Relationship between language lateralization and handedness in left-hemispheric partial epilepsy.

OBJECTIVE: To investigate the relationship between language lateralization and handedness in patients with epilepsy and a left-sided seizure focus and in healthy control subjects. METHODS: We recruited a consecutive series of 74 patients and 70 control subjects. Functional MRI, using a noun-verb generation task, was performed to establish the language laterality index (LI). Handedness was quantified using the Edinburgh Handedness Inventory. RESULTS: Patients showed a shift toward atypical language lateralization (0.43 +/- 0.47; controls 0.57 +/- 034; p < or = 0.05) and left-handedness (55 +/- 57; controls 74 +/- 39; p < or = 0.05). The LI and handedness were correlated in patients (r = 0.54; F = 25.9; p < 0.001) but not in control subjects (r = 0.1; F = 0.64; NS). A combination of left-handedness and atypical LI was more frequent in patients (12%) than control subjects (0%; p < or = 0.05). Crossed hemispheric specialization (e.g., right-handedness associated with atypical LI) was equally frequent in patients (20%) and control subjects (16%; NS). CONCLUSION: In epilepsy patients with a left-sided seizure focus, language lateralization is correlated to handedness. The increased frequency of left-handedness and associated atypical language lateralization is most likely related to the left-hemispheric seizure focus, influencing hemispheric specialization for both domains.

Pathologic and physiologic function in the subcortical band of double cortex.

Double cortex is a neuronal migration disorder, associated with impaired cognitive function and seizures, and characterized by a subcortical band of neurons. Using functional MRI, we assessed the involvement of the subcortical band in language function and with interictal discharges. In both girls assessed, language-associated activation was in typical cortical areas, as well as in parts of the subcortical band. Interictal discharges were associated with deactivation in the subcortical band. This suggests involvement of the subcortical neurons in physiologic and pathologic functions.

Typical childhood absence seizures are associated with thalamic activation.

Functional MRI with simultaneously acquired EEG (fMRI/EEG) can identify areas of signal change associated with interictal discharges. We report the fMRI/EEG study of a child with newly-diagnosed IGE, performed prior to the start of antiepileptic medication. The 7-years-old girl had very frequent absences, associated with eyelid myoclonia. Her EEG showed frequent, typical 3/sec discharges. Functional MRI was performed with a 3T scanner using whole brain gradient echo-planar imaging, and the EEG was recorded with 18, non-metallic, scalp electrodes. Ten bursts of generalized discharges were captured during 30 minutes fMRI/EEG acquisition. The bursts lasted 3.4 (SD +/- 0.6) seconds. Event-related analysis was performed with SPM2 and iBrain software. Functional MRI showed prominent, bilateral thalamic activation, and less pronounced areas of cortical activation and deactivation. This study demonstrates thalamic activation in typical, untreated childhood absence epilepsy. The cortical signal change may be related to a thalamo-cortical circuit.

Structural abnormalities remote from the seizure focus: a study using T2 relaxometry at 3 T.

OBJECTIVE: To determine the extent and severity of mesial temporal and subcortical signal abnormalities in patients with partial epilepsy. METHODS: T2 relaxation time maps were acquired in 50 consecutive patients and 55 control subjects on a 3 T MRI scanner. Twenty-two patients had hippocampal sclerosis (HS), 16 had malformations of cortical development (MCD), and 12 had no obvious MR abnormalities (normal MR). The following eight regions were measured bilaterally: hippocampus, anterior temporal lobe (ATL) white matter, amygdala, frontal lobe white matter, caudate, putamen, pallidum, and thalamus. RESULTS: In patients with HS, increased T2 relaxation times were found in the ipsilateral hippocampus and ATL but not in subcortical nuclei. In patients with MCD, increased T2 relaxation times were found in the temporal lobe (hippocampus, ATL) and in subcortical areas (caudate, putamen, and pallidum); in patients with normal MR, increased T2 relaxation times were found in the hippocampus and putamen. The degree of abnormality did not correlate with the duration of epilepsy or the estimated seizure load. CONCLUSIONS: Mesial temporal structures show increased T2 relaxation times not only in patients with hippocampal sclerosis but also in patients with a seizure focus remote from the hippocampus. Patients with normal MR and focal malformations of cortical development have increased T2 relaxation times in subcortical structures. Therefore, abnormalities in T2 relaxation time can be found remote from the seizure focus. They cannot be simply attributed to secondary seizure effects.

LGI1 mutations in temporal lobe epilepsies.

BACKGROUND AND OBJECTIVES: A number of familial temporal lobe epilepsies (TLE) have been recently recognized. Mutations in LGI1 (leucine-rich, glioma-inactivated 1 gene) have been found in a few families with the syndrome of autosomal dominant partial epilepsy with auditory features (ADPEAF). The authors aimed to determine the spectrum of TLE phenotypes with LGI1 mutations, to study the frequency of mutations in ADPEAF, and to examine the role of LGI1 paralogs in ADPEAF without LGI1 mutations. METHODS: The authors performed a clinical and molecular analysis on 75 pedigrees comprising 54 with a variety of familial epilepsies associated with TLE and 21 sporadic TLE cases. All were studied for mutations in LGI1. ADPEAF families negative for LGI1 mutations were screened for mutations in LGI2, LGI3, and LGI4. RESULTS: Four families had ADPEAF, 22 had mesial TLE, 11 had TLE with febrile seizures, two had TLE with developmental abnormalities, and 15 had various other TLE syndromes. LGI1 mutations were found in two of four ADPEAF families, but in none of the other 50 families nor in the 21 individuals with sporadic TLE. The mutations were novel missense mutations in exons 1 (c.124T-->G; C42G) and 8 (c.1418C-->T; S473L). No mutations in LGI2, LGI3, or LGI4 were found in the other two ADPEAF families. CONCLUSION: In TLE, mutations in LGI1 are specific for ADPEAF but do not occur in all families. ADPEAF is genetically heterogeneous, but mutations in LGI2, LGI3, or LGI4 did not account for families without LGI1 mutations.

Longitudinal study of MRS metabolites in Rasmussen encephalitis.

This study analyses the evolution of metabolite changes in an 8-year-old boy with focal Rasmussen encephalitis. Five MRI examinations, including magnetic resonance spectroscopy (MRS) were performed over 9 months. Following complex partial status, T2-weighted imaging showed transient dramatic signal increase in the left superior temporal gyrus and mesial temporal structures. Subsequent scans showed resolution of the swelling and signal normalization, with development of slight focal atrophy. MRS after status showed a reduction in N-acetylaspartate, total creatine and trimethylamines. Subsequent scans showed complete resolution of these metabolite abnormalities, followed later by development of further abnormal metabolite values. Lactate and glutamine/glutamate were elevated after status. After surgery, ex vivo high-field (1)H and (31)P MRS confirmed metabolite abnormalities (elevated choline and decreased aspartate, N-acetylaspartate, [(1)H]glutamate together with altered [(31)P]phospholipid ratios. These findings suggested active disease process in the anterior region of the excised superior temporal gyrus. We conclude that Rasmussen encephalitis is a combination of progressive encephalitic damage and fluctuating seizure effects, in which neuronal injury and recovery can occur. MRS measurements at a single time point should consider the fluctuating metabolite profile related to seizure activity.

Hypertensive encephalopathy: antecedent to hippocampal sclerosis and temporal lobe epilepsy?

The authors describe three patients with refractory temporal lobe epilepsy (TLE) following an episode of hypertensive encephalopathy as their only identified antecedent event. All patients had typical MR features of hippocampal sclerosis (HS), and the two operated cases had typical HS histology and became seizure-free postoperatively. These cases suggest that hypertensive encephalopathy may be a rare form of initial precipitating injury, leading to TLE and HS.

Spike-triggered fMRI in reading epilepsy: involvement of left frontal cortex working memory area.

OBJECTIVE: To determine the origin of epileptiform activity in reading epilepsy (RE) and the association between these regions and regions activated by reading, and to assess brain morphometry in these areas. METHODS: In two subjects with RE, EEG was recorded inside the three tesla MRI while subjects read silently. Spike-triggered fMRI images were compared to baseline. In a second fMRI study, 30 seconds of silent reading was compared to visual fixation. Morphometry of these areas was assessed using curvilinear surface reconstruction. Left central sulcal patterns in three subjects with RE were compared to three subjects with idiopathic generalized epilepsy (IGE) and 12 normal controls. RESULTS: One subject with RE showed spike-related activity (17 spikes) in the left precentral gyrus, and bilaterally in the central sulcus and globus pallidus. The other showed no definite activation owing to low spike numbers (4 spikes). In both subjects, the block reading task recruited normal visual and language areas including the left posterior middle frontal gyrus. Two subjects with RE showed an unusual gyrus branching anteriorly off the left central sulcus. A similar sulcal pattern was seen in none of the subjects with IGE and only 1 of 12 controls. CONCLUSION: Spike activity overlapped with reading activity in the left middle frontal gyrus, a structure recruited during working memory cognitive tasks. The authors postulate that, because of a local structural anomaly, the spikes of reading epilepsy spread from working memory areas into adjacent motor cortex, activating a cortical subcortical circuit.

Brain reorganisation in cerebral palsy: a high-field functional MRI study.

Early brain damage may induce alternative organisation of cortical brain functions. This may happen even if there is no damage to the cortex. We assessed a 15-year-old girl with a perinatal left-sided subcortical lesion without cortical damage by functional MRI at 3 Tesla. The patient had congenital hemiparesis, mirrored limb movements and normal language function. Functional MRI was used to assess language using orthographic-lexical retrieval and noun-verb generation tasks, and demonstrated right-sided language dominance. Functional MRI of motor function was assessed for both hands separately, by squeezing a rubber balloon. Both hand movements induced asymmetric bilateral activation of the motor cortex, with a predominance of contralateral activation. Language-associated activity is usually left-hemispheric, but was found in the undamaged right-sided hemisphere. Motor function was associated with the unusual pattern of bilateral cortical activation. The MR findings explain the clinical features and suggest widespread alternative cortical organisation in the presence of a focal lesion confined to subcortical structures.

Seizures in family members of patients with hippocampal sclerosis.

OBJECTIVE: To characterize seizures in family members of patients with refractory temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS). METHODS: The authors systematically investigated family history (FH) of seizures in 66 probands with histologically proven HS, and in 51 control subjects. A positive FH was defined as at least one first-to-third-degree relative being affected. The odds ratio (OR) to be affected with seizures was calculated for siblings, parents, and aunts/uncles. RESULTS: An FH of seizures was found in 58% of patients, and in 24% of control subjects (p = 0.02). A variety of seizure types were found. Siblings of patients were more likely to be affected than siblings of control subjects (OR 11.5; 95% CI = 1.5 to 86.9 p = 0.003), with febrile convulsions occurring in 5.8% of the siblings of patients. The OR of being affected was 5.7 for parents of patients, and 1.9 for aunts/uncles of patients (p = NS). CONCLUSION: FH of seizures, particularly febrile convulsions, are a risk factor for TLE with HS. These data suggest that a variety of genes contributing to epilepsy phenotypes in relatives may be involved in the pathogenesis of HS.

Comparison of hippocampal volumetry at 1.5 tesla and at 3 tesla.

PURPOSE: Hippocampal volumetry using magnetic resonance imaging (MRI) is a common clinical study in epilepsy patients. Most clinical MR scans operate at 1.5 tesla (T); however, there is increasing use of scanners of a higher field strength. We analyzed whether control data of hippocampal volumes can be used across different field-strength scanners. METHODS: We studied eight adult healthy controls twice at both 1.5 and 3 T. Bilateral hippocampal volumes were measured by manual outlining. Measurement error was analyzed based on the variability between two measurements at the same field strength, and intrascanner variability was analyzed based on the difference between measurements obtained at 1.5 and at 3 T. RESULTS: The measurement error was 4.0% (+/-3.1) at 1.5 T, and 3.4% (+/-2.5) at 3 T. The intrascanner variability between measurements at 1.5 and at 3 T was 6% (+/-3.9). The intrascanner variability was not different from the measurement error. CONCLUSIONS: Control hippocampal volume measurements obtained at 1.5 and at 3 T were not different.

Hippocampal sclerosis following brief generalized seizures in adulthood.

This report describes a patient who had a first generalized tonic clonic seizure (GTCS) at the age of 18 years. The initial MRI scan was normal on visual and quantitative examination. After a further six GTCS, a second MRI scan showed reduced hippocampal volume and increased hippocampal T2 signal, which was confirmed in a third scan. Therefore, hippocampal sclerosis may be acquired in adulthood after brief GTCS.

Causes of epilepsies: insights from discordant monozygous twins.

Whereas some patients with epilepsy have known acquired or genetic causes, in many the cause is unknown. By analyzing monozygotic twins, discordant for epilepsy, subtle etiological factors may be detected. We analyzed 12 monozygotic, discordant twins for factors explaining discordancy. These factors were presence of major clinical risk factors, presence of possibly epileptogenic lesions on brain magnetic resonance imaging (MRI), and quantitative brain volume abnormalities. Major risk factors, with associated acquired lesions were found in 4 of 12 twins. An MRI lesion without a major risk factor was found in a further 4 of 12 twins. Two of these had unilateral malformations of cortical development, 1 had bilateral periventricular heterotopia, and 1 had focal atrophy. Significant twin-twin differences in MRI volumes without obvious MRI lesions or major risk factors were found in 2 of 12 twins. Both had larger volumes than their co-twins, and idiopathic generalized epilepsy. No clinical or MRI findings accounting for discordance for epilepsy were found in 2 of 12 twins. In 10 of 12 pairs a clinical or MR correlate of epilepsy was found; some of those were subtle and only apparent by twin-twin comparison. They may be due to occult acquired factors, such as prenatal insults, or to genetic abnormalities resulting from postfertilization genetic processes.

Idiopathic generalized epilepsies: do sporadic and familial cases differ?

PURPOSE: Genetic factors are the only identified cause of idiopathic generalized epilepsies (IGEs), but the majority of cases do not have affected first-degree relatives. Here we investigate whether subjects with sporadic and familial IGE differ in terms of antecedent events and clinical and EEG features. Differences would support the hypothesis of a different etiology for sporadic cases, which has implications for choice of subjects for genetic association studies. METHODS: We analyzed 98 patients with IGE, diagnosed on clinical and EEG criteria. All patients and, if possible, one relative were interviewed, with special emphasis on potential antecedent events and family history. Patients with first-degree relatives affected with epileptic seizures were regarded as "familial," and the other patients were regarded as "sporadic." RESULTS: Of the 98 IGE patients, 32 (33%) patients were familial. The risk for seizures was 13.2% for siblings, and 7.7% for parents. The distribution of the IGE subsyndromes, the presence of antecedent events, and other electroclinical features did not differ between familial and sporadic IGE groups. CONCLUSIONS: No differences were found between familial and sporadic IGE patients. This does not the support the hypothesis that sporadic and familial IGE cases have separate etiologies.

Men may be more vulnerable to seizure-associated brain damage.

BACKGROUND: Repetitive seizures may be associated with progressive neuronal damage measurable by quantitative MRI. OBJECTIVE: To investigate whether gender is a risk factor for this damage. METHODS: Sixty patients with refractory temporal lobe epilepsy (TLE) (28 men, 32 women) and 54 healthy controls (28 men, 26 women) were compared by quantitative MRI methods. RESULTS: Male patients had ipsilateral hemicranial volume loss of 12% (CI 8% to 16%) and contralateral volume loss of 7% (CI:3% to 11%) compared with male controls (p < or =0.004, analysis of variance). Female patients were 4% (CI:0.3% to 8%, p = 0.04) smaller than controls in the ipsilateral hemicranium, and not different contralaterally. The patient-to-control difference was greater in men than in women for the ipsilateral (p = 0.003) and contralateral hemicranial volume (p = 0.02). In men, 14% of the ipsilateral (F = 4.7, p = 0.004) and 16% of the contralateral (F = 5.1, p = 0.03) hemicranial volume loss could be attributed to generalized tonic clonic seizures. Compared with controls, patients averaged a 29% smaller ipsilateral and a 5% smaller contralateral hippocampus. CONCLUSION: Men with TLE have more brain atrophy than women with TLE. Seizure frequency is a factor contributing to reduced brain volumes in men but not in women. Men, therefore, may be more vulnerable to seizure-associated brain abnormalities.

TLE patients with postictal psychosis: mesial dysplasia and anterior hippocampal preservation.

The authors studied six patients with refractory temporal lobe epilepsy and postictal psychosis using quantitative MRI and histopathology, and compared the results with 45 patients with temporal lobe epilepsy without postictal psychosis. Total hippocampal volumes were not different between the two groups. However, patients with postictal psychosis had a relatively preserved anterior hippocampus, and temporal lobe dysplasia was more frequent (p = 0.006, chi-square test). These findings may be associated with the clinical symptoms.

APOE epsilon4 genotype is associated with an earlier onset of chronic temporal lobe epilepsy.

The authors analyzed the association between APOE epsilon4 genotype and clinical and MRI findings in 43 refractory temporal lobe epilepsy patients. The distribution of the alleles were normal. Ten patients (23%) had an APOE epsilon 4 allele and had an earlier onset of habitual seizures (with epsilon4 5 +/- 5 years; without epsilon4 15 +/- 10 years). Quantitative MRI findings were not influenced by the APOE epsilon4 genotype. APOE epsilon4 may shorten the latency between an initial injury and seizure onset.

Occurrence of hippocampal sclerosis: is one hemisphere or gender more vulnerable?

PURPOSE: We analyzed a large group of patients investigated for suspected seizures to test whether gender or side are important factors in the origins of hippocampal sclerosis (HS). METHODS: We studied 996 consecutive patients (48% men, 52% women) by using standard hippocampal T2-relaxometry methods. RESULTS: HS was associated with a highly abnormal T2 time (< or =113 ms). Categoric analysis showed that hippocampal T2 time was independent of gender and side. T2 time was bilaterally normal in 81% of men and in 79% of women; it was unilaterally abnormal in 15% of both men and women; and bilaterally abnormal in 4% of men and in 6% of women. Highly abnormal T2 relaxometry, suggesting HS, occurred with equal frequency in men and women and on the right and left sides. Quantitative analysis of hippocampal T2 times showed values not differing significantly between men and women or between the right and left hemispheres. There was no significant interaction between gender and side. CONCLUSIONS: In patients with seizure disorders, hippocampal T2 relaxometry is not different in adult men and women and in the right and left hemispheres.