Phillip L. Pearl

Language dominance in partial epilepsy patients identified with an fMRI reading task

Background fMRI language tasks readily identify frontal language areas; temporal activation has been less consistent. No studies have compared clinical visual judgment to quantitative region of interest (ROI) analysis. Objective To identify temporal language areas in patients with partial epilepsy using a reading paradigm with clinical and ROI interpretation. Methods Thirty patients with temporal lobe epilepsy, aged 8 to 56 years, had 1.5-T fMRI. Patients silently named an object described by a sentence compared to a visual control. Data were analyzed with ROI analysis from t-maps. Regional asymmetry indices (AI) were calculated ([L−R]/[L+R]) and language dominance defined as >0.20. t-Maps were visually rated by three readers at three t thresholds. Twenty-one patients had intracarotid amobarbital test (IAT). Results The fMRI reading task provided evidence of language lateralization in 27 of 30 patients with ROI analysis. Twenty-five were left dominant, two right, one bilateral, and two were nondiagnostic; IAT and fMRI agreed in most patients, three had partial agreement, none overtly disagreed. Interrater agreement ranged between 0.77 to 0.82 (Cramer V;p < 0.0001); agreement between visual and ROI reading with IAT was 0.71 to 0.77 (Cramer V;p < 0.0001). Viewing data at lower thresholds added interpretation to 12 patients on visual analysis and 8 with ROI analysis. Conclusions An fMRI reading paradigm can identify language dominance in frontal and temporal areas. Clinical visual interpretation is comparable to quantitative ROI analysis.

fMRI language task panel improves determination of language dominance.

Background: fMRI language tasks reliably identify language areas in presurgical epilepsy patients, but activation using single paradigms may disagree with the intracarotid amobarbital test (IAT). Objective: To determine whether a panel of fMRI tasks targeting different aspects of language processing increases accuracy in determining hemisphere language dominance. Methods: Twenty-six patients age 12 to 56 years, predominantly with temporal lobe epilepsy, were studied using whole-brain 1.5 T fMRI (echo planar imaging, blood oxygenation level–dependent) with three task categories using a block design: verbal fluency, reading comprehension, and auditory comprehension. fMRI t maps were visually rated at three thresholds. All patients had assessment of language lateralization by IAT. Results: fMRI showed left dominance in 21 patients, right dominance in 2, and bilateral activation in 2; raters disagreed over a left vs right bilateral rating in 1 patient. There was full agreement between IAT and fMRI in 21 of 25 patients (IAT failed in 1). In three instances of partial disparity with IAT, the fMRI panel showed consistent findings across raters. Agreement between raters was excellent (partial disagreement in only one patient); the panel of tasks was superior to any single task for interrater agreement (Cramer V 0.93 [range 0.91 to 1.0] vs 0.72 [range 0.60 to 0.86]). Conclusions: A panel of fMRI language paradigms may be more accurate for evaluating partial epilepsy patients than a single task. A panel of tasks reduces the likelihood of nondiagnostic findings, improves interrater reliability, and helps confirm language laterality.

Inherited disorders of GABA metabolism

Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the mammalian central nervous system, is produced from glutamic acid in a reaction catalysed by glutamic acid decarboxylase. The sequential actions of GABA-transaminase (converting GABA to succinic semialdehyde) and succinic semialdehyde dehydrogenase (oxidizing succinic semialdehyde to succinic acid) allow oxidative metabolism of GABA through the tricarboxylic acid cycle. The inherited disorders of GABA metabolism include: (1) pyridoxine-dependent seizures (?glutamic acid decarboxylase deficiency) (> 50 patients); (2) GABA-transaminase deficiency (2 patients/1 family); (3) succinic semialdehyde dehydrogenase deficiency (32 patients/21 families); and (4) homocarnosinosis associated with serum carnosinase deficiency (3 patients/1 family). Homocarnosine is a brain-specific dipeptide of GABA and L-histidine. Of these four defects, definitive enzymatic diagnoses have been made only for GABA-transaminase and succinic semialdehyde dehydrogenase deficiencies. The presumptive mode of inheritance for all disorders is autosomal recessive, and all are associated with central nervous system dysfunction. Only succinic semialdehyde dehydrogenase deficiency manifests organic aciduria, which may account for the higher number of patients identified with this disorder; identification of additional patients with some of the other disorders will require increased request for analysis of cerebrospinal fluid metabolites by paediatricians and neurometabolic specialists.

Clinical spectrum of succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder affecting CNS γ-aminobutyric acid (GABA) degradation. SSADH, in conjunction with GABA transaminase, converts GABA to succinate. In the absence of SSADH, GABA is converted to 4-OH-butyrate. The presence of 4-OH-butyrate, a highly volatile compound, may be undetected on routine organic acid analysis. Urine organic acid testing was modified at the authors’ institution in 1999 to screen for the excretion of 4-OH-butyrate by selective ion monitoring gas chromatography-mass spectrometry in addition to total ion chromatography. Since then, five patients with 4-hydroxybutyric aciduria have been identified. The authors add the clinical, neuroimaging, and EEG findings from a new cohort of patients to 51 patients reported in the literature with clinical details. Ages ranged from 1 to 21 years at diagnosis. Clinical findings include mild-moderate mental retardation, disproportionate language dysfunction, hypotonia, hyporeflexia, autistic behaviors, seizures, and hallucinations. Brain MRI performed in five patients at the authors’ institution revealed symmetric increased T2 signal in the globus pallidi. SSADH deficiency is an under-recognized, potentially manageable neurometabolic disorder. Urine organic acid analysis should include a sensitive method for the detection of 4-hydroxybutyrate and should be obtained from patients with mental retardation or neuropsychiatric disturbance of unknown etiology.

Magnetic resonance spectroscopy of neurotransmitters in human brain

Magnetic resonance spectroscopy (MRS) is a noninvasive method that permits measurement of the concentration of specific biochemical compounds in the brain and other organ systems in precisely defined regions guided by MR imaging (MRI). Recently, MRS methods have been developed to measure specific neurotransmitters in the brain. More advanced MRS methods have been developed to measure the synthesis rates and turnover of specific neurotransmitters. These turnover rates can provide measures of brain metabolism similar to radioisotope techniques. Also, investigations of the relationship of brain metabolism and specific neurotransmitter systems are now possible using MRS. Here, we review the MRS techniques and studies of neurotransmitters in the human brain. A discussion of the potential use of these techniques in the context of certain pediatric neurotransmitter disorders will be presented. Ann Neurol 2003;54 (Suppl 6):S25–S31

Atypical language in lesional and nonlesional complex partial epilepsy

Objective: We investigated the relationship between partial epilepsy, MRI findings, and atypical language representation. Methods: A total of 102 patients (4 to 55 years) with left hemisphere epileptogenic zones were evaluated using three fMRI language tasks obtained at 1.5 or 3T with EPI BOLD techniques: verbal fluency, reading comprehension, and auditory comprehension. fMRI maps were visually interpreted at a standard threshold and rated as left or atypical language. Results: Atypical language dominance occurred in 30 patients (29%) and varied with MRI type (p < 0.01). Atypical language representation occurred in 36% (13/36) with normal MRI, 21% (6/29) with mesial temporal sclerosis, 14% (4/28) with focal cortical lesions (dysplasia, tumor, vascular malformation), and all (6/6) with a history of stroke. Multivariate logistic regression analysis found handedness, seizure onset, and MRI type accounted for much of the variance in language activation patterns (χ2 = 24.09, p < 0.01). Atypical language was more prevalent in patients with early seizure onset (43.2%, p < 0.05) and atypical handedness (60%, p < 0.01). None of the three clinical factors were correlated with each other (p > 0.40). Patients with atypical language had lower verbal abilities (F = 6.96, p = 0.01) and a trend toward lower nonverbal abilities (F = 3.58, p = 0.06). There were no differences in rates of atypical language across time, age groups, or MRI scanner. Conclusion: Early seizure onset and atypical handedness, as well as the location and nature of pathologic substrate, are important factors in language reorganization. GLOSSARY: FOV = field of view; MTS = mesial temporal sclerosis; RRN = read response naming; TE = echo time; TR = repetition time; WAIS = Wechsler Adult Intelligence Scale; WISC = Wechsler Intelligence Scale for Children.

The Landau-Kleffner Syndrome

Landau-Kleffner syndrome (LKS), or acquired epileptiform aphasia, is an epilepsy syndrome involving progressive neuropsychological impairment related to the appearance of paroxysmal electroencephalograph (EEG) activity. LKS appears to share a common pathophysiologic mechanism with continuous spike-wave of sleep (CSWS), acquired epileptic opercular syndrome (AEOS), and even benign childhood epilepsy with centrotemporal spikes (BECTS), with differentiating factors including age of onset, area of primary epileptogenicity, and severity of clinical presentation. This article covers the clinical, diagnostic, therapeutic, and prognostic features of LKS. In a child with autistic spectrum disorder, the presence of a fluctuating clinical course or regression should raise suspicion for the presence of associated epilepsy.

Cerebral MRI abnormalities associated with vigabatrin therapy.

Purpose:  Investigate whether patients on vigabatrin demonstrated new‐onset and reversible T2‐weighted magnetic resonance imaging (MRI) abnormalities.

Succinic semialdehyde dehydrogenase deficiency in children and adults

Succinic semialdehyde dehydrogenase deficiency is a rare disorder of the degradation pathway of γ‐aminobutyric acid. The disorder is detected when 4‐hydroxybutyric aciduria is present on urine organic acid analysis, and is subsequently confirmed by enzyme measurement on leucocytes. The disorder has been identified in approximately 350 individuals worldwide. We review the clinical features in 60 patients. The most common characteristics are developmental delay maximally involving expressive language, hypotonia, mental retardation, ataxia, and behavioral problems. Seizures occur in approximately half of patients, and include tonic‐clonic, absence, and myoclonic seizures, including status epilepticus. Electroencephalographic findings are background slowing and generalized and focal epileptiform discharges. Magnetic resonance imaging typically reveals increased T2‐weighted signal of the globus pallidus bilaterally, with variable involvement of white matter and the cerebellar dentate nucleus. Preliminary human cerebrospinal fluid measurements are consistent with neurometabolic aberrations documented in the murine animal model, with elevations in γ‐aminobutyric acid, γ‐hydroxybutyrate, and homocarnosine, and low glutamine. Succinic semialdehyde dehydrogenase deficiency may be an underrecognized neurometabolic disorder with a nonspecific and wide phenotypic spectrum, and carries implications for a comprehensive fundamental understanding of interrelations between multiple neurotransmitter systems. Ann Neurol 2003;54 (suppl 6):S73–S80

Seizure focus affects regional language networks assessed by fMRI.

Objective: To investigate the degree of language dominance in patients with left and right hemisphere seizure foci compared to normal volunteers using a fMRI reading comprehension task. Methods: Fifty patients with complex partial epilepsy, aged 8 to 56 years and 33 normal volunteers, aged 7 to 34 had fMRI (1.5 T) and neuropsychological testing. Participants silently named an object described by a sentence compared to a visual control. Data were analyzed with region of interest (ROI) analysis based on t maps for inferior frontal gyrus (IFG), midfrontal gyrus (MFG), and Wernicke area (WA). Regional asymmetry indices (AIs) were calculated [(L − R)/(L + R)]; AI >0.20 was deemed left dominant and AI <0.20 as atypical language. Results: Left hemisphere focus patients had a higher likelihood of atypical language than right hemisphere focus patients (21% vs 0%, χ2 < 0.002). Left hemisphere focus patients, excluding those with atypical language, had lower regional AI in IFG, MFG, and WA than controls. Right hemisphere focus patients were all left language dominant and had a lower AI than controls in WA and MFG, but not for IFG. AI in MFG and WA were similar between left hemisphere focus/left language patients and right hemisphere focus patients. Patients activated more voxels than healthy volunteers. Lower AIs were attributable to greater activation in right homologous regions. Less activation in the right-side WA correlated with better verbal memory performance in right focus/left hemisphere-dominant patients, whereas less strongly lateralized activation in IFG correlated better with Verbal IQ in left focus/left hemisphere-dominant patients. Conclusions: Patients had lower asymmetry indices than healthy controls, reflecting increased recruitment of homologous right hemisphere areas for language processing. Greater right hemisphere activation may reflect greater cognitive effort in patient populations, the effect of epilepsy, or its treatment. Regional activation patterns reflect adaptive efforts at recruiting more widespread language processing networks that are differentially affected based on hemisphere of seizure focus.