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3.
Epilepsy Behav ; 17(4): 531-5, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20189461

ABSTRACT

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a nonlesional condition associated with mutation of the gene coding for the alpha4 nicotinic acetylcholine receptor (nAChR). The nAChR modulates aspects of memory and attention. We examined the neuropsychological phenotype of ADNFLE, with a particular emphasis on understanding the impact on frontal lobe functions. We used standard clinical tests as well as focused measures of frontal lobe function in a well-defined group of patients with ADNFLE. Their performance was compared with that of a group of age-, sex-, and education-matched control participants. Patients with ADNFLE showed impairments on tasks requiring cognitive flexibility against a background of well-preserved intellectual abilities. In accord with existing research, verbal memory impairments were identified in the patient group; the level of impairment on these tasks correlated with disease-related factors. In our study of ADNFLE associated with one mutation, cognitive flexibility appears to be the core cognitive deficit.


Subject(s)
Circadian Rhythm/genetics , Cognition Disorders/etiology , Epilepsy, Frontal Lobe/complications , Epilepsy, Frontal Lobe/genetics , Genetic Predisposition to Disease , Mutation/genetics , Receptors, Nicotinic/genetics , Adult , Association Learning/physiology , Epilepsy, Frontal Lobe/pathology , Female , Frontal Lobe/pathology , Gene Frequency , Genotype , Humans , Male , Middle Aged , Neuropsychological Tests , Pedigree , Phenylalanine/genetics , Polysomnography , Serine/genetics , Young Adult
4.
Epilepsia ; 49(5): 826-31, 2008 May.
Article in English | MEDLINE | ID: mdl-18363710

ABSTRACT

BACKGROUND: Alpha-[11C]methyl-L-tryptophan (alpha-MTrp) positron emission tomography (PET) is a promising tool in the localization of the epileptogenic area in selected group of focal epilepsy patients. Electrophysiological evidence suggests the involvement of the neocortex in periventricular nodular heterotopia (PVNH). PURPOSE: To determine whether alpha-MTrp PET can detect neocortical changes in patients with PVNH. METHODS: Four patients (2 male, mean age 28, range 23-35 years) with PVNH and intractable seizures were studied. The functional image in each patient was compared with those from 21 healthy controls (mean age 34.6 +/- 14.2 years) by using statistical parametric mapping (SPM). The location of increased alpha-MTrp uptake was compared with the location of the EEG focus. A significant cluster was defined as a cluster with a height p = 0.005 and an extent threshold 100. RESULTS: Alpha-MTrp PET revealed increased cortical uptake in two of four patients. The area of increased alpha-MTrp uptake in one patient was widespread. In the other patient, the area of increased uptake did not include the region where most seizures were generated on EEG. alpha-MTrp PET did not show increased uptake in the heterotopic nodules in any of the patients. CONCLUSIONS: Alpha-MTrp PET suggests abnormal metabolism of tryptophan in the neocortex. The increased uptake may be diffuse and may not co-localize with the EEG focus. This preliminary study suggests that alpha-MTrp PET may be useful, in conjunction with other evaluations, in localizing epileptic focus in patients with PVNH and refractory seizures.


Subject(s)
Carbon Radioisotopes , Epilepsy/diagnostic imaging , Periventricular Nodular Heterotopia/diagnostic imaging , Tryptophan/analogs & derivatives , Adult , Brain Mapping , Carbon Radioisotopes/metabolism , Control Groups , Electroencephalography/statistics & numerical data , Epilepsy/metabolism , Female , Humans , Magnetic Resonance Imaging , Male , Neocortex/metabolism , Neocortex/physiopathology , Periventricular Nodular Heterotopia/metabolism , Positron-Emission Tomography/statistics & numerical data , Serotonin/metabolism , Tryptophan/metabolism
5.
J Neuroophthalmol ; 28(4): 289-92, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19145127

ABSTRACT

A 47-year-old woman with postural headache, episodic stupor, and vertical gaze palsy had brain imaging findings consistent with spontaneous intracranial hypotension (SIH), including severe descent of the mesodiencephalic structures and diffuse pachymeningeal enhancement. The source of the cerebrospinal fluid leakage was a ruptured dorsal perineural cyst. Clinical symptoms improved after a targeted epidural blood patch was performed. Dorsal midbrain syndrome has not been reported previously as a manifestation of SIH. Perhaps distortion of structures in this brain region can occur in SIH as it does in obstructive hydrocephalus.


Subject(s)
Hernia/etiology , Hernia/pathology , Intracranial Hypotension/complications , Intracranial Hypotension/pathology , Mesencephalon/pathology , Tarlov Cysts/complications , Blood Patch, Epidural , Cerebrospinal Fluid Pressure/physiology , Female , Headache/etiology , Hernia/physiopathology , Humans , Intracranial Hypotension/physiopathology , Magnetic Resonance Imaging , Meninges/pathology , Meninges/physiopathology , Mesencephalon/diagnostic imaging , Mesencephalon/physiopathology , Middle Aged , Ocular Motility Disorders/etiology , Ocular Motility Disorders/pathology , Ocular Motility Disorders/physiopathology , Recovery of Function/physiology , Spinal Canal/physiopathology , Tarlov Cysts/physiopathology , Tarlov Cysts/surgery , Thoracic Vertebrae , Tomography, X-Ray Computed , Treatment Failure , Unconsciousness/etiology , Unconsciousness/pathology , Unconsciousness/physiopathology
6.
J Clin Endocrinol Metab ; 93(2): 634-7, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18042647

ABSTRACT

BACKGROUND: Pulsatile GH secretion from the anterior pituitary is a key mediator of human growth regulation and is affected by a number of genetic and environmental factors. Activation of neuronal nicotinic acetylcholine (nACh) receptors promotes GH release, but the role of these receptors in growth regulation is unknown. AIM: Our aim was to assess the effect of a mutation in the alpha4 subunit of the nACh receptor on cholinergic-mediated GH release. METHODS: Forty-one healthy volunteers (24 male, age 36.2 +/- 12.2 yr, mean +/- sd) and 13 subjects with the alpha4-Ser248Phe mutation (four male, age 43.2 +/- 16.8 yr) were studied. Serum levels of GH, LH, FSH, prolactin, TSH, free T(4), and cortisol were measured at baseline and at regular intervals after infusion of physostigmine. Height and weight were recorded in all participants as well as from additional family members with (n = 11, four male) and without (n = 16, seven male) the mutation. RESULTS: Subjects with the mutation were shorter (1.62 +/- 0.08 vs. 1.72 +/- 0.09 m, P < 0.05) and had a greater body mass index (31 +/- 6 vs. 24 +/- 3 kg/m(2), P < 0.05) than healthy volunteers and unaffected members of the pedigree. In controls, physostigmine markedly increased the serum levels of GH (mean increase, +732%). In contrast, the response to physostigmine was markedly blunted in subjects with the mutation (+104%, P > 0.2 vs. control). CONCLUSIONS: These findings suggest a role of the nACh receptor in human growth regulation.


Subject(s)
Body Height/genetics , Growth Disorders/genetics , Human Growth Hormone/physiology , Receptors, Nicotinic/genetics , Adolescent , Adult , Aged , Body Mass Index , Cholinesterase Inhibitors/pharmacology , Female , Follicle Stimulating Hormone/blood , Growth Disorders/blood , Human Growth Hormone/blood , Humans , Hydrocortisone/blood , Luteinizing Hormone/blood , Male , Middle Aged , Physostigmine/pharmacology , Point Mutation , Prolactin/blood , Thyrotropin/blood , Thyroxine/blood
7.
Cereb Cortex ; 18(3): 664-9, 2008 Mar.
Article in English | MEDLINE | ID: mdl-17615250

ABSTRACT

A missense mutation of the gamma2 subunit of the gamma-aminobutyric acid A (GABA(A)) receptor has been linked to an inherited human generalized epilepsy. As synaptic inhibition in the human brain is largely mediated by the GABA(A) receptor, we tested the hypothesis that the GABRG2(R43Q) mutation alters cortical excitability. Fourteen subjects affected by the GABRG2(R43Q) mutation (5 males, mean age: 44 +/- 15 years) and 24 controls (11 males, mean age: 38 +/- 11 years) were studied with transcranial magnetic stimulation (TMS). To assess the specificity of the effect of the mutation, 4 additional family members unaffected by the GABRG2(R43Q) mutation (2 males, mean age: 41 +/- 16 years) were included. Subjects affected by the GABRG2(R43Q) mutation demonstrated reduced net short-interval intracortical inhibition and increased intracortical facilitation assessed with paired-pulse stimulation. Subjects with the mutation had similar motor thresholds to controls both at rest and with weak voluntary activation. No significant differences were noted between groups in the cortical silent period. Our findings provide in vivo evidence for increased intracortical excitability in subjects affected by the GABRG2(R43Q) mutation. These findings are also likely to represent an important clue to the mechanisms linking this gene defect and the epilepsy phenotype.


Subject(s)
Cerebral Cortex/physiology , Evoked Potentials, Motor/genetics , Mutation, Missense/physiology , Receptors, GABA-A/genetics , Adolescent , Adult , Aged , Epilepsy/genetics , Epilepsy/physiopathology , Evoked Potentials, Motor/physiology , Female , Humans , Male , Middle Aged , Mutation, Missense/genetics , Phenotype , Receptors, GABA-A/physiology , Transcranial Magnetic Stimulation/methods
8.
Neuroimage ; 32(3): 995-1000, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16875845

ABSTRACT

Understanding the consequences of newly discovered single gene mutations causing human epilepsy has the potential to yield new insights into the underlying mechanisms of this disorder. A mutation of the gamma2 subunit of the GABA(A) receptor, which substitutes glutamine for arginine at position 43 (R43Q) has been found in a familial generalized epilepsy. We tested the hypothesis that individuals affected by the GABRG2(R43Q) mutation have reduced binding to the GABA(A) receptor complex using positron emission tomography (PET) and the benzodiazepine receptor ligand [(11)C]-flumazenil. Fourteen subjects with the GABRG2(R43Q) mutation and 20 controls were studied. Benzodiazepine receptor binding was reduced in subjects with the mutation (mean whole brain binding potential for [(11)C]-flumazenil: GABA(A) mutation 0.66+/-0.1; controls 0.89+/-0.1; P<0.003). The greatest change in benzodiazepine binding occurred anteriorly, with peak differences in insular and anterior cingulate cortices revealed by statistical parametric mapping. Our findings provide in vivo evidence of reduced benzodiazepine receptor binding in subjects with the mutation. As synaptic inhibition in the human brain is largely mediated by the GABA(A) receptor, these findings are likely to represent an important clue to the mechanisms linking this gene defect and the epilepsy phenotype.


Subject(s)
Epilepsy, Generalized/genetics , Mutation/physiology , Receptors, GABA-A/genetics , Receptors, GABA-A/metabolism , Adult , Aged , Brain Mapping , Epilepsy, Generalized/diagnostic imaging , Female , Flumazenil/metabolism , GABA Modulators/metabolism , Gyrus Cinguli/diagnostic imaging , Gyrus Cinguli/metabolism , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Middle Aged , Positron-Emission Tomography
9.
J Clin Neurosci ; 11(7): 745-7, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15337138

ABSTRACT

Neurofibromatosis type 1 (NF1) is an inherited disorder in which affected individuals develop both benign and malignant tumours at an increased frequency. Glioneuronal tumours, such as ganglioglioma and dysembryoplastic neuroepithelial tumour, have been previously reported in patients with NF1. We describe two patients with glioneuronal tumours and typical clinical features of NF1. Molecular analysis of these tumours did not demonstrate loss of the NF1 gene by fluorescence in situ hybridization (FISH) or immunohistochemistry analysis, suggesting they might not be causally associated with gross defects in NF1 expression. Because of the excellent prognosis following the resection of these tumours, it is important to distinguish them from other NF1-associated tumours.


Subject(s)
Brain Neoplasms/pathology , Ganglioglioma/pathology , Magnetic Resonance Imaging , Neoplasms, Neuroepithelial/pathology , Neurofibromatosis 1/pathology , Adult , Brain Neoplasms/complications , Brain Neoplasms/genetics , Female , Ganglioglioma/complications , Ganglioglioma/genetics , Humans , In Situ Hybridization, Fluorescence/methods , Male , Neoplasms, Neuroepithelial/complications , Neoplasms, Neuroepithelial/genetics , Neurofibromatosis 1/complications , Neurofibromatosis 1/genetics , Neurofibromin 1/genetics
10.
Epilepsy Res ; 52(3): 203-13, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12536053

ABSTRACT

Epilepsy surgery has been successfully performed in patients with tuberous sclerosis complex (TSC) and seizures arising from a restricted epileptogenic area. The outcome of cortical excision depends on accurate pre-surgical identification of the epileptogenic tuber. [11C] alpha-methyl-L-tryptophan (alpha-MTrp) was originally developed to measure serotonin synthesis in vivo with positron emission tomography (PET). However in pathologic conditions its uptake may also depend on the synthesis of quinolinic or kynurenic acid via the kynurenine pathway. Increased levels of serotonin and quinolinic acid have been observed in epileptogenic lesions, raising the possibility that alpha-MTrp PET may localize the epileptogenic area. The aim of this study was to correlate alpha-MTrp PET uptake with the localization of the epileptogenic area and with interictal spike frequency in patients with TSC. alpha-MTrp uptake was measured in 8 patients (2 males, mean age 29.6+/-14.9 years, range 3-50 years) with intractable partial epilepsy due to TSC. All patients underwent scalp EEG monitoring during the PET scan. In four (50%), increased uptake of alpha-MTrp occurred in the epileptogenic area alone. Two (25%) patients showed multifocal abnormalities and the remaining two (25%) did not show focal changes. PET localization was mostly seen in patients with frequent interictal abnormalities on the EEG. Furthermore, there was a significant correlation between alpha-MTrp uptake and the frequency of interictal spikes (r=0.6; P<0.05). alpha-MTrp PET is a promising diagnostic tool in the localization of the epileptogenic area in patients with TSC.


Subject(s)
Radiopharmaceuticals , Seizures/diagnostic imaging , Tryptophan/analogs & derivatives , Tuberous Sclerosis/diagnostic imaging , Adolescent , Adult , Carbon Radioisotopes , Child, Preschool , Electroencephalography , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Radiopharmaceuticals/pharmacokinetics , Tomography, Emission-Computed , Tryptophan/pharmacokinetics
11.
Neurology ; 59(8): 1246-8, 2002 Oct 22.
Article in English | MEDLINE | ID: mdl-12391356

ABSTRACT

Although precipitation of seizures by exercise has been described, the reproducible induction of temporal lobe seizures by exercise is unusual. The authors report two patients with left temporal lobe seizures induced by exercise. In one patient the family history suggested autosomal-dominant inheritance. Prolonged hyperventilation, simple movements, and visualization of a competitive game did not produce epileptiform discharges on the interictal EEG.


Subject(s)
Epilepsy, Temporal Lobe/physiopathology , Exercise Test/adverse effects , Adolescent , Adult , Electroencephalography/statistics & numerical data , Epilepsy, Temporal Lobe/diagnosis , Exercise/physiology , Exercise Test/statistics & numerical data , Humans , Male
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