Cerebral and cerebellar volume reduction in children with intractable epilepsy

PURPOSE: Adult epilepsy studies have demonstrated cerebral and cerebellar volume reduction beyond the epileptogenic zone, correlating this with an inferior surgical outcome. We determined whether brain volumes were reduced in childhood epilepsy and the significance of this. METHODS: Cerebral, cerebellar, and hippocampal volumes were measured by quantitative magnetic resonance imaging on 112 children (ages 4-18) with epilepsy syndrome determined by video-EEG telemetry. Eighty-seven had partial epilepsy and 25 had generalized epilepsy or indeterminate syndrome. Normative volumes were obtained from 44 child controls from the community. RESULTS: A significant reduction in cerebral (12.6%) and cerebellar (7.9%) volume was present in the epilepsy group compared with controls. Analysis of subgroups revealed that cerebral volume was significantly decreased in frontal lobe and nonlocalized partial epilepsies. The mean hippocampal ratio of 0.73 for mesial temporal lobe epilepsy was significantly less than for all other syndromes and controls. There was no difference in the rate of hippocampal volume reduction between syndromes. There was a significant correlation between IQ and cerebral and cerebellar volume, but not duration or age of onset of epilepsy. CONCLUSIONS: Cerebral and cerebellar volume reduction is common in intractable epilepsy syndromes of childhood. These cross-sectional data suggest that brain volume reduction is present at epilepsy onset and is not a result of intractable seizures. Hippocampal asymmetry is more sensitive than volume reduction as a marker for mesial temporal lobe epilepsy, but neither measure is specific.     

Clinical significance of isolated hippocampal volume asymmetry in childhood epilepsy

This study defines the clinical characteristics and evolution of 16 epileptic children with hippocampal asymmetry (HA) without sclerosis on MRI. The association of a positive family history of epilepsy (11/16), low incidence of febrile seizures (2/16), and benign prognosis (seizure control in monotherapy in 11/16, mean follow-up = 4.3 years, range 1 to 10) suggest a different clinical presentation than patients with mesial temporal sclerosis. Genetic studies of these mostly French Canadian families should help confirm the existence of a distinct syndrome.     

Temporal lobe epilepsy, depression, and hippocampal volume

Objective:   To evaluate the relationship between hippocampal volume loss, depression, and epilepsy.
Background:   There is a significantly increased incidence of depression and suicide in patients with epilepsy. Both epilepsy and depression are associated with reduced hippocampal volumes, but it is uncertain whether patients with both conditions have greater atrophy than those with epilepsy alone. Previous studies used depression measures strongly weighted to current state, and did not necessarily assess the influence of chronic major depressive disorder ("trait"), which could have a greater impact on hippocampal volume.
Methods:   Fifty-five epilepsy patients with complex partial seizures (CPS) confirmed by electroencephalography (EEG) had three-dimensional (3D)-spoiled gradient recall (SPGR) acquisition magnetic resonance imaging (MRI) scans for hippocampal volumetric analysis. Depression screening was performed with the Beck Depression Inventory (BDI, 51 patients) and with the structured clinical inventory for DSM-IV (SCID, 34 patients). For the BDI, a score above 10 was considered mild to moderate, above 20 moderate to severe, and above 30 severe depression. MRI and clinical analysis were performed blinded to other data. Statistical analysis was performed with Systat using Student's t test and analysis of variance (ANOVA).
Results:   There was a significant interaction between depression detected on SCID, side of focus, and left hippocampal volume. Patients with a diagnosis of depression and a right temporal seizure focus had significantly lower left hippocampal volume. A similar trend for an effect of depression on right hippocampal volume in patients with a right temporal focus did not reach statistical significance.
Conclusions:   Our results suggest that patients with right temporal lobe epilepsy and depression have hippocampal atrophy that cannot be explained by epilepsy alone.     

Predictors and underlying causes of medically intractable localization-related epilepsy in childhood

The goal of this study is to clarify the prognostic factors in childhood localization-related epilepsy in a tertiary medical center. Children (n = 113) with symptomatic and cryptogenic localization-related epilepsy were divided into groups of intractable patients (average seizure frequency: one or more per month during the 6 months before the last follow-up; n = 40) and well-controlled patients (no seizures for at least 1 year before the last follow-up; n = 73). Clinical and electroencephalogram (EEG) factors were examined to elucidate prognostic factors. The subtypes of epilepsies and causes were also investigated. Univariate analyses indicated that the following factors were correlated with seizure outcome: (1) seizure type at the first visit; (2) seizure frequency; (3) underlying cause; (4) age at onset of epilepsy; (5) status epilepticus occurring as the first seizure and before the first visit; and (6) diffuse epileptic discharges on first visit interictal EEGs. Multivariate analyses revealed that seizure type at the first visit, seizure frequency, status epilepticus before the first visit, and underlying causes were significant independent predictive factors. The rate of intractable patients was highest in multilobar epilepsy, followed by frontal-lobe epilepsy. Regarding etiologies, the intractable group contained nine patients with encephalitis of unknown origin and three each with localized cortical malformation and mesial temporal sclerosis.     

Associations among parenting experiences during childhood and adolescence, hypothalamus-pituitary-adrenal axis hypoactivity, and hippocampal gray matter volume reduction in young adults

Recent human studies have indicated that adverse parenting experiences during childhood and adolescence are associated with adulthood hypothalamus-pituitary-adrenal (HPA) axis hypoactivity. Chronic HPA axis hypoactivity inhibits hippocampal gray matter (GM) development, as shown by animal studies. However, associations among adverse parenting experiences during childhood and adolescence, HPA axis activity, and brain development, particularly hippocampal development, are insufficiently investigated in humans. In this voxel-based structural magnetic resonance imaging study, using a cross-sectional design, we examined the associations among the scores of parental bonding instrument (PBI; a self-report scale to rate the attitudes of parents during the first 16 years), cortisol response determined by the dexamethasone/corticotropin-releasing hormone test, and regional or total hippocampal GM volume in forty healthy young adults with the following features: aged between 18 and 35 years, no cortisol hypersecretion in response to the dexamethasone test, no history of traumatic events, or no past or current conditions of significant medical illness or neuropsychiatric disorders. As a result, parental overprotection scores significantly negatively correlated with cortisol response. Additionally, a significant positive association was found between cortisol response and total or regional hippocampal GM volume. No significant association was observed between PBI scores and total or regional hippocampal GM volume. In conclusion, statistical associations were found between parental overprotection during childhood and adolescence and adulthood HPA axis hypoactivity, and between HPA axis hypoactivity and hippocampal GM volume reduction in healthy young adults, but no significant relationship was observed between any PBI scores and adulthood hippocampal GM volume.     

Effects of cerebellar stimulation on epilepsy, the EEG and cerebral palsy in man.

Eighteen of the first 29 patients with intractable epilepsy treated by chronic cerebellar stimulation (CCS) demonstrated a marked suppression of seizures. Sixty-eight of 100 patients with cerebral palsy showed clinical improvement after CCS. Electroencephalographic studies in three epileptic patients revealed a significant (P less than 0.001) reduction in number and duration of paroxysmal EEG discharges during epochs when the stimulator was on; prolonged effects were seen at stimulation rates of 200 c/sec and 10 c/sec (monophasic capacitively coupled stimuli). "Rebound" increases in numbers and durations of paroxysmal discharges occurred after cessation of CCS: immediate "rebounds" occurred within the next 5 min; such rebound effects were also seen in the frequency of clinical seizures. CCS at voltages well above threshold for the production of changes in H reflexes, late motor responses (V1 and V2), and evoked potentials resulted in increased "rebound" effects after cessation of stimulation and such effects were seen clinically and neurophysiologically in epileptic and cerebral palsy patients. Variability in the effects of CCS on seizures and the EEG may have been due to technical factors such as positions and impedances of electrodes, output of the stimulator, effects of anticonvulsant medication and patient differences; there was no clinical or physiological evidence of any undesirable neurological effect of CCS. In one patient, onset of CCS was frequently associated with cessation of polyspike and wave discharges; such results raise the possibility of triggering CCS from paroxysmal discharges in the EEG (contingency feedback) but rebound effects may complicate such therapy.     

Anterior hippocampal volume reduction in male patients with schizophrenia

Quantitative high resolution magnetic resonance imaging (MRI) was utilized to measure anterior, posterior, and total hippocampal volumes in 27 male patients with chronic schizophrenia and 24 male controls. To optimize measurement techniques, hippocampal volumes were: (1) acquired with 1.4-mm slices; (2) excluded with the amygdala; (3) normalized for position; and (4) corrected for total intracranial volume (ICV). The results of a linear mixed effects regression analysis, which made it possible to analyze total anterior and total posterior hippocampal volumes separately, indicated that the anterior hippocampus was significantly smaller in the schizophrenic group relative to the control group. There were no significant group differences with respect to posterior hippocampal volumes, and no significant correlations between hippocampal volumes and illness duration. A significant lateralized asymmetry was also noted in both groups with the right hippocampal volume being larger than the left. These preliminary findings support a significant anterior hippocampal volume reduction in men with schizophrenia as well as a similar hippocampal volume asymmetry in both male controls and schizophrenics.     

Bilateral hippocampal volume predicts verbal memory function in temporal lobe epilepsy

The present study used quantitative volume estimates of the hippocampus based on structural magnetic resonance imaging (MRI) to predict memory performance of individuals with epilepsy of temporal lobe origin (TLE). Twenty individuals with TLE completed standardized neuropsychological tests and a quality of life inventory, and participated in a brain MRI protocol designed to obtain high-resolution images of the hippocampus. The combined volume of the left and right hippocampi was found to be the best predictor of objective verbal memory performance. This finding is consistent with the functional adequacy model of hippocampal function. In contrast, the asymmetry between right and left hippocampal volume was the best predictor of subjective ratings of cognitive functioning, which is consistent with the functional reserve model. The collective and complementary functions of the left and right hippocampi merit further exploration in prospective studies of memory function and TLE.     

Reflex-mediated reduction in human cerebral blood volume.

Adrenergic nerves innervate the human cerebrovasculature, yet the functional role of neurogenic influences on cerebral hemodynamics remains speculative. In the current study, regional cerebrovascular responses to sympathoexcitatory reflexes were evaluated. In eight volunteers, contrast-enhanced computed tomography was performed at baseline, -40 mmHg lower body negative pressure (LBNP), and a cold pressor test (CPT). Cerebral blood volume (CBV), mean transit time (MTT), and cerebral blood flow (CBF) were evaluated in cortical gray matter (GM), white matter (WM), and basal ganglia/thalamus (BGT) regions. Lower body negative pressure resulted in tachycardia and decreased central venous pressure while mean arterial pressure was maintained. Cold pressor test resulted in increased mean arterial pressure concomitant with tachycardia but no change in central venous pressure. Neither reflex altered end-tidal carbon dioxide. Cerebral blood volume was reduced in GM during both LBNP and CPT (P<0.05) but was unchanged in WM and BGT. Mean transit time was reduced in WM and GM during CPT (P<0.05). Cerebral blood flow was only modestly affected with either reflex (P<0.07). The combined reductions in GM CBV (approximately -25%) and MTT, both with and without any change in central venous pressure, with small CBF changes (approximately -11%), suggest that active venoconstriction contributed to the volume changes. These data demonstrate that CBV is reduced during engagement of sympathoexcitatory reflexes and that these cerebrovascular changes are heterogeneously distributed.     

Bilateral reductions in hippocampal volume in adults with epilepsy and a history of febrile seizures

OBJECTIVES—To examine the degree and frequency ofreductions in hippocampal volume in patients with temporal lobeepilepsy with and without a history of febrile seizures.
METHODS—In vivo measures of hippocampal volumewere computed from three dimensional gradient echo (FLASH) images in 44 patients undergoing comprehensive evaluations for epilepsy surgery.Twenty one patients (48%) reported a history of febrile seizures. Thevolumes from these patients were compared with those from 23 patientswithout a history of febrile seizures and 34 healthy controls.
RESULTS—The febrile seizure group had significantreductions in volume, both ipsilateral (30% decrease) andcontralateral (15% decrease), to the EEG seizure focus. Twelve of 18 patients with febrile seizures exhibited clinically significantipsilateral volume reductions, defined as volumes falling 2 SD belowthe mean obtained from the control sample. Only four of 19 patientswithout febrile seizures exhibited this degree of reduction. Nosignificant correlations were found between seizure variables (forexample, duration of epilepsy, seizure frequency) and ipsilateralreductions in volume. However, a significant inversecorrelation (r=−0.45, P<0.05) between seizure frequencyand the volume of the hippocampus contralateral to the seizure focuswas found in the febrile seizure group.
CONCLUSION—These results suggest that a historyof febrile seizures is associated with the finding of a smallerhippocampus on the side ipsilateral to the subsequent temporal lobefocus whereas chronic factors seem to be be related to pathologycontralateral to the seizure focus.

     

Penicillin-induced epilepsy model in rats: dose-dependant effect on hippocampal volume and neuron number

This study was designed to evaluate the penicillin-induced epilepsy model in terms of dose-response relationship of penicillin used to induce epilepsy seizure on hippocampal neuron number and hippocampal volume in Sprague-Dawley rats. Seizures were induced with 300, 500, 1500 and 2000IU of penicillin-G injected intracortically in rats divided in four experimental groups, respectively. Control group was injected intracortically with saline. Animals were decapitated on day 7 of treatment and brains were removed. The total neuron number of pyramidal cell layer from rat hippocampus was estimated using the optical fractionator method. The volume of same hippocampal areas was estimated using the Cavalieri method. Dose-dependent decrease in hippocampal neuron number was observed in three experimental groups (300, 500 and 1500IU of penicillin-G), and the effects were statistically significant when compared to the control group (P<0.009). Dose-dependent decrease in hippocampal volume, on the other hand, was observed in all three of these groups; however, the difference compared to the control group was only statistically significant in 1500IU of penicillin-G injected group (P<0.009). At the dose of 2000IU penicillin-G, all animals died due to status seizures. These results suggest that the appropriate dose of penicillin has to be selected for a given experimental epilepsy study in order to demonstrate the relevant epileptic seizure and its effects. Intracortical 1500IU penicillin-induced epilepsy model may be a good choice to practice studies that investigate neuroprotective mechanisms of the anti-epileptic drugs.     

A decrease in regional cerebral blood volume and hematocrit in crossed cerebellar diaschisis.

BACKGROUND AND PURPOSE: The pathophysiology of crossed cerebellar diaschisis (CCD) remains to be elucidated. In CCD, the metabolic suppression resulting from deafferentation may cause vasoconstriction, which may result in a decrease in cerebral blood volume (CBV) and may differentially affect the flows of red blood cells and of plasma. The purpose of this study was to investigate whether CCD decreases the total CBV (cerebral red blood cell volume [CRCV] plus cerebral plasma volume [CPV]) and, if so, whether CCD differentially affects the CRCV and CPV, resulting in a change in hematocrit. METHODS: We used positron emission tomography to study 7 patients with a unilateral supratentorial infarct and CCD. The distributions of CRCV and CPV were assessed by using 15O-labeled carbon monoxide and 62Cu-labeled human serum albumin-dithiosemicarbazone tracers, respectively. The CRCV, CPV, and calculated hematocrit values were compared between the cerebellar hemispheres. RESULTS: In the cerebellar cortex contralateral to the supratentorial infarct, the values of CRCV, CPV, and total CBV were significantly decreased compared with those in the ipsilateral cerebellar cortex. The CRCV was decreased to a greater degree than the CPV, and the value of the hematocrit was decreased in the contralateral cerebellar cortex. CONCLUSIONS: CCD may decrease the total CBV, which may reflect vasoconstriction caused by decreased metabolism due to deafferentation. In addition, the more pronounced decrease in CRCV than in CPV may result in a decrease in hematocrit in CCD.     

Predictors of intellectual functioning after epilepsy surgery in childhood: The role of socioeconomic status

ObjectiveThe objective of this study was to evaluate the association between socioeconomic status and intellectual functioning in children with medically refractory epilepsy, before and after resective epilepsy surgery. Family environment is a strong contributor to cognitive development in children and has been recently shown to play a significant role in intellectual outcome after surgery in children with epilepsy.MethodsOne hundred children who had undergone resective epilepsy surgery and completed preoperative and postoperative assessments of IQ as part of clinical care were included in the study. We evaluated the impact of epilepsy-related variables, income quintile, and residence location on IQ.ResultsGreater improvements in IQ after surgery were associated with an older age at surgery (β = .235, p = .018). Higher IQ scores at follow-up were associated with an older age of seizure onset (β = .371, p < .001), older age at surgery (β = .356, p < .001), unilobar epileptogenic focus (β = .394, p < .001), and mesial temporal sclerosis (β = .338, p = .001) or tumor (β = .457, p < .001) in comparison with malformation of cortical development; age at seizure onset did not remain as a significant predictor in multivariable regression analysis. Income quintile, residence location, seizure control, and antiepileptic medication use were not significant predictors.ConclusionsEpilepsy-related variables were the strongest predictors of IQ and postoperative change in IQ. We were unable to identify a significant association between IQ and socioeconomic status. Future research should evaluate the impact of multiple aspects of family environment.