Delayed posthypoxic demyelination. Association with arylsulfatase A deficiency and lactic acidosis on proton MR spectroscopy.

Delayed demyelination is a rare and poorly understood complication of hypoxic brain injury. A previous case report has suggested an association with mild-to-moderate deficiency of arylsulfatase A. We describe a 36-year-old man who recovered completely from an episode of hypoxia related to drug overdose, and 2 weeks later progressed from a confusional state to deep coma. MRI showed diffuse white matter signal changes, and brain biopsy demonstrated a noninflammatory demyelinating process. Proton magnetic resonance spectroscopy revealed elevated choline and lactate and reduced N-acetyl aspartate signal in the affected white matter, consistent with demyelination and a shift to anaerobic metabolism. Arylsulfatase A activity from peripheral leukocytes was approximately 50% of normal, consistent with a "pseudodeficiency" phenotype. These findings confirm the hypothesis that relative arylsulfatase A deficiency predisposes susceptible individuals to delayed posthypoxic leukoencephalopathy and implicates lactic acidosis in the pathogenesis of this disorder.

Calcium dependence of glutamate receptor-evoked alkaline shifts in hippocampus.

Glutamate receptor activation induces an extracellular alkalinization in rodent hippocampus. We studied its Ca2+ dependence and pharmacology in hippocampal slices. Glutamate-evoked alkaline shifts were blocked by 0 Ca2+ saline. Alkalinizations induced by AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and NMDA (N-methyl-D-aspartate) were abolished by 20 microM CNQX (6-cyano-7-nitro-nitroquinoxaline-2,3-dione) and 50 microM APV (DL-2-amino-5-phosphonovalerate), respectively. The AMPA- and NMDA-evoked alkaline shifts were blocked by 0 Ca2+, however, AMPA-induced [K+]o elevation was unaffected. These data suggest that the glutamate receptor-channel does not mediate H+ influx, and support a role for Ca(2+)-H+ exchange.

Central nervous system Sjögren's syndrome in a child: case report and review of the literature.

We describe a case of pediatric Sjögren's syndrome with progressive neurologic involvement. At age 4 years, she had been diagnosed with Melkersson-Rosenthal syndrome. After being stable with facial diplegia and swelling for 5 years, she acutely presented with diplopia, vertigo, and ataxia. Cranial magnetic resonance imaging (MRI) showed a left dorsal midbrain lesion. Serologic and histopathologic findings confirmed primary Sjögren's syndrome. She responded well to intravenous methylprednisolone, with subsequent clinical improvement and MRI resolution. This report reviews the pediatric literature and underscores the importance of considering Sjögren's syndrome in a child with unexplained facial weakness and in the differential diagnosis of pediatric stroke.

Benzolamide inhibits low-threshold calcium currents in hippocampal pyramidal neurons.

1. Benzolamide is a poorly permeant sulfonamide inhibitor of the enzyme carbonic anhydrase. We studied the effect of benzolamide on low-threshold (LT) Ca currents in neonatal hippocampal CAl neurons. 2. In hippocampal slices, benzolamide (2-10 microM) inhibited the LT current 30-75% in voltage-clamped CAl pyramidal cells (n = 6). In slices bathed in N-2-hydroxypiperazine-N'-2-ethane-sulfonic acid (HEPES)-buffered Ringer, benzolamide also reduced the LT current, indicating that the action of the drug was not bicarbonate dependent. 3. Benzolamide inhibited LT Ca currents 20-75% in acutely dissociated CAl neurons in HEPES (n = 18): inhibition was 36 +/- 8% (mean +/- SE; n = 7) and 50 +/- 8% (n = 7) at 10 and 50 microM benzolamide, respectively. By contrast, high-threshold calcium currents recorded in CAl pyramidal cells (n = 18) and dorsal root ganglion neurons (n = 4) were virtually unaffected by benzolamide. 4. These results indicate that benzolamide inhibits LT Ca channels in central neurons and suggest caution in the use of this agent to inhibit extracellular carbonic anhydrase in excitable tissues.

Temporal resolution of activity-dependent pH shifts in rat hippocampal slices.

1. The rise time of activity-dependent extracellular pH shifts was measured in the CA1 stratum radiatum of rat hippocampal slices by recording pH-sensitive fluorescence of a fluorescein-conjugated dextran. Optical data were compared with simultaneous pH microelectrode recordings. 2. The pH shifts generated by CO2 or by stimulation of the Schaffer collaterals were paralleled by shifts in fluorescence emissions at 535 nm when the probe was excited with 490-nm light (delta F490). Emissions at 535 nm induced by 440-nm light were unchanged in these paradigms. 3. A train of three stimuli at 100 Hz was repeated at 30-s intervals and the stimulus-triggered delta F490 was averaged. The mean rise time of the delta F490 was 69 +/- 24 (SE) ms (range 20-200 ms, n = 6). The mean increase in emission was 0.75 +/- 0.22% of baseline, associated with a pH microelectrode response of +0.06 +/- 0.02 unit pH. 4. These data demonstrate that synaptically evoked alkaline transients develop within tens of milliseconds. The occurrence of the alkalinization in the same time frame as excitatory postsynaptic currents indicates that these pH shifts arise with sufficient speed to modulate synaptic transmission.

Endogenous H+ modulation of NMDA receptor-mediated EPSCs revealed by carbonic anhydrase inhibition in rat hippocampus.

1. The occurrence of extracellular alkaline transients during excitatory synaptic transmission suggests that the NMDA receptor H(+)-modulatory site may have a physiological role. Here we amplify these pH shifts using benzolamide (a carbonic anhydrase inhibitor) and describe concomitant effects on EPSCs in whole-cell clamped CA1 neurones in rat hippocampal slices. 2. In CO2-HCO3(-)-buffered media, benzolamide increased the time to 50% decay (t50) of the EPSCs by 78 +/- 14% (P < 0.01, n = 10). This occurred simultaneously with amplification of the extracellular alkaline shift (154 +/- 14%). 3. In CO2-HCO3(-)-buffered media containing DL-2-amino-5-phosphonovalerate (APV), the EPSC t50 was unaltered by benzolamide, while the extracellular alkaline shifts were increased (111 +/- 23%, n = 8). 4. In Hepes-buffered media, neither the EPSC t50 nor the extracellular alkaline shift was altered by benzolamide (n = 9). 5. These data demonstrate that NMDA receptor activity is dependent on the buffering kinetics of the brain extracellular space. The results suggest that endogenous pH shifts can modulate NMDA receptor function in a physiologically relevant time frame.

Optimized EPI for fMRI studies of the orbitofrontal cortex.

A common problem in gradient-echo echo planar imaging (EPI) is the occurrence of image distortions and signal losses caused by susceptibility gradients near air/tissue interfaces. Since EPI is frequently used for functional magnetic resonance imaging experiments based on the blood oxygenation level-dependent effect, functional studies of certain brain regions affected by susceptibility gradients, such as the temporal lobes and the orbitofrontal cortex, may be compromised. In this work a method for signal recovery in certain regions of the orbitofrontal cortex is presented. The influence of in-plane susceptibility gradients is reduced by optimization of the imaging slice orientation. Through-plane susceptibility gradients are partly compensated by means of a moderate preparation gradient pulse similar to z-shimming. In contrast to several other techniques proposed in the literature for reducing susceptibility effects, this method does not compromise the temporal resolution and is therefore applicable to event-related studies.