage.

A continuous monitoring of the germinal layer by linear scanning ultrasound has been proposed for the purpose of ascertaining the moment of intraventricular hemorrhage (IVH). Using a VHS videotape, we performed the 48 hours monitoring in 7 immature infants weighing less than 1,000 g who required respiratory support. Four cases of these developed IVH. In one case, which was 755 g in birth weight and 24 weeks in gestational age, the moment of IVH was successfully demonstrated on the ultrasonic monitor. At that moment, there were no significant changes in heart rate and systemic blood pressure. No direct manipulation or treatment, such as an endotracheal suctioning or a heel puncture which might induce a blood pressure fluctuation, was being given at the moment of IVH. About 15 minutes after the episode, abnormal seizure-like movement periodically developed.

Visualization of the cerebrospinal fluid drainage into the Galen's vein.

Arachnoid granulations are not always present in lower mammals and primate newborns. In order to visualize the route for the cerebrospinal fluid (CSF) to drain into the venous system, horseradish peroxidase (HRP) was injected into the lateral ventricle or cisterna cerebellomedullaris of the mouse and rat. From 30 to 60 min after the commencing of a slow infusion for 15-30 min of 0.05-0.1 ml solution containing 10-20 mg HRP, the mouse, whose skull had been exposed, was dropped into cold acetone at dry ice temperature; other animals were fixed by perfusion with aldehyde solution. The frozen head was dissected in a cryostat kept at -18 degrees C to remove the skull, but leave the dura mater and the falx cerebri. The brain with meninges was cut into 30-45 microns sagittal sections in the cryostat, and processed for peroxidase reaction. The perfusion-fixed brains were used for scanning electron microscopy and for electron microscope observation of the tracer. The reaction product was found within fenestrated venous capillaries of the choroid plexus. The route for the HRP in the CSF to drain into the sinus rectus via the vena choroidea and vena cerebri magna was directly visualized in the mouse.