Suspected antibody negative autoimmune limbic encephalitis: outcome of immunotherapy.

OBJECTIVES: Whether and when to immunologically treat epilepsy patients with suggested autoantibody (AB)-negative limbic encephalitis (LE) is clinically challenging. Therefore, we evaluated the clinical outcome and eventual outcome predictors of immunotherapy in a group of AB-negative patients with recent-onset temporal lobe epilepsy (TLE), magnetic resonance imaging (MRI) indicators of LE, subjective cognitive decline, and/or psychiatric symptoms. METHODS: This retrospective, observational, uncontrolled study monitored 28 TLE patients with suggested AB-negative LE along with methylprednisolone immunotherapy. RESULTS: All patients had seizures, amygdala and/or -hippocampal enlargement, subjective cognitive decline and/or behavioral problems. Eighty-six percent (24/28) were impaired in executive or memory functions, 39% (10/25) depressed, 81% were on antiepileptic drugs when pulse therapy started. After a median follow-up of 18 months, 46% (13/28) of the patients were seizure free (>2 months), 48% (13/27) showed MRI improvements (amygdala and/or hippocampal volume reduction), cognition improved in 57% (16/28), worsened in 32% (9/28), mood improved in 14% (4/25), and deteriorated in 11% (3/25). Immunotherapy was discontinued in 75% (21/28). Clinical changes did not correlate to each other. Outcomes could not be predicted. CONCLUSION: Immunological treatment of suggested AB-negative LE showed reasonable seizure control, MRI and cognitive improvements. Treatment success was not predictable from clinical features, nor definitely attributable to immunological treatment. Lacking biomarkers for the reliable diagnosis of AB-negative LE, we suggest that in presence of mild manifestations, and after initiating antiepileptic drug therapy, negative dynamics in MRI, seizures, cognition, and behavior should be documented before immunosuppressive treatment is initiated.

Seizure control and cognitive improvement via immunotherapy in late onset epilepsy patients with paraneoplastic versus GAD65 autoantibody-associated limbic encephalitis.

OBJECTIVE: To determine the efficacy of immunotherapy in limbic encephalitis (LE) associated epilepsies with autoantibodies against intracellular antigens in the forms of paraneoplastic autoantibodies versus glutamic acid decarboxylase 65 (GAD)-autoantibodies. METHODS: Eleven paraneoplastic-antibodies+ and eleven age- and gender-matched GAD-antibodies+ patients with LE were compared regarding EEG, seizure frequency, MRI volumetry of the brain, and cognition. All patients received immunotherapy with corticosteroids add-on to antiepileptic therapy. A few patients underwent additional interventions like immunoglobulins or immunoadsorption. RESULTS: Immunotherapy led to a significantly greater proportion of seizure-free patients in the paraneoplastic antibodies+(55%) as compared to GAD-antibodies+(18%) patients (p<0.05). Impaired cognition was evident initially (total cognitive performance score based on attentional-executive function, figural/verbal memory and word fluency) in 100% of the paraneoplastic-antibodies+ and 73% of the GAD-antibodies+ group. After therapy, cognition improved significantly in the paraneoplastic-antibodies+, but not in the GAD-antibodies+ patients (p<0.05). Cognitive change did not correlate with the change in the number of antiepileptic drugs over time. MRI showed larger and unchanged volumes of the amygdala, presubiculum and subiculum in GAD-antibodies+as compared to paraneoplastic-antibodies+patients (p<0.05) over time. CONCLUSIONS: Our data provide evidence of a beneficial effect of immunotherapy added to antiepileptic drugs on seizure frequency and cognition only in the paraneoplastic-antibodies+ subgroup of LE presenting autoantibodies against intracellular antigens.

Overlap of musical and linguistic syntax processing: intracranial ERP evidence.

The present study investigated the co-localization of musical and linguistic syntax processing in the human brain. EEGs were recorded from subdural electrodes placed on the left and right perisylvian cortex. The neural generators of the early potentials elicited by syntactic errors in music and language were localized by means of distributed source modeling and compared within subjects. The combined results indicated a partial overlap of the sources within the bilateral superior temporal gyrus, and, to a lesser extent, in the left inferior frontal gyrus, qualifying these areas as shared anatomic substrates of early syntactic error detection in music and language.

Human mediotemporal EEG characteristics during propofol anesthesia.

Evidence for a response-control-related kind of declarative memory during deep propofol anesthesia has recently been reported. Connectivity within the mediotemporal lobe (MTL), and in particular rhinal-hippocampal synchronization within the gamma band, has been shown to be crucial for declarative memory formation. Thus, we analyzed EEG recordings obtained from the scalp, as well as directly from within the hippocampus and from the anterior parahippocampal gyrus, which is covered by rhinal cortex, in patients with unilateral temporal lobe epilepsy during propofol anesthesia, which preceded electrode explantation. For the gamma band a power decrease starting with induction of anesthesia was observed at scalp position Cz, but a power increase was detected at MTL locations. In contrast to prior results for sleep recordings, rhinal-hippocampal coherence did not decrease within the gamma band at deeper levels of anesthesia. These findings may represent an indirect electrophysiological correlate of partially intact declarative memory formation during deep propofol sedation. Furthermore, we investigated how well the plasma propofol level, as well as different stages of anesthesia including the burst suppression phase, could be monitored by different spectral as well as by nonlinear EEG measures. We observed that conventional spectral power measures, most prominently those recorded from mediotemporal locations, are most closely correlated with the plasma propofol level, whereas different stages of anesthesia can be distinguished best by nonconventional spectral as well as nonlinear measures.

An open study of tacrolimus therapy in Rasmussen encephalitis.

Seven patients with Rasmussen encephalitis (RE) were treated with the immunosuppressant tacrolimus and followed for a median of 22.4 months. They were compared with 12 historical untreated RE patients (median follow-up 13.9 months). The tacrolimus-treated patients had a superior outcome regarding neurologic function and progression rate of cerebral hemiatrophy but no better seizure outcome. No treated patient, but 7 of 12 control patients, became eligible for hemispherectomy. Tacrolimus did not have any major side effects.

The epileptic process as nonlinear deterministic dynamics in a stochastic environment: an evaluation on mesial temporal lobe epilepsy.

The theory of deterministic chaos addresses simple deterministic dynamics in which nonlinearity gives rise to complex temporal behavior. Although biological neuronal networks such as the brain are highly complicated, a number of studies provide growing evidence that nonlinear time series analysis of brain electrical activity in patients with epilepsy is capable of providing potentially useful diagnostic information. In the present study, this analysis framework was extended by introducing a new measure xi, designed to discriminate between nonlinear deterministic and linear stochastic dynamics. For the evaluation of its discriminative power, xi was extracted from intracranial multi-channel EEGs recorded during the interictal state in 25 patients with unilateral mesial temporal lobe epilepsy. Strong indications of nonlinear determinism were found in recordings from within the epileptogenic zone, while EEG signals from other sites mainly resembled linear stochastic dynamics. In all investigated cases, this differentiation allowed to retrospectively determine the side of the epileptogenic zone in full agreement with results of the presurgical workup.

Quantification of depth of anesthesia by nonlinear time series analysis of brain electrical activity

We investigate several quantifiers of the electroencephalogram (EEG) signal with respect to their ability to indicate depth of anesthesia. For 17 patients anesthetized with sevoflurane, three established measures (two spectral and one based on the bispectrum), as well as a phase space based nonlinear correlation index were computed from consecutive EEG epochs. In the absence of an independent way to determine anesthesia depth, the standard was derived from measured blood plasma concentrations of the anesthetic via a pharmacokinetic/pharmacodynamic model for the estimated effective brain concentration of sevoflurane. In most patients, the highest correlation is observed for the nonlinear correlation index D*. In contrast to spectral measures, D* is found to decrease monotonically with increasing (estimated) depth of anesthesia, even when a "burst-suppression" pattern occurs in the EEG. The findings show the potential for applications of concepts derived from the theory of nonlinear dynamics, even if little can be assumed about the process under investigation.

Nonlinear EEG analysis and its potential role in epileptology.

Deterministic chaos offers a striking explanation for apparently irregular behavior of the brain that is evidenced in the EEG. Recent developments in the physical-mathematical framework of the theory of nonlinear dynamics (colloquially often termed chaos theory) provide new concepts and powerful algorithms to analyze such time series. Because of its high versatility, nonlinear time series analysis has already gone beyond the physical sciences and, at present, is being successfully applied in a variety of disciplines, including cardiology, neurology, psychiatry, and epileptology. However, it is well known that different influencing factors limit the use of nonlinear measures to characterize EEG dynamics in a strict sense. Nevertheless, when interpreted with care, relative estimates of, e.g., the correlation dimension or the Lyapunov exponents, can reliably characterize different states of normal and pathologic brain function. In epileptology, extraction of nonlinear measures from the intracranially recorded EEG promises to be important for clinical practice. In addition to an immense reduction of information content of long-lasting EEG recordings, previous studies have shown that these measures enable (a) localization of the primary epileptogenic area in different cerebral regions during the interictal state, (b) investigations of antiepileptic drug effects, (c) analyses of spatio-temporal interactions between the epileptogenic zone and other brain areas, and (d) detection of features predictive of imminent seizure activity. Nonlinear time series analysis provides new and supplementary information about the epileptogenic process and thus contributes to an improvement in presurgical evaluation.

Spatial distribution of neuronal complexity loss in neocortical lesional epilepsies.

PURPOSE: Nonlinear EEG analysis is valuable in characterizing the spatiotemporal dynamics of the epileptogenic process in mesial temporal lobe epilepsy. We examined the ability of the measure neuronal complexity loss (L*) to characterize the primary epileptogenic area of neocortical lesional epilepsies during the interictal state. METHODS: Spatial distribution of L* (L* map) was extracted from electrocorticograms (n = 52) recorded during presurgical assessment via subdural 64-contact grid electrodes covering lesions in either frontal, parietal, or temporal neocortex in 15 patients. The exact location of recording contacts on the brain surface was identified by matching a postimplant lateral x-ray of the skull with a postoperatively obtained sagittal MRI scan. Reprojecting L* maps onto the subject's brain surface allowed us to compare the spatial distribution of L* with the resection range of the extended lesionectomy. RESULTS: In each of the six patients who became seizure-free, maximum values of L* were restricted to recording sites coinciding with the area of resection. In contrast, L* maps of most patients who had no benefit from the resection indicated a more widespread extent or the existence of additional, probably autonomous, foci. The mean of L* values obtained from recording sites outside the area of resection correctly distinguished 13 patients (86.7 %) with respect to seizure outcome. CONCLUSIONS: Relevant information obtained from long-lasting interictal electrocorticographic recordings can be compressed to a single L* map that contributes to a spatial characterization of the primary epileptogenic area. In neocortical lesional epilepsies, L* allows for identification and characterization of epileptogenic activity and thus provides an additional diagnostic tool for presurgical assessment.

Is it possible to anticipate seizure onset by non-linear analysis of intracerebral EEG in human partial epilepsies?

Detection of electrophysiological features preceding and indicative of imminent seizures in patients with epilepsy would be a major breakthrough with immense scientific and clinical implications. The definition of a "pre-ictal state" several minutes prior to seizure onset would open a new time window for studying mechanisms of seizure generation as well as for possible therapeutic interventions. In this review we present recent findings from nonlinear time series analysis of intracranially recorded EEG that may allow to forecast seizure onset in patients with partial epilepsy.

Reduced signal complexity of intracellular recordings: a precursor for epileptiform activity?

Recent studies have shown that time windowed extraction of nonlinear parameters like an effective correlation dimension from intracranially recorded EEG of epileptic patients often allows to detect and identify an unequivocal "pre-ictal phase" preceding an epileptic seizure. In another study, however, such an anticipation could not be made. These conflicting findings may indicate that observed changes in nonlinear parameters probably depend on the type of elementary mechanisms underlying epileptic processes and/or the spatial distribution of neurons primarily involved in generation of epileptiform discharges. To test the existence of such dependencies, the transition from normal to epileptiform activity (EA) of CA3-neurons in hippocampal slices was analyzed in four epilepsy models, using a time windowed computation of an effective correlation dimension. Indeed, in xanthine and penicillin models, signal complexity in intracellular recordings was reduced before manifestation of paroxysmal depolarization shifts (PDS), whereas a preceding loss of complexity was missing in low-magnesium and veratridine models. These findings indicate that interictal-like EA is predictable only in some epilepsy models.

Aggravation of focal epileptic seizures by antiepileptic drugs.

Aggravation of focal epileptic seizures in adults is common after the antiepileptic drug (AED) therapy is initiated. Sometimes aggravation is mimicked by clustering of the seizures. Therefore, it is always necessary to analyze the patient's history and therapy carefully before drawing any conclusions. It is likely that a paradoxical aggravation of epileptic seizures can be attributed to the given AED and is sometimes, but only rarely, due to drug interactions.

DAPAS, a computerised workplace for Digital Acquisition and Processing of Analog Signals, with up to two gigabytes data per registration.

A comprehensive and flexible arrangement for Digital long-term Acquisition and Processing of Analog Signals (DAPAS) has been developed. It is especially designed for neurophysiological laboratories and mainly based on IBM-compatible PC components. A/D converters are used, which allow sampling rates of up to 100 kHz (up to 16 bits, 1-16 channels). Signals are stored continuously on DOS devices and on a fast tape streamer, which uses standard video-8 tapes, and which is 2.8 times faster than DAT-based systems. As the recording speed is adapted to the sampling rate, one tape allows recording times of (uncompressed) data acquired at a sampling rate of 100 or 10 kHz of 6.8 and 68 h, respectively. Using a coprocessor-video device, recordings may be scrolled on- or off-line on the screen. In addition, up to eight multi-channel oscilloscopes are displayed simultaneously. DAPAS allows the use of a conventional matrix printer which can act as an inertia-free multi-pen recorder. Defined stored signals are recalled by means of a time code or textual markers. All sections of recordings lasting milliseconds to hours may be displayed within seconds. DAPAS supports export filters for further processing. Thus, this system replaces analog devices (multi-pen recorder, oscilloscope, data recorder), and enables quick, complete digital processing and analysis of neurophysiological data.

Rhythm generation in organotypic medullary cultures of newborn rats.

Organotypic transverse medullary slices (obex level) from six-day-old rats, cultured for two to four weeks in chemically defined medium contained rhythmically discharging neurones which were activated by CO2 and H+. The mechanisms underlying this rhythmicity and the spread of excitation and synaptic transmission within this organotypic tissue were examined by modifying the composition of the external solution. Our findings showed that (1) Exposure to tetrodotoxin (0.2 microM) or to high magnesium (6 mM) and low calcium (0.2 mM) concentrations abolished periodic activity. (2) Neither the blockade of GABAergic potentials with bicuculline methiodide (200 microM) and/or hydroxysaclofen (200 microM) nor the blockade of glycinergic potentials with strychnine hydrochloride (100 microM) abolished rhythmicity. (3) While atropine sulphate (5 microM) was ineffective in modulating periodic discharges nicotine (100 microM) - like CO2-shortened the intervals between the periodic events; hexamethonium (50-100 microM) reduced both periodic and aperiodic activity. (4) Exposure to the NMDA antagonist 2-aminophosphonovaleric acid (50 microM) suppressed periodic events only transiently. In the presence of 2-aminophosphonovaleric acid rhythmicity recovered. However, the AMPA-antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (10-50 microM), abolished periodic activity reversibly within less than 5 min. When 6-cyano-7-nitroquinoxaline-2,3-dione and nicotine were administered simultaneously periodic events persisted for up to 10 min. These findings indicate that synaptic excitatory drive is a prerequisite for the generation of rhythmic discharges of medullary neurones in this preparation. This drive may activate voltage-dependent channels or it may facilitate endogenous cellular mechanisms which initiate oscillations of intracellular calcium concentration. To test the latter possibility (5) calcium antagonists were added to the bath saline. The organic calcium antagonists verapamil and flunarizine (50-100 microM each) and the inorganic calcium antagonists cobalt (2 mM) and magnesium (6 mM) suppressed periodic activity and abolished or weakened the chemosensitivity towards CO2/acidosis. (6) Dantrolene (10 microM). an inhibitor of intracellular calcium release decreased the periodicity, while thapsigargin (2 microM) which blocks endoplasmic Ca(2+)-ATPase, transiently accelerated the occurrence of periodic events. (7) Oscillations of intracellular free calcium concentrations in Fura-2 AM-loaded cells were weakened or abolished by cobalt (2 mM). The results of (5)-(7) indicate that transmembrane calcium fluxes as well as intracellular Ca(2+)-release and -clearance mechanisms are a prerequisite for intracellular free calcium oscillations which may be important in the generation of rhythmic discharges in medullary neurones.

Suppression of rhythmic discharges of medullary neurones in organotypic cultures of new-born rats by calcium antagonists.

The contribution of transmembrane calcium flux to the generation of periodic bioelectric activity in cultured organotypic medullary tissue of 6 day old rats was determined by adding calcium antagonists (CA) to the recording saline and by lowering the calcium concentration of this saline. Organic CA flunarizine and verapamil (50-100 mumol/l) reversibly suppressed rhythmic discharge and diminished the CO2 response of medullary neurones within 30-60 min. Inorganic CA cobalt and magnesium exerted the same effects within a few minutes. After lowering the calcium concentration rhythmic activity became unstable, but recovered on exposure to increased CO2 concentration, the excitatory effect of which was strongly reduced. These findings point to a significant role for transmembrane calcium flux and intracellular calcium concentration in sustaining both periodic activity and the CO2 response of medullary neurones.

Venous blood concentrations after subarachnoid administration of bupivacaine.

Peripheral venous blood concentrations of bupivacaine were measured in 51 patients given 0.5% (4 ml, 20 mg) or 0.75% (3 ml, 22.5 mg) bupivacaine, both solutions with or without glucose, for spinal anesthesia. The initial absorption of bupivacaine, as measured in peripheral venous blood, was rapid, although the blood concentrations were low. The mean peak concentration (Cmax) did not differ when glucose was added to 0.5 or 0.75% bupivacaine. When glucose-free and glucose-containing bupivacaine groups were combined, 22.5 mg bupivacaine give a significantly higher venous blood concentration than 20 mg of the solution. The mean time between subarachnoid injection and the time when Cmax was reached (tpeak) was influenced by the density of bupivacaine, i.e., the tpeak of bupivacaine with glucose was significantly shorter than with glucose-free solution (35 min; P less than 0.05). No correlation was found between Cmax and the age, height, or weight of the patients, or between Cmax and the maximum cephalad level of analgesia in the different groups. In addition, there was no correlation between tpeak and the age, height, or weight of the patients. The maximal cephalad level of analgesia did not influence tpeak in the different groups (the correlation coefficients less than 0.3).

A double-blind study of motor blockade in the lower limbs. Studies during spinal anaesthesia with hyperbaric and glucose-free 0.5% bupivacaine.

Sensory and motor blockade were studied double-blind during spinal anaesthesia in 20 urology patients who received 0.5% bupivacaine solution 4 ml with or without glucose. Using a new method for determining muscle strength, motor blockade during anaesthesia was recorded quantitatively for flexion of the hip, extension of the knee and plantar flexion of the big toe. Movements of the lower part of the thoracic cage were recorded at the same time. Complete motor blockade of longer duration was observed for all three movements following the administration of the glucose-free solution compared with the solution containing glucose. During the regression phase, the muscle strength returned significantly later (knee extension and hip flexion) when glucose-free bupivacaine solution was given. There was no significant difference between the two anaesthetic solutions regarding plantar flexion of the big toe during this phase. For hip flexion (L1-L3) there was no noteworthy difference between the levels of analgesia and the motor blockade, whereas for plantar flexion of the big toe (L5-S2) the level of analgesia was 2-3 segments higher than the level of motor blockade. Thoracic movements (maximal inspiration to normal expiration) did not appear to be notably influenced by the level of analgesia. Complete regression of motor blockade was not observed for any of the movements at grade O of a modified Bromage scale. Not until 1.5-2 h after the attainment of this grade was the muscle strength of all movements restored (90% of control value).

A comparison of bupivacaine and tetracaine in spinal anaesthesia with special reference to motor block.

Thirty-six patients received spinal anesthesia with either glucose-free bupivacaine (22.5 mg) or glucose-containing solutions of bupivacaine (20 mg) or tetracaine (15 mg). The duration of analgesia in the lower thoracic and lumbar segments was significantly longer with glucose-free bupivacaine than with the other solutions. Using a quantitative method for measuring muscle strength, the motor block was recorded for three types of movements: hip flexion, knee extension and plantar flexion of the big toe. Movements of the lower part of the thoracic cage were recorded at the same time. The length of time from spinal injection to complete motor block was short and without notable difference between all three groups. Regression of the motor block tended to start earlier for hip flexion and knee extension than for plantar flexion of the big toe. For all three movements the regression of the motor block began significantly later in the glucose-free bupivacaine group than in the other groups. During the regression phase, muscle strength returned significantly later in the glucose-free bupivacaine group than in the bupivacaine group containing glucose and knee extension returned significantly later in the glucose-free bupivacaine group than in the tetracaine group. No difference in motor block was found between the hyperbaric solutions of bupivacaine and tetracaine. For hip flexion (L1-L3), there was no noteworthy difference between the level of analgesia and the motor block segments, whereas for plantar flexion of the big toe (L5-S2) the level of analgesia lay 2-3 segments higher than the motor block segments. In seven patients, during spinal anaesthesia there was a reduction in respiratory deflections corresponding to the lower thorax.(ABSTRACT TRUNCATED AT 250 WORDS)