Vogt-Koyanagi-Harada disease presenting initially as aseptic meningoencephalitis.

Vogt-Koyanagi-Harada (VKH) disease in a Gypsy woman was diagnosed 4 months after her initial complaints. The delay is explained by the facts that: (1) the characteristic ophthalmological symptoms, which usually herald the disease and ensure early diagnosis, developed only late during the course; and (2) only retrospective analysis of the cerebrospinal fluid (CSF) cell preparation proved the presence of melanin-laden macrophages (MLMs), specific for the syndrome. We emphasize that VKH syndrome may initially present as aseptic meningitis, without specific ophthalmological symptoms. In suspected cases a very detailed CSF cell analysis is needed, because the presence of MLMs could confirm the diagnosis. However, VKH syndrome has a much higher incidence in Asia; cases in other races, including white people in Europe, also occur.

[Analysis of the activity of neurologic intensive care units]. / Neurológiai intenzív részlegek müködésének elemzése.

The authors analysed six-year activity of the intensive Care Unit of Department of Neurology, Medical University of Pécs (POTEI), and two-year activity of the Intensive Care Unit of Department of Neurology, Semmelweis University of Medicine, Budapest (SOTEI). Mortality at POTEI and SOTEI was 33.9% and 32.2%, respectively. Mean duration of stay of survivors at POTEI was 10 +/- 12.8 days, and 7 +/- 6.8 days at SOTEI; mean duration of care of the deceased patients at POTEI was 6.3 +/- 10.5 days, and 10 +/- 13.7 days at SOTEI. At POTEI 60.7%, at SOTEI 63% of the patients was admitted because of cerebrovascular insult. Mortality of patients with brain haemorrhage at POTEI and SOTEI was 53.4% and 57.7% respectively. Mortality of the ischaemic group was 40.6% (POTEI) and 35.3% (SOTEI). In the group of intracranial tumours 44.4% mortality was recorded at POTEI and 47.6% at SOTEI. At POTEI 240 patients (15.9%), while at SOTEI 94 patients (21%) were admitted to treat epileptic seizures. Among the 510 patients, who died within one month 284 patients (55.6%) were unconscious at admission. From those with coma due to severe structural lesion of the brain (brain ischaemia, bleeding, meningitis) only 15 patients survived. Among the 184 patients, who were comatose and survived, the most frequent diagnosis was suicidal attempt with hypnotics (n = 67), metabolic encephalopathy (n = 19) and epilepsy (n = 12). At SOTEI among the 144 deceased patients 102 (70.8%) were unconscious at admission. Coma at admission proved to be a strong predictor of mortality. Mortality of the ventilated patients was 83% at POTEI and of those having subclavian catheter (n = 592) was 47.1%. In the acute phase of brain ischaemia at POTEI 39%, at SOTEI 10.7% of the patients received heparin. At SOTEI the cost of medication of patients who died after two weeks of care was 65.2% higher than that of the survived patients.

Gamma frequency oscillation in the hippocampus of the rat: intracellular analysis in vivo.

Gamma frequency field oscillations reflect synchronized synaptic potentials in neuronal populations within the approximately 10-40 ms range. The generation of gamma activity in the hippocampus was investigated by intracellular recording from principal cells and basket cells in urethane anaesthetized rats. The recorded neurones were verified by intracellular injection of biocytin. Gamma frequency field oscillations were nested within the slower theta waves. The phase and amplitude of intracellular gamma were voltage dependent with an almost complete phase reversal at Cl- equilibrium potential in pyramidal cells. Basket cells fired at gamma frequency and were phase-locked to the same phase of the gamma oscillation as pyramidal cells. Current-induced depolarization coupled with synaptically induced inhibition resulted in gamma frequency discharge (30-80 Hz) of pyramidal cells without accommodation. These observations suggest that at least part of the gamma frequency field oscillation reflects rhythmic hyperpolarization of principal cells, brought about by the rhythmically discharging basket neurones. Resonant properties of pyramidal cells might facilitate network synchrony in the gamma frequency range.

Theta oscillations in somata and dendrites of hippocampal pyramidal cells in vivo: activity-dependent phase-precession of action potentials.

Theta frequency field oscillation reflects synchronized synaptic potentials that entrain the discharge of neuronal populations within the approximately 100-200 ms range. The cellular-synaptic generation of theta activity in the hippocampus was investigated by intracellular recordings from the somata and dendrites of CA1 pyramidal cells in urethane-anesthetized rats. The recorded neurons were verified by intracellular injection of biocytin. Transition from non-theta to theta state was characterized by a large decrease in the input resistance of the neuron (39% in the soma), tonic somatic hyperpolarization and dendritic depolarization. The probability of pyramidal cell discharge, as measured in single cells and from a population of extracellularly recorded units, was highest at or slightly after the negative peak of the field theta recorded from the pyramidal layer. In contrast, cyclic depolarizations in dendrites corresponded to the positive phase of the pyramidal layer field theta (i.e. the hyperpolarizing phase of somatic theta). Current-induced depolarization of the dendrite triggered large amplitude slow spikes (putative Ca2+ spikes) which were phase-locked to the positive phase of field theta. In the absence of background theta, strong dendritic depolarization by current injection led to large amplitude, self-sustained oscillation in the theta frequency range. Depolarization of the neuron resulted in a voltage-dependent phase precession of the action potentials. The voltage-dependent phase-precession was replicated by a two-compartment conductance model. Using an active (bursting) dendritic compartment spike phase advancement of action potentials, relative to the somatic theta rhythm, occurred up to 360 degrees. These data indicate that distal dendritic depolarization of the pyramidal cell by the entorhinal input during theta overlaps in time with somatic hyperpolarization. As a result, most pyramidal cells are either silent or discharge with single spikes on the negative portion of local field theta (i.e., when the somatic region is least polarized). However, strong dendritic excitation may overcome perisomatic inhibition and the large depolarizing theta rhythm in the dendrites may induce spike bursts at an earlier phase of the extracellular theta cycle. The magnitude of dendritic depolarization is reflected by the timing of action potentials within the theta cycle. We hypothesize that the competition between the out-of-phase theta oscillation in the soma and dendrite is responsible for the advancement of spike discharges observed in the behaving animal.

Dendritic spikes are enhanced by cooperative network activity in the intact hippocampus.

In vitro experiments suggest that dendritic fast action potentials may influence the efficacy of concurrently active synapses by enhancing Ca2+ influx into the dendrites. However, the exact circumstances leading to these effects in the intact brain are not known. We have addressed these issues by performing intracellular sharp electrode recordings from morphologically identified sites in the apical dendrites of CA1 pyramidal neurons in vivo while simultaneously monitoring extracellular population activity. The amplitude of spontaneous fast action potentials in dendrites decreased as a function of distance from the soma, suggesting that dendritic propagation of fast action potentials is strongly attenuated in vivo. Whereas the amplitude variability of somatic action potentials was very small, the amplitude of fast spikes varied substantially in distal dendrites. Large-amplitude fast spikes in dendrites occurred during population discharges of CA3-CA1 neurons concurrent with field sharp waves. The large-amplitude fast spikes were associated with bursts of smaller-amplitude action potentials and putative Ca2+ spikes. Both current pulse-evoked and spontaneously occurring Ca2+ spikes were always preceded by large-amplitude fast spikes. More spikes were observed in the dendrites during sharp waves than in the soma, suggesting that local dendritic spikes may be generated during this behaviorally relevant population pattern. Because not all dendritic spikes produce somatic action potentials, they may be functionally distinct from action potentials that signal via the axon.

GABAergic cells are the major postsynaptic targets of mossy fibers in the rat hippocampus.

Dentate granule cells communicate with their postsynaptic targets by three distinct terminal types. These include the large mossy terminals, filopodial extensions of the mossy terminals, and smaller en passant synaptic varicosities. We examined the postsynaptic targets of mossy fibers by combining in vivo intracellular labeling of granule cells, immunocytochemistry, and electron microscopy. Single granule cells formed large, complex "mossy" synapses on 11-15 CA3 pyramidal cells and 7-12 hilar mossy cells. In contrast, GABAergic interneurons, identified with immunostaining for substance P-receptor, parvalbumin, and mGluR1a-receptor, were selectively innervated by very thin (filopodial) extensions of the mossy terminals and by small en passant boutons in both the hilar and CA3 regions. These terminals formed single, often perforated, asymmetric synapses on the cell bodies, dendrites, and spines of GABAergic interneurons. The number of filopodial extensions and small terminals was 10 times larger than the number of mossy terminals. These findings show that in contrast to cortical pyramidal neurons, (1) granule cells developed distinct types of terminals to affect interneurons and pyramidal cells and (2) they innervated more inhibitory than excitatory cells. These findings may explain the physiological observations that increased activity of granule cells suppresses the overall excitability of the CA3 recurrent system and may form the structural basis of the target-dependent regulation of glutamate release in the mossy fiber system.

Feed-forward and feed-back activation of the dentate gyrus in vivo during dentate spikes and sharp wave bursts.

Intermittently occurring field events, dentate spikes (DS), and sharp waves (SPW) in the hippocampus reflect population synchrony of principal cells and interneurons along the entorhinal cortex-hippocampus axis. We have investigated the cellular-synaptic generation of DSs and SPWs by intracellular recording from granule cells, pyramidal cells, and interneurons in anesthetized rats. The recorded neurons were anatomically identified by intracellular injection of biocytin. Extracellular recording electrodes were placed in the hilus to record field DSs and multiple units and in the CA1 pyramidal cell layer to monitor SPW-associated fast field oscillations (ripples) and unit activity. DSs were associated with large depolarizing potentials in granule cells, but they rarely discharged action potentials. When they were depolarized slightly with intracellular current injection, bursts of action potentials occurred concurrently with extracellularly recorded DSs. Two interneurons in the hilar region were also found to discharge preferentially with DSs. In contrast, CA1 pyramidal cells, recorded extracellularly and intracellularly, were suppressed during DSs. In association with field SPWs, extracellular recordings from the CA1 pyramidal layer and the hilar region revealed synchronous bursting of these cell populations. Intracellular recordings from CA3 and CA1 pyramidal cells, granule cells, and from a single CA3 region interneuron revealed SPW-concurrent depolarizing potentials and action potentials. These findings suggest that granule cells may be discharged anterogradely by entorhinal input or retrogradely by the CA3-mossy cell feedback pathway during DSs and SPWs, respectively. Although both of these intermittent population patterns can activate granule cells, the impact of DSs and SPWs is diametrically opposite on the rest of the hippocampal circuitry. Entorhinal cortex activation of the granule cells during DSs induces a transient decrease in the hippocampal output, whereas during SPW bursts every principal cell population of the hippocampal formation may be recruited into the population event.

Spectral EEG analysis following hemispheric stroke: evidences of transhemispheric diaschisis.

Quantitative EEG frequency analysis was performed within the acute stage and after the recovery in 40 patients with hemispheric stroke in order to analyze ipsi- and contralateral alpha peak frequency (APF) and band power changes. Localization of hemispheric lesion was determined by computer tomography. Changes of clinical scores were compared with the alpha asymmetries. In the cases of small subcortical infarcts good improvement of alpha activity was observed over the affected hemisphere; contralateral APF was relatively preserved. Bilateral symmetric reduction of APF was found in territorial middle cerebral artery infarcts, with poor tendency of recovery of alpha power and neurologic status. These findings suggest transitory derangement of alpha generators in the contralateral hemisphere evidenced by APF and power asymmetries. EEG signs of contralateral alpha reduction may be due to the remote effect of primary ischemic lesion indicating an electrical diaschisis phenomenon in the acute phase of stroke. EEG signs of diaschisis may anticipate a poor recovery of alpha activity and clinical status in the post-stroke period.

Mechanisms of antihistamine-induced sedation in the human brain: H1 receptor activation reduces a background leakage potassium current.

Antihistamines, more formally termed H1 receptor antagonists, are well known to exert sedative effects in humans, yet their locus and mechanism of action in the human brain remains unknown. To better understand this phenomenon, the effects of histamine upon human cortical neurons were studied using intracellular recordings in brain slices maintained in vitro. Bath application of 50 microM histamine induced a depolarization which could be attributed to reduction of a background voltage-independent "leakage" potassium current: the depolarization was associated with an increase in apparent input resistance, under voltage clamp its reversal potential approximated the potassium reversal potential, and the histamine-induced current exhibited little voltage dependence. The pharmacology of the histamine-induced depolarization of human cortical neurons was studied by use of both agonists and antagonists. Depolarizing responses were blocked by the H1 antagonist mepyramine, but not by the H2 antagonist cimetidine nor the H3 antagonist thioperamide. The H3 receptor agonist R-alpha-methyl-histamine did not mimic the effects of histamine. Thus, histamine depolarizes human cortical neurons via action at an H1 receptor. These effects of neuronal histamine upon cortical neurons are likely to affect synaptic transmission in several ways. The depolarization per se should increase the likelihood that excitatory synaptic potentials will evoke an action potential. The increase in whole-cell input resistance evoked by H1 receptor activation should make the cell more electrotonically compact, thereby altering its integrative properties. We hypothesize that these mechanisms would allow histamine, acting at cortical H1 receptors, to enhance behavioral arousal. During waking when histamine release is highest, blockade of H1 receptors by systemically administered H1 receptor antagonists would be sedating.

Relation of laboratory and clinical variables to the grade of carotid atherosclerosis.

BACKGROUND AND PURPOSE: To clarify diagnostic entities in ischemic stroke we analyzed the relation between the severity of carotid atherosclerosis, coagulation parameters, lipoproteins, neurological status, and risk factors in 232 patients. METHODS: Duplex ultrasonography, computed tomography scan, and laboratory investigations were performed between the third and tenth days after stroke. Based on carotid ultrasound scores, we categorized the patients into four groups (A, B, C, and D) according to severity of atherosclerosis. Corresponding laboratory variables and clinical data were statistically analyzed. RESULTS: Ultrasound scores were significantly (P < .05) higher in the male (n = 126) versus female (n = 106) patients. The hematocrit was significantly higher and thrombin time was significantly shorter in the male group compared with the female group. Severe atherosclerosis (group C) and occlusion (group D) of the internal carotid artery was associated with smoking (C = 56%; D = 78%), hypertension (C = 43%; D = 35%), claudication (C = 13%; D = 5%), and antecedent myocardial infarction (C = 9%; D = 13%). There was no statistical correlation between ultrasound scores and the patients' neurological condition. Cholesterol and plasma fibrinogen levels were significantly higher and high-density lipoprotein cholesterol was significantly lower in groups with severe atherosclerosis compared with patients with slight intimal damage. The presence of multiple plaques or thrombosis of the internal carotid artery was concordant with the prevalence of single cerebral infarcts. CONCLUSIONS: Severity of carotid atherosclerosis corresponded well with the following factors: age, smoking, and low concentration of high-density lipoprotein cholesterol. Elevation of plasma fibrinogen combined with a loss of high-density lipoprotein cholesterol is strongly associated with severe atherosclerosis and results in brain infarction.

Topographic EEG analysis in two patients with basilar thrombosis.

The EEG activity of two patients with occlusion of the vertebral and basilar arteries was analyzed. Power maps, peak power frequency, and field power differences during both photic drive and verbal command were evaluated. Clinical findings of one patient fit the criteria of locked-in syndrome. Photic stimulation and event related desynchronization paradigm was used for testing the reactivity of EEG. Averaged EEG epochs during intended movement after verbal command showed significant alpha and sub-alpha power reduction. Regional differences of EEG reactivity were assumed secondary to the underlying hemispheric infarcts. Awareness of the patient in a locked-in state was documented by EEG analysis. In the second case permanent vegetative state was associated with a nonreactive rhythmic alpha pattern. Time sequence analysis of power ratios showed spontaneous alternating activity of alpha and sub-alpha generators. The authors conclude that pseudo-periodic fluctuation of alpha activity reflects partial preservation of thalamo-cortical connections.

Membrane properties of mesopontine cholinergic neurons studied with the whole-cell patch-clamp technique: implications for behavioral state control.

1. The whole-cell patch-clamp technique was used to study the membrane properties of identified cholinergic and noncholinergic laterodorsal tegmental neurons in slices of rat brain maintained in vitro. 2. On the basis of their expression of the transient outward potassium current IA and the transient inward calcium current IT, three classes of neurons were observed: type I neurons exhibited a large IT; type II neurons exhibited a prominent IA; and type III neurons exhibited both IA and IT. 3. Combining intracellular deposition of biocytin with NADPH diaphorase histochemistry revealed that the vast majority of type III neurons were cholinergic, whereas only a minority of type I and type II neurons were cholinergic. Thus mesopontine cholinergic neurons possess intrinsic ionic currents capable of inducing burst firing. 4. Delineation of the intrinsic membrane properties of identified mesopontine cholinergic neurons, in concert with recent results regarding the responses of these neurons to neurotransmitter agents, has led us to present a unifying and mechanistic hypothesis of brain stem cholinergic function in the control of behavioral states.

Serotonin hyperpolarizes cholinergic low-threshold burst neurons in the rat laterodorsal tegmental nucleus in vitro.

Serotonergic suppression of cholinergic neuronal activity implicated in the regulation of rapid eye movement sleep and its associated phenomenon, pontogeniculooccipital waves, has long been postulated, but no direct proof has been available. In this study, intracellular and whole-cell patch-clamp recording techniques were combined with enzyme histochemistry to examine the intrinsic electrophysiological properties and response to serotonin (5-HT) of identified cholinergic rat laterodorsal tegmental nucleus neurons in vitro. Sixty-five percent of the recorded neurons demonstrated a prominent low-threshold burst, and of these, 83% were cholinergic. In current-clamp recordings 64% of the bursting cholinergic neurons tested responded to the application of 5-HT with a membrane hyperpolarization and decrease in input resistance. This effect was mimicked by application of the selective 5-HT type 1 receptor agonist carboxamidotryptamine maleate. Whole-cell patch-clamp recordings revealed that the hyperpolarizing response was mediated by an inwardly rectifying K+ current. Application of 5-HT decreased excitability and markedly modulated the discharge pattern of cholinergic bursting neurons: during a 5-HT-induced hyperpolarization these neurons exhibited no rebound burst after hyperpolarizing current input and a burst in response to depolarizing current input. In the absence of 5-HT, the relatively depolarized cholinergic bursting neurons responded to an identical hyperpolarizing current input with a burst and did not produce a burst after depolarizing current input. These data provide a cellular and molecular basis for the hypothesis that 5-HT modulates rapid eye movement sleep phenomenology by altering the firing pattern of bursting cholinergic neurons.

Hyperpolarization-activated inward current in histaminergic tuberomammillary neurons of the rat hypothalamus.

1. Intracellular recordings were obtained from histaminergic tuberomammillary (TM) neurons of rat hypothalamus in an in vitro slice preparation. The properties of a time- and voltage-dependent inward current activated on hyperpolarization, Ih, were studied by use of the single-electrode voltage-clamp technique. 2. The activation curve of Ih was well fit by a sigmoidal function, with half-maximal activation occurring at -98 +/- 6 mV. 3. The estimated reversal potential of Ih (Eh) in TM neurons was -35 +/- 9 (SD) mV. 4. The time constant of activation was well fit by a single exponential function and exhibited marked voltage dependence: at -90 mV, Ih activated with a time constant of 823 +/- 35 ms, whereas at -130 mV, Ih activated with a time constant of 280 +/- 65 ms. The time constant of deactivation of Ih at -60 mV was 302 +/- 35 ms. 5. Raising the extracellular potassium concentration ([K+]o) to 10 mM shifted Eh to a more depolarized value, while lowering the extracellular sodium concentration [( Na+]o) shifted Eh in the negative direction. Altering the extracellular chloride concentration ([Cl-]o) had little effect on Eh. 6. Increasing [K+]o to 10 mM increased the amplitude of both Ih and its underlying conductance gh, while reducing [Na+]o caused a small reduction in the amplitude of Ih with no measurable effect on gh. 7. The time constant of activation of Ih became shorter in raised [K+]o and longer in lowered [Na+]o. 8. Extracellularly applied cesium blocked Ih in a voltage-dependent manner. Extracellular barium reduced Ih but was less effective than cesium. 9. We conclude that Ih, carried by sodium and potassium ions, accounts for inward rectification of TM neurons. By increasing the whole-cell conductance during periods of prolonged hyperpolarization, Ih may act as an ionic shunt, decreasing the efficacy of synaptic inputs. This effect would be most apparent during rapid-eye-movement sleep, when TM neurons fall silent.

Perforant path activation of the hippocampus: spatial distribution, effects of urethane and atropine.

Spatial distribution of field responses evoked by perforant path stimulation were studied in the hippocampus of both anaesthetized and drug-free rats. Simultaneous recordings with an array of 4 electrodes allowed us to construct a 2-dimensional map of the evoked field potentials. In addition, we examined the effects of atropine-SO4 and urethane on the amplitude of the dentate response. Trisynaptic activation of the CA1 region occurred regularly in the drug-free rat while CA1 population spikes were rarely seen in the anaesthetized animal. The latency of the CA1 population spike was shortest at the fimbrial side and increased gradually towards the subicular side. In the dentate gyrus atropine increased the amplitude of the population spike. We suggest that atropine may interfere with the septo-hippocampal feed-forward inhibition, and urethane may decrease the effectiveness of the perforant path-granule cell synapse, as well as the intrahippocampal excitatory circuit.