Subclinical Activity Research Articles

Reversible disability associated with epilepsy.

Epilepsy is a syndrome complex in which the impairments include seizures, cognitive arrest and regression, psychiatric illness, and motor and visual disorders. In both lesional and non-lesional epilepsy there is evidence of reversibility of these impairments in some patients which provides compelling evidence that there is a dynamic pathogenetic mechanism which can 'take-out' discreet or global cortical functions. The best evidence that we have suggests that seizures themselves particularly sub-clinical seizure activity are the major factor. Numerous examples of partial and even complete recoveries as a result of medical and surgical treatments are now available. These support the notion that in addition to direct seizure activity there is a pervasive element to the syndromes of epilepsy which causes anything from mild attention deficit or difficulties with language processing to catastrophic loss of cognitive and social functioning. The malignant seizure syndromes are mostly defined by the high risk of these impairments. The challenge of the developmental epilepsies is to explore the pathogenesis and develop new treatments. Perhaps the most difficult aspect of this work is to understand the critical periods for recovery and thus how to avoid irreparable damage.

650 Subclinical epileptiform activity in children with developmental disturbances as a sign of impaired brain maturation

650 Subclinical epileptiform activity in children with developmental disturbances as a sign of impaired brain maturation

Three-dimensional localization of subclinical ictal activity by magnetoencephalography: Correlation with invasive monitoring

BACKGROUND Although magnetoencephalography (MEG) provides accurate information on the spatial distribution and temporal patterns of the “interictal” epileptic activities, it is interictal in nature and therefore also prone to all the problems associated with interictal data. METHODS We investigated the subclinical “ictal” epileptic activity with a 37-channel, large-array biomagnetometer and mapped the data onto a three-dimensional image in a patient with intractable frontal lobe epilepsy. Dipole source localization was calculated based on magnetic fields for both the interictal and subclinical ictal activities. RESULTS The current dipoles of the interictal MEG spikes (MEG irritative zone) were revealed to be scattered in the left anterior frontal lobe, whereas that of the subclinical ictal onset (MEG subclinical ictal onset zone) was surrounded by the interictal dipole cluster. The dipole source localization of the propagating activities was not calculated with a single dipole model. The MEG subclinical ictal onset zone correlated well with the ictal onset zone subsequently recorded by invasive subdural electrophysiological monitoring. After multiple subpial transection of the deduced epileptogenic area, a dramatic reduction of the seizures occurred. CONCLUSION These results illustrate the potential of MEG for localizing the epileptogenic foci with high spatial and temporal resolution.

Seizures: Classification, etiologies, and pathophysiology

Epilepsy is a disorder of recurrent seizures that are neural in origin. Partial seizures are usually due to a structural cerebrocortical lesion and may be simple or complex. Brain injuries may alter inherent neuronal properties and neuronal circuits and lead to recurrent excitatory activity. Potentiation of excitatory synapses and depression of inhibitory synapses are probable critical events in epileptogenesis. The pathogenic factors underlying primary or idiopathic generalized seizures are not as well understood. A more diffuse or multifocal state of neuronal excitability may be the result of early congenital events that are magnified over time. The progression of subclinical neuronal excitatory activity to a clinical seizure may relate directly to the phenomenon of cortical plasticity.

Developmental disturbances in children with subclinical epileptiform activity

Developmental disturbances in children with subclinical epileptiform activity

Urine flow cytometry as a predictor of renal allograft function.

The value of urine flow cytometry (UFC) in diagnosing acute renal allograft rejection (AR) was recently established in a prospective double-blind study. In this study, we report the 1-year follow-up of three groups of patients identified during the previous study: group 1--stable patients (no ARs) with persistently negative UFCs (n=7); group II--patients who had early ARs (<3 months after transplantation), with positive UFCs that completely normalized with antirejection therapy (n=8); group III--stable patients (no ARs) with positive UFCs (n=7). By definition, group III consists of patients previously considered to have "false positive" UFCs. All patients received standard immunosuppressive therapy, with regimens that included cyclosporine at doses adjusted to maintain target levels. Serum creatinine (SCr) levels (mg/dl) were similar in all three groups at 1 month after transplantation. However, at 1 year after transplantation, SCr was 1.4 +/- 0.2 in group I, 2.0 +/- 0.9 in group II, and 1.9 +/- 0.3 in group III (P=0.004 group I vs. group III). There were no ARs clinically diagnosed during this follow-up period in any of the three groups of patients, but there were significantly higher SCr increments among group III patients after the 1 year of follow-up. The detection of an active urine sediment by flow cytometry in "clinically stable" allograft recipients may indicate ongoing, subclinical acute rejection activity, which in this study was found to be associated with worse renal function at the end of the first posttransplant year as compared with patients with persistently negative UFCs. Increased immunosuppression may be indicated for these patients with persistently positive UFCs.

Surgical treatment of severe autistic regression in childhood epilepsy

We report 2 children with partial epilepsy who manifested social and language regression and partial recovery after surgical treatment. One child had seizures since the first 2 weeks of life, caused by a right temporal dysembryoplastic neuroepithelial tumor and regression in the latter part of the first year; seizures were relieved and some functions were recovered after temporal lobe resection at 12 months of age. The second child developed epilepsy at 3 years 3 months, and between 5 years 9 months and 6 years 1 month he became aphasic (Landau-Kleffner syndrome) and lost social functioning, manifesting a very severe behavior disorder. He exhibited a significant improvement in communication, social functioning, and behavior after left multiple subpial transections. Both children manifested evidence of subclinical seizure activity in both temporal lobes. Their clinical picture was one of combined language and autistic regression, and the autistic features demonstrated a clear response to surgical treatment. We suggest that in pediatric epilepsy surgical programs, autistic regression should prompt urgent investigation if drug treatment is not effective.

Brain MRI follow‐up of patients with persistent isolated optic neuritis

In this study a brain MRI long‐term follow‐up of 19 patients at presentation with Acute Isolated Optic Neuritis (AION), who did not develop further neurological disturbances, was performed to evaluate the frequency of subclinical evolution of the pathological process. At presentation, the brain MRI in nine patients was abnormal and in 10 normal. CSF oligoclonal bands were found in 11 patients, five of whom had normal basal MRI. All patients with abnormal basal MRI had new lesions on follow‐up scans, while only one of the patients with a normal basal brain MRI had multiple lesions on the second scan. Our data suggest that about 50% of patients with AION had subclinical activity, even though there were no new clinical relapses.

Localization of subclinical ictal activity by functional magnetic resonance imaging: Correlation with invasive monitoring

Functional magnetic resonance imaging (fMRI) with susceptibility-based contrast was used to detect focal changes in cerebral blood flow and metabolism in a patient with focal epilepsy. The patient presented with frequent partial motor seizures involving his right lower face that spread to produce speech arrest and occasionally right arm jerking. Consciousness was never impaired during these events. A multislice echoplanar technique was used to acquire 16 contiguous axial slices every 4 seconds for 11 minutes. Although no overt seizures were observed or reported by the patient during the scanning, a time series analysis of the functional data revealed focal signal-intensity changes in the posterior left frontal lobe, which correlated well both in duration and spatial localization with ictal activity subsequently recorded by invasive electrophysiological monitoring. The spatial localization of fMRI was more accurate than electroencephalography recorded from a subdural grid in predicting the site of successful surgical therapy. These results illustrate the potential of functional MRI for localizing seizure foci with high spatial and temporal resolution. Such studies can be readily combined with high-resolution anatomical imaging, task-activation studies, and other magnetic resonance techniques.

False Lateralization of Temporal Lobe Epilepsy with FDG Positron Emission Tomography

We report 2 patients in whom visual interpretation of interictal positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG) suggested false lateralization of an epileptic focus. PET scans were interpreted as showing diffuse left temporal lobe hypometabolism in 1 patient and lateral temporal hypometabolism in the other. However, seizures began in the right mesial temporal lobe in both patients, and both responded favorably to right temporal lobectomy. In 1 patient, the intracranial EEG showed continuous asymptomatic subclinical seizure activity emanating from the right amygdala. These limbic discharges probably caused unrecognized right temporal lobe hypermetabolism. In the other case, quantitative analysis of metabolic rates showed conflicting mesial and lateral metabolic indexes. Frequent mesial interictal discharges might have increased lateral temporal metabolism. We conclude that asymptomatic epileptiform activity may alter temporal lobe metabolism and that quantitative PET analysis helps clarify contradictory visual PET interpretations.

NMDA and Not Non-NMDA Receptor Antagonists Are Protective against Seizures Induced by Homocysteine in Neonatal Rats

Homocysteine induces seizures in adult, as well as in immature, experimental animals, but the mechanism of its action is still unknown. The aim of the present study was to examine whether homocysteine in immature animals may act via excitatory amino acids receptors. Seizures were induced in 7-day-old rats by ip administration of homocysteine (16.5 mmol/kg) and the effects of selected antagonists at NMDA and non-NMDA receptor sites were investigated. The anticonvulsant effect was evaluated not only in terms of behavioral changes, but also in terms of some indicators of brain energy metabolism. Rat pups were sacrificed during generalized clonic-tonic seizures, corresponding approximately to 15-30 min after homocysteine administration. Comparable time intervals were used for sacrificing pups in the groups with protective drugs. Non-NMDA antagonists, l-glutamic acid diethylester (GDEE) (4 mmol/kg, ip) and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline (NBQX) (two doses, 30 mg/kg each, ip), failed to protect neonatal rats against homocysteine-induced seizures. Although NBQX prevented the tonic phase, the severity of clonic movements was even more pronounced. Metabolic changes accompanying the seizures (decreases of glucose and glycogen and a rise of lactate) were also not influenced by GDEE or NBQX pretreatment. On the contrary, NMDA antagonists, both competitive (AP7, 0.33 mmol/kg, ip) and noncompetitive (MK-801, 0.5 mg/kg, ip), had a clear-cut anticonvulsant effect. They not only suppressed the behavioral signs of seizures, but also prevented most of the metabolic changes accompanying seizures. Whether incomplete normalization of lactate levels reflects subclinical seizure activity or whether it is due to the effect of anatagonists (AP7, MK-801) themselves is not clear. All drugs, besides GDEE, when given alone caused a rise in brain glucose. This is the first demonstration that seizures induced by homocysteine can be blocked by NMDA antagonists. The findings thus suggest that, at least in neonatal rats, enhanced activation of NMDA receptors is implicated in homocysteine-induced seizures.

Lidocaine unmasks silent demyelinative lesions in multiple sclerosis.

Blockage of a small number of sodium channels may prevent impulse conduction in some demyelinated segments of nerve fibers with low safety factors, thereby unmasking subclinical demyelinative lesions. On the basis of this hypothesis, lidocaine, a sodium channel blocker, was administered intravenously to 28 MS patients and to 19 normal subjects and seven patients with nondemyelinating diseases. As predicted, lidocaine (mean plasma level, 2.7 micrograms/ml) elicited reversible subclinical symptoms in 23 of the MS patients, but it had not effect on the control subjects. We made a quantitative study of the visual functions (visual acuity, color vision, visual evoked potential [VEP]) that were impaired in 15 MS patients. Of the 23 affected eyes, nine showed normal VEPs, indicative of the test's sensitivity to focal lesions. This test should be useful in the diagnosis of MS and in the evaluation of the subclinical activity of MS as well.

Comparison between tape‐recorded and amplitude‐integrated EEG monitoring in sick newborn infants

In 15 ill newborn infants a comparison between long-term multichannel and single-channel recordings of simultaneously tape-recorded (Medilog system) and amplitude-integrated EEG (Cerebral Function Monitor) was made. There was good agreement between the main type of background activity diagnosed with the tape-recorded and the amplitude-integrated EEG for all recordings. Two infants had repetitive subclinical and subtle seizure activity, lasting for several hours, which was detected by both techniques. Short, single seizures were diagnosed in the recordings of nine infants. When a single electrographic seizure appeared in an otherwise stable recording, it was identified by both the tape-recorded and the amplitude-integrated EEG. Very short (5-30 s) seizure patterns, which were diagnosed with the tape-recorded EEG, were not identified in the cerebral function monitor recordings. In the single-channel recordings of both the EEG and the cerebral function monitor there were, on some occasions, difficulties in distinguishing single seizures from interference due to external artefacts. In the multichannel recordings the diagnosis of seizure patterns was facilitated by comparison with the other channels. Both the Medilog EEG and the cerebral function monitor are feasible techniques for following cerebral electrical activity in sick neonates, although neither technique is specifically constructed for this purpose. For clinical use in the neonatal intensive care unit the advantage with the cerebral function monitor is the immediately available recording. The tape-recorded EEG offers possibilities of more channels and a higher reliability when diagnosing short subclinical seizures, however, only after offline analysis.

Education and Epilepsy: Assessment and Remediation

Learning difficulties in children with epilepsy may be caused by brain damage and should be investigated. In many cases, however, seizures and/or electroencephalographic (EEG) findings are the only signs of pathology. Frequency and type of seizures may be determining factors that should, if necessary, be evaluated by long-term EEG monitoring, preferably during school performance or in conjunction with neuropsychological assessment. This may prove that subclinical epileptiform discharges in the EEG can adversely affect the child's performance. Secondary psychological problems in epilepsy patients, combined with side effects of antiepileptic drugs, may cause or heighten learning problems. Prophylactic control of seizures with one appropriate drug may alleviate learning problems. Computerized neuropsychological testing with simultaneous EEG recording may reveal the influence of epileptiform discharges on cognitive function and also help to evaluate the effects of antiepileptic drugs. Objective assessment of subclinical epileptiform activity makes it easier to treat the pathology identified by the EEG with optimal dosage of the most appropriate drug. A balance is required because epileptiform discharges and even occasional seizures may be less disabling than side effects from large doses of several drugs. Information to the school and the parents concerning the patient's abilities and limitations may be as important as seizure control. Specialized teaching should be started early, when necessary, with the patient integrated into a normal school if possible. However, good functioning in a special school is preferable to marginal functioning in a normal school.

Heparin Dosing and Monitoring for Cardiopulmonary Bypass. A Comparison of Techniques with Measurement of Subclinical Plasma Coagulation

Subclinical plasma coagulation during cardiopulmonary bypass has been associated with marked platelet and clotting factor consumption in monkeys. To better define subclinical coagulation in man, we measured plasma fibrinopeptide A concentrations before, during, and after cardiopulmonary bypass. Patients were assigned to one of three groups of heparin management: group 1 (n = 10)--initial heparin dose 300 IU/kg, with supplemental heparin if the activated coagulation time fell below 400 seconds; group 2 (n = 6)--initial heparin dose 250 IU/kg, with supplemental heparin if activated coagulation time was less than 400 seconds; and group 3 (n = 5)--initial heparin dose 350 to 400 IU/kg, with supplemental heparin if whole blood heparin concentration was less than or equal to 4.1 IU/ml. Activated coagulation time and heparin concentration were measured every 30 minutes during cardiopulmonary bypass, and fibrinopeptide A was measured at hypothermia, normothermia, and whenever activated coagulation time was less than 400 seconds. Quantitative and qualitative blood clotting competence was assessed after cardiopulmonary bypass, including mediastinal drainage for the first 24 hours. Fibrinopeptide A values were markedly elevated during cardiopulmonary bypass but were well below the levels present before and after cardiopulmonary bypass. Fibrinopeptide A correlated inversely with heparin concentration during cardiopulmonary bypass (r = -0.46, p = 0.03), but higher fibrinopeptide A levels during cardiopulmonary bypass did not correlate with post-cardiopulmonary bypass coagulopathy. Group 3 patients received the highest heparin doses (p less than 0.05) and had the greatest postoperative blood loss (p less than 0.05). Protamine dose and heparin concentration during cardiopulmonary bypass correlated best with postoperative mediastinal drainage. Our findings support the following conclusions: (1) compensated subclinical plasma coagulation activity occurs during cardiopulmonary bypass despite activated coagulation time greater than 400 seconds or heparin concentration greater than or equal to 4.1 IU/ml; (2) post-cardiopulmonary bypass mediastinal drainage correlates strongly with increased heparin concentration during cardiopulmonary bypass (p less than 0.05) and protamine dose (p less than 0.05); and (3) during cardiopulmonary bypass at both normothermia and hypothermia, activated coagulation times greater than 350 seconds result in acceptable fibrinopeptide A levels and post-cardiopulmonary bypass blood clotting.

Heparin dosing and monitoring for cardiopulmonary bypass: A comparison of techniques with measurement of subclinical plasma coagulation

Subclinical plasma coagulation during cardiopulmonary bypass has been associated with marked platelet and clotting factor consumption in monkeys. To better define subclinical coagulation in man, we measured plasma fibrinopeptide A concentrations before, during, and after cardiopulmonary bypass. Patients were assigned to one of three groups of heparin management: group 1 (n = 10)--initial heparin dose 300 IU/kg, with supplemental heparin if the activated coagulation time fell below 400 seconds; group 2 (n = 6)--initial heparin dose 250 IU/kg, with supplemental heparin if activated coagulation time was less than 400 seconds; and group 3 (n = 5)--initial heparin dose 350 to 400 IU/kg, with supplemental heparin if whole blood heparin concentration was less than or equal to 4.1 IU/ml. Activated coagulation time and heparin concentration were measured every 30 minutes during cardiopulmonary bypass, and fibrinopeptide A was measured at hypothermia, normothermia, and whenever activated coagulation time was less than 400 seconds. Quantitative and qualitative blood clotting competence was assessed after cardiopulmonary bypass, including mediastinal drainage for the first 24 hours. Fibrinopeptide A values were markedly elevated during cardiopulmonary bypass but were well below the levels present before and after cardiopulmonary bypass. Fibrinopeptide A correlated inversely with heparin concentration during cardiopulmonary bypass (r = -0.46, p = 0.03), but higher fibrinopeptide A levels during cardiopulmonary bypass did not correlate with post-cardiopulmonary bypass coagulopathy. Group 3 patients received the highest heparin doses (p less than 0.05) and had the greatest postoperative blood loss (p less than 0.05). Protamine dose and heparin concentration during cardiopulmonary bypass correlated best with postoperative mediastinal drainage. Our findings support the following conclusions: (1) compensated subclinical plasma coagulation activity occurs during cardiopulmonary bypass despite activated coagulation time greater than 400 seconds or heparin concentration greater than or equal to 4.1 IU/ml; (2) post-cardiopulmonary bypass mediastinal drainage correlates strongly with increased heparin concentration during cardiopulmonary bypass (p less than 0.05) and protamine dose (p less than 0.05); and (3) during cardiopulmonary bypass at both normothermia and hypothermia, activated coagulation times greater than 350 seconds result in acceptable fibrinopeptide A levels and post-cardiopulmonary bypass blood clotting.

Preischemic hyperglycemia enhances postischemic depression of cerebral metabolic rate.

The objective of the present study was to explore metabolic correlates to the appearance of postischemic seizures and the enhancement of brain damage observed in subjects that are made hyperglycemic prior to the induction of ischemia. To that end, transient forebrain ischemia of 10-min duration was induced in normo- and hyperglycemic rats, with subsequent measurements of local CMRglc (LCMRglc) after 3, 6, 12, and 18 h of recirculation. We posed the questions of whether postischemic depression of LCMRglc is exaggerated by preischemic hyperglycemia and whether there are signs of localized increases in LCMRglc in hyperglycemic rats, reflecting subclinical seizure activity. The results confirmed the presence of a long-lasting postischemic depression of LCMRglc in normoglycemic rats. This depression was partially but not tightly related to the degree of reduction of local CBF during ischemia. The depression was most pronounced in neocortical areas and in the hippocampus, but notably it was less pronounced in the densely ischemic caudoputamen. Little or no reduction of LCMRglc was observed in moderately or mildly ischemic structures such as the hypothalamus, red nucleus, and cerebellum. Preischemic hyperglycemia markedly accentuated the postischemic depression of LCMRglc. For example, although the subjects quickly regained wakefulness and motility, they had LCMRglc values in neocortical areas that remained below 50% of control. Corresponding but quantitatively less pronounced reductions in LCMRglc were observed in other areas. Notably, preischemic hyperglycemia reduced postischemic LCMRglc also in areas that showed only moderate to mild reductions in CBF during the ischemia. The results thus demonstrate that preischemic hyperglycemia has pronounced metabolic effects in the postischemic recovery period. The data provide no indication that postischemic seizures, which develop after a recovery period of approximately 24 h, are preceded by the appearance of hypermetabolic "seizure" foci.

Ambulatory cassette electroencephalography of psychiatric patients.

Indications and results of ambulatory cassette electroencephalography obtained on 133 hospitalized psychiatric patients were reviewed. Interictal epileptiform abnormalities were detected in 15 patients (11%), of whom six had an established diagnosis of epilepsy. Actual seizures were recorded in two patients, of whom one had an established diagnosis of epilepsy. Subclinical seizure activity was detected in only one patient, who also experienced overt seizures. Routine screening of psychiatric patients with ambulatory cassette electroencephalography does not seem to be justified, although the test can provide useful adjunctive evidence to support the diagnosis of epilepsy and clarify the nature of suspicious clinical episodes in selected patients.

Suprasegmentally induced motor unit activity in paralyzed muscles of patients with established spinal cord injury.

In an attempt to demonstrate the presence of functional descending fibers in patients with clinically apparent functional spinal cord transection, we examined electromyographically recorded paralyzed leg muscle responses to the Jendrassik and other reinforcement maneuvers. Two patterns were observed: a low-amplitude, short onset time reinforcement maneuver response (RMR) restricted to one to three muscle groups (RMR1), and a larger-amplitude response with a longer onset time that occurred bilaterally in essentially all of the recorded muscles (RMR2). The responses imply preserved descending facilitory influence on isolated populations of motor units (RMR1) or on segmental interneuron pools (RMR2). Such findings indicate the presence of functioning fibers traversing the injured portion of the spinal cord in patients diagnosed as having a complete lesion. In such cases, it is possible for patients to initiate subclinical motor unit activity or suprasegmentally induced gross movement through reinforcement maneuvers, but not to control the amplitude or duration of the response.

EEG subclinical paroxysmal rhythmic activity

We studied 33 non-epileptic adults presenting with subclinical paroxysmal rhythmic activity (SPRA) on EEG examination. Sixteen patients showed the psychomotor-variant pattern described by GIBBS et al. in 1963. Seventeen patients presented a Naquet-type pattern (Naquet et al., 1961). Regardless of SPRA type, patients had similar non-specific neuropsychiatric symptoms. Only 3 patients were diagnosed as having a neurological disorder, this being dementia. Mode of onset, appearance and location of SPRA, amplitude, duration and response to sensory stimuli were identical in all patients studied. Several patients with Naquet-type discharges presented Gibbs' patterns as well. Gibbs' pattern is analogous to the longer lasting, intermediate phase of Naquet-type SPRA. We believe that both these types of SPRA may manifest a common electro-encephalographic phenomenon, and are not necessarily related to cerebral circulatory insufficiency.