Magnetic Resonance Imaging Abnormalities in Familial Temporal Lobe Epilepsy With Auditory Auras FREE

THE FAMILIAL occurrence of temporal lobe epilepsy (FTLE) was first described as a benign clinical form of TLE.¹ Magnetic resonance imaging (MRI) studies in mesial FTLE demonstrated signs of hippocampal sclerosis, not only in patients with refractory seizures, but in patients with good seizure control and seizure remission. These findings indicate a strong genetic factor for the development of hippocampal sclerosis in some families.^{2 - 3}

Another form of familial TLE was first reported by Ottman et al⁴ and later by other authors.^{5 - 7} Seizure semiology pointed to an extrahippocampal epileptogenic area, and characteristically, most patients reported auditory auras. Patients had good seizure control, and epileptiform discharges were observed in the posterior temporal regions. Molecular studies identified linkage to chromosome 10q,^{4 - 7} and the gene has recently been cloned (leucine-rich, glioma-inactivated 1 gene [LGI1]).⁸ No MRI abnormalities have been described in these patients so far.^{4 - 7} The objective of this study was to investigate MRI abnormalities in a large kindred with familial TLE with auditory auras, linked to chromosome 10q.

We studied one large family, segregating TLE from auditory auras by detailed clinical and MRI evaluation. Molecular studies were performed in all available family members after informed consent was obtained. A family pedigree was obtained, and all possibly affected individuals were clinically assessed by at least one of us. Seizures and epilepsy syndromes were determined according to the recommendations of the International League Against Epilepsy,^{9 - 10} and all affected individuals were also classified by the clinical outcome.

Genomic DNA was extracted from blood samples and genotyped for 7 dinucleotide repeat markers (D10S583, D10S185, D10S574, D10S1680, D10S577, D10S192, and D10S566),¹¹ which flank the 15-centimorgan (cM) candidate interval on ch10q. We calculated 2-point lod scores using the MLink program of the Linkage package (Centre d'Etude des Polimorphisme Humaine, Paris, France; University of Utah, Salt Lake City¹² and Columbia University, New York, NY, assuming an autosomal dominant inheritance with 80% penetrance. For mutation analyses, we screened the entire coding region of the LGI1 (leucine-rich, glioma-inactivated 1) gene by polymerase chain reaction, using primers that flanked all intron-exon junctions. Nucleotide sequences were analyzed using dye-terminator chemistry for megaBACE 1000 (Amersham Pharmacia Biosciences UK Ltd, Buckinghamshire, England).

Magnetic resonance imaging was performed by a 2-T scanner, with T1- and T2-weighted images in 3 orthogonal planes, including thin coronal (3 mm) T1 inversion recovery images perpendicular to the long axis of the hippocampus. In addition, a 3-dimensional T1 acquisition was obtained for multiplanar reconstruction.

Magnetic resonance imaging acquisition parameters were: (1) sagittal T1 spin-echo (6-mm thick; flip angle, 180^o; repetition time [TR], 430 milliseconds; echo time [TE], 12 milliseconds; matrix, 200 × 350; field of view [FOV], 25 × 25 cm); (2) coronal, perpendicular to the long axis of the hippocampus, defined by the sagittal images: [a] T2-weighted fast spin-echo (4-mm thick; flip angle, 120^o; TR, 4800 milliseconds; TE, 129 milliseconds; matrix, 252 × 320; FOV, 18 × 18 cm); [b] T1-weighted inversion recovery (3-mm thick; flip angle, 200^o; TR, 2800 milliseconds; TE, 14 milliseconds; inversion time, 840 ms; matrix, 130 × 256; FOV, 16 × 18 cm); (3) axial images parallel to the long axis of the hippocampi: [a] T1-weighted gradient echo (3-mm thick; flip angle, 70^o; TR, 200 milliseconds; TE, 5 milliseconds; matrix, 180 × 232; FOV, 22 × 22 cm); [b] T2-weighted fast spin-echo (4-mm thick; flip angle, 120^o; TR, 6800 milliseconds; TE, 129 milliseconds; matrix, 252 × 328; FOV, 21 × 23 cm); (4) T1-weighted 3-dimensional gradient echo, acquired in the sagittal plane (1-mm thick; flip angle, 35^o; TR, 22 milliseconds; TE milliseconds, 9; matrix, 256 × 220; FOV, 23 × 25 cm).

Visual analyses were performed using a workstation (OMNIPRO; Elscint, Haifa, Israel) for multiplanar reconstruction. Independent analyses were performed by 2 investigators (E.K. and F.C.) who were blinded to clinical status, and both agreed with the conclusion. Quantitative analyses of hippocampal formation and the anterior aspect of the temporal lobes (volumetry) were done according to a standardized protocol,¹³ using thin coronal T1 inversion recovery images and the National Institutes of Health Image program (http://rsb.info.nih.gov/nih-image/). Volumes were compared with those in a control group of 20 healthy adult volunteers, and data were transformed into z scores (number of SDs from the mean of control group).

We identified 23 possibly affected subjects (5 were deceased) in the pedigree (Figure 1). We evaluated 18 of them: 11 men and 7 women. The mean age at seizure onset was 19 years (range, 10-35 years). None of the evaluated individuals who met the clinical criteria for TLE with auditory auras had a history of risk factors (febrile convulsions, head trauma, or meningitis). All patients had a benign clinical course.

Auditory auras were reported by 12 (66%) of 18 patients, and were described as a radio sound or a motorcycle running by most of them (Table 1). Other reported symptoms are presented in Table 1, and included déjà vu, visual misperception, with distortion of faces or objects, and episodes in which they suddenly were unable to hear or understand what people said (aphasic aura). There was only 1 patient (III-22) who did not report auras, but she had only a few generalized tonic-clonic seizures during sleep. Secondarily generalized tonic-clonic seizures were reported as a rare manifestation by 12 patients. One individual (V-6) had only recurrent febrile seizures during childhood but no clinical findings of TLE with auditory auras.

Two-point lod scores were greater than Zmax = 3.0 for all 7 markers genotyped on chromosome 10q (Table 2): Zmax = 5.61 at θ = 0 for D10S583; Zmax = 6.35 at θ = 0 for D10S185; Zmax = 4.79 at θ = 0 for D10S574; Zmax = 4.77 at θ = 0 for D10S1680; Zmax = 4.26 at θ = 0 for D10S577; Zmax = 5.55 at θ = 0 for D10S192; and Zmax = 4.26 at θ = 0.05 for D10S566. Nucleotide sequence analysis of the LGI1 gene showed a point mutation, IVS7-2A>G, that was likely to abolish the splicing site. We predict that this mutation results in exon 8 skipping, thus producing a truncated protein. The point mutation was present in all affected individuals. An interictal electroencephalogram performed in 6 patients detected no abnormalities.

Twenty-two family members underwent MRI (7 asymptomatic, 4 of them haplotype carriers). In Table 3, we present the affected status, the presence of the chromosome 10q haplotype, and the visual and quantitative MRI studies for each subject. Visual analysis showed lateral temporal lobe dysgenetic features (Figure 2 and Figure 3) in 10 (45%) of 22 patients. Their left temporal lobes seemed enlarged, sometimes with protrusion of brain parenchyma with an encephalocelelike appearance (Figure 2). However, anterior temporal lobe volumetry showed a significant global increase in volumes in only 2 individuals.

Volumetric studies revealed mildly reduced hippocampi in 4 individuals, with z scores ranging from –2.0 to –2.5. In 2 of them, a mildly increased hippocampal T2 signal was also observed on visual analysis. However, none of these 4 patients fulfilled the criteria for determining MRI evidence of mesial temporal sclerosis on visual analysis, as commonly encountered in mesial FTLE.²

Although the description of auditory auras in FTLE is remarkable, some patients also report other sensory and psychic symptoms, in isolation or accompanying the auditory symptoms.¹⁴ Auditory features may vary among affected family members, from undefined sounds to auditory illusions, such as distortions and volume changes. In addition, some patients had an ictal aphasia. All of these positive and negative manifestations suggest a lateral temporal lobe seizure focus involving the cortex of posterior temporal regions.

The identification of temporal lobe abnormalities on MRI in patients with this specific form of TLE, linked to chromosome 10q, has not been reported so far. We found clear-cut signs of lateral temporal malformations in 53% of affected individuals and in 1 asymptomatic carrier of the haplotype. Although 4 individuals had mildly reduced hippocampal volumes on volumetry, this was not sufficient to define MRI evidence of mesial temporal sclerosis. However, this mild volume loss and altered shape of the hippocampus and parahippocampal gyrus may influence the pattern of propagation of ictal discharges and seizure semiology.

The relationship of the mesial and lateral aspects of the temporal lobe has been extensively studied.¹⁵ Although it is well recognized that in mesial TLE, the main structures implied in the pathogenesis of epilepsy are the hippocampus, amygdala, and other mesial temporal lobe structures, the lateral temporal cortex may also play an important role in this scenario. The subcortical connections of mesial temporal structures are bidirectional, and include afferents from the hypothalamus, the auditory system, and the lower brainstem nuclei involved in viscerosensory and gustatory functions.¹⁵

Several types of perceptual phenomena can occur in temporal lobe seizures. Visual and auditory hallucinations and illusions are commonly elicited by temporal lobe seizure discharge. Auditory illusions are usually changes in the loudness of perceived sounds. Most of these changes are attributable to discharge in the auditory association cortex, but occasionally they can be reproduced by amygdaloid stimulation.¹⁶ These illusions frequently have experiential qualities. Elementary auditory and visual hallucinations indicate discharge in the primary auditory and visual cortices. The stimulation response map of Penfield and Perot shows that the points in the temporal isocortex from which auditory experiential phenomena could be elicited occupy the first temporal convolution. Experiential phenomena with auditory features may be elicited by stimulation with intracranial electrodes of several temporal lobe structures.¹⁶ These have been observed with an after-discharge beyond the stimulated site in 22 (29%) of 75 individuals.¹⁶ In addition, there were reports of auditory hallucinations/illusions (one with associated visual hallucination) in 3 patients after hippocampus stimulation. Experiential phenomena without an after-discharge or with discharges limited to the stimulated site were elicited in 20 (27%) of 75 patients, and 3 of them had auditory hallucinations/illusions combined with visual features (one from temporal isocortex stimulation and 2 from amygdala stimulation).¹⁶

At this point, we cannot be sure that the developmental structural abnormalities in the temporal lobes found in our patients are directly implicated in seizure origin. However, the MRI findings in this family with TLE with auditory auras are clearly distinct from the MRI findings in mesial FTLE, and these different abnormalities are consistent with the distinct seizure semiology in these 2 forms of familial TLE.

Corresponding author and reprints: Fernando Cendes, MD, PhD, Departamento de Neurologia, FCM–UNICAMP, Cidade Universitária Zeferino Vaz, Campinas SP, Brazil, CEP 13083-970 (e-mail: fcendes@unicamp.br).

Accepted for publication April 1, 2003.

Author contributions: Study concept and design (Drs Kobayashi, Sardinha, Lopes-Cendes, and Cendes); acquisition of data (Drs Kobayashi, Santos, Sardinha, Lopes-Cendes, and Cendes and Messrs Torres and Secolin); analysis and interpretation of data (Drs Kobayashi, Sardinha, Lopes-Cendes, and Cendes); drafting of the manuscript (Drs Kobayashi, Sardinha, Lopes-Cendes, and Cendes); critical revision of the manuscript for important intellectual content (Drs Kobayashi, Santos, Sardinha, Lopes-Cendes, and Cendes and Messrs Torres and Secolin); obtained funding (Drs Kobayashi, Sardinha, Lopes-Cendes, and Cendes); administrative, technical, and material support (Dr Santos and Messrs Torres and Secolin); study supervision (Drs Kobayashi, Sardinha, Lopes-Cendes, and Cendes).

This study was supported by grants 97/07584-3 and 99/10702-3 from Fundação, de Amparo à Pesquisa do Estado de São Paulo, São Paulo, Brazil.

This article was corrected on 12/3/2003.