European Journal of Cardiovascular Medicine

The hippocampus is a bi-layered structure composed of grey matter found medially within the temporal lobe, which extends over the temporal horn of the lateral ventricle and occupies the medial area of its base. This structure features two intertwined grey matter folds, the cornu ammonis and the dentate gyrus ^[1]. A seizure represents a sudden electrical discharge of neurons in the brain that leads to a change in function or behaviour. The clinical presentation of seizures depends on factors such as the cortex region involved, the direction and speed of the electrical discharge, and the child's age. Seizures are observed in around 4% to 10% of children, with those under 3 years old experiencing the highest frequency of occurrences ^[2]. Partial seizures begin in one hemisphere of the brain. A simple partial seizure does not result in a loss of consciousness and typically presents as unusual motor activity. When consciousness is affected, the seizure is categorised as a complex partial seizure. About 30% of children experience generalised seizures. A generalised seizure affects both hemispheres of the brain and may be associated with a decreased level of consciousness ^[2].

While most clinical Magnetic Resonance (MR) imaging techniques adequately detect significant Hippocampal Atrophy (HA), early indicators of subtle HA associatewiththe initial stages of the disease are frequently overlooked. To enhance clinical evaluations, quantitative volumetric approaches have been devised, which demonstrate a strong correlation with manual tracing methods and histologically validated hippocampal cell loss ^[3]. Studies have indicated that individuals with epilepsy tend to have smaller volumes in the hippocampal lobes. This research aims to investigate the relationship between hippocampal volume and seizure activity in children. The objective is to quantify the right and left hippocampal lobe volumes in children aged 16 years or younger who are experiencing seizures through MR volumetric assessment. Additionally, the study seeks to examine the relationship between hippocampal volume, seizure types, and the frequency of seizures.

OBJECTIVES

1. To establish the normogram values of hippocampal lobe volumes on 3 Tesla MRIs.
2. To assess the volume of the hippocampal lobe in patients with Mesial Temporal Sclerosis.

Study Design

 A prospective hospital-based study.

Study area

Department of Radio Diagnosis, M. V. J Medical College & Research Hospital, Hoskote, Bangalore.

Study Period

1 year.

Study population

 Paediatric patients referred to the Department of Radio-diagnosis with clinical suspicion of partial seizures in the age group of 0 – 16 years

Sample size

 The study consisted of 40 subjects.

Sampling method

Simple random technique.

Inclusion criteria

• All the paediatric patients (0 – 16) years presenting with seizures clinically.
• Patients diagnosed with epilepsy
• Follow-up patients of partial seizures.

Exclusion Criteria

• Patients having a history of claustrophobia.
• Patients having a history of metallic implant insertion, cardiac pacemakers and metallic foreign body in situ.
• Patients clinically unstable.

Ethical consideration

Institutional Ethical Committee permission was obtained before the commencement of the study.

Study tools and Data collection procedure

The case group comprised 40 children. Thirty-eight children had manifested complex partial seizures (CPS) with secondary generalisation with interictal data localised to one or both temporal lobes, and two children manifested simple partial seizures with interictal data localised to the right temporal lobe.

Technique

Magnetic resonance imaging methods

All MRI examinations were performed using a GE Healthcare DISCOVERY 750W 3 Tesla MRI Scanner. Brain and temporal lobe series MRIs were performed. MRI of the brain consisted of sagittal T1, axial T1, T2, and Fluid Attenuation Inversion Recovery (FLAIR). These sequences were performed with a 5 mm thickness and a 2 mm gap. The temporal lobe series consisted of coronal T2, FLAIR, IR, and 3D fast spoiled gradient-recalled echo (SPGR). All coronal series were perpendicular to the long axis of the temporal lobe with a 4 mm thickness and a 1 mm gap, except the 3D SPGR, which was carried out with a 2 mm thickness and a 1 mm gap. The T1- T1-weighted series used an echo time of 11 ms, repetition time of 420 ms, 20 mm × 20 mm field of view, and 2.0 NEX. The hippocampal volume was measured on coronal IR, and ICV was measured on the T1-weighted sagittal view.

HCVs were measured from the oblique coronal MR images perpendicular to the long axis of HC. MRI sequences and parameters are presented in the table. We could not perform T2-relaxometry on the hippocampal regions due to technical reasons and relied on T2-FLAIR images to define the signal abnormalities. The total acquisition time was 6 min and 30 secs for each subject.

Hippocampal volume measurement:

Boundaries of the HC were determined according to the method described by Watson and Jack et al. HCVs were manually delineated on successive coronal slices using a modified protocol based on previously published methods. The left and right parts of HCV were obtained using manual tracing. A slice volume was calculated by multiplying the area outlined by the slice thickness. The whole volume was calculated by adding all the slice volumes. The total average time required for a trained individual to segment and calculate the HCV was 1 hour.

Statistical analysis

HCVs were normalised to control variations in ICV using analysis of covariance (ANOVA). The raw and normalised volume samples were checked using normal distribution tests and expressed as mean ± standard deviation (SD). The mean value and 95% confidence intervals were calculated for each age and gender group separately for each side. Paired t-tests were used to compare the difference between the right and left HCVs within each group. ANCOVA was used to consider the impact of age and gender on HCVs. All statistical analyses were calculated with SAS statistical software (Version 8.2). The level of statistical significance was P < 0.05 (two-tailed).

Forty paediatric patients (n=40) with partial seizures were evaluated. Subjects were divided into three groups according to age: 0-6 years, 6-9 years and 9-16 years. In the study, the normal range of hippocampal volume is determined to be 2.6+/-.35 cc3 on right side and 2.5+/-.35 cc3 on the left side. Of the 40 children with positive clinical history, hippocampal volume loss is seen in 12 patients with a mean of right hippocampal volume 2.1+/-.35 cc3 and of left hippocampal volume 2.0+/-.35 cc3.

Table No 1: Distribution of age and gender

Table No 2: Distribution of MTS in total number of case

Table No 3: Distribution of Hippocampal volume loss in total number of cases

Table No 4: Distribution of MTS in cases with Hippocampal Atrophy

Table No 5: Gender-wise distribution in Hippocampal volume loss

Table No 6: Location-wise distribution in Hippocampal volume loss

Table No 7: Gender-wise distribution in Hippocampal volume loss with MTS

Table No 8: Location-wise distribution in Hippocampal volume loss with MTS

Table No 9: Gender-wise distribution in Hippocampal volume loss without MTS

Table No 10: Location-wise distribution in Hippocampal volume loss without MTS

Figure No 1: GE Healthcare DISCOVERY 750W 3T MRI.

                      Figure No 2: Bilateral MTS showing bilateral hippocampal volume loss (Left > Right)

Figure No 3: Right MTS showing ipsilateral hippocampal volume loss.

Figure No 4: Patient with normal hippocampal volume

Figure No 5: Right MTS showing hippocampal volume loss on the same side

Figure No 6: Axial FSPGR sequence showing normal hippocampal volume

Magnetic resonance imaging is a non-invasive, multiplanar and highly accurate method with better inherent contrast that demonstrates the lesion accurately. MRI provides an accurate assessment of the hippocampal changes in paediatric epilepsy, especially in MTS

Table No 11: Mean and Standard deviations of original & Normalised hippocampal volumes

The mean left and right HCVs before normalisation were 2050.40 ± 70.04 mm3 and 2073.93 ± 62.15 mm3 among children with hippocampal atrophy and 2053.65 ± 73.65 mm3 and 2075.59 ± 77.59 mm3 among normal children respectively. The normalised mean HCV in the left and right was 2.0+/-.35 cc3 and 2.1+/- .35 cc3 in case children, 2.5+/-.35 cc3 and 2.6+/-.35 cc3 in normal children.

Table No 12: Statistics of Right, Left & Total hippocampal volumes

The comparison revealed no significant difference between the original and normalised mean hippocampal volumes for all subjects (P > 0.05). Both sides of HCV increased by age before normalisation and decreased by age after normalisation. Normal distribution tests and 95% confidence intervals of left and right HCV among normal subjects were 2030.68 to 2076.63 mm3 and 2046.78 to 2104.39 mm3, respectively. The original hippocampal volume of the right hippocampus was significantly larger (P < 0.05) than that of the left in 85% of subjects. The comparison of the mean differences of the right and left hippocampi is summarised. Similarly, there was a significant difference between the mean normalised hippocampal volume of the right and left hippocampi (P < 0.05).

Table No 13: Statistics of Original & Normalised hippocampal volumes

*** P < 0.05 indicates significant by paired-sampled t-test.

Mulani et al.⁴ conducted a pilot study to estimate the normal volumetric data for the Indian pediatric population between 6 and 12 years of age. The study group comprised 20 children, 6–12 years old, without a history of epilepsy or other neurological deficits. There were nine boys and 11 girls. All scans were performed on a 1.5T GE echo speed scanner. 3D fast SPGR sequence was prescribed in the coronal plane. The images were post-processed on an Advantage Windows 3.1 workstation. Using an automated program, the same observer calculated the hippocampal area in cubic centimetres, clockwise and anticlockwise. The study derived the mean HCV of the left and right side to be 2.49 cm3 and 2.75 cm3 in 20 children aged 6 to 12 years. In a study conducted by Zang et al.⁵, a correlation between age and HCV was observed, but there was no correlation with gender.

Statistically significant differences were found between HCV and age (P < 0.0l). On the left side of the cases group, t=8.06, F=65, P < 0.001 and on the right side of the cases group, t=8.03, F=64.47, P < 0.001. On the left side of the normal group, t=6.87, F=47.22, P < 0.001 and the right side of the normal group, t = 6.05, F = 36.56, P < 0.001. There were no statistically significant differences in either raw or normalised volumes between gender groups (P>0.05). The right-side HC was consistently larger than the left in both the cases group and NC group (raw and normalised volume). The right normalised HCV was larger than the left side (mean value 18.09 ± 65.87 mm3), although the difference was not statistically significant (P=0.1915, P>0.05).

Obenaus et al.⁶ found the mean HCV of the left and right sides to be 2.44 mL and 2.59 mL in four normal children aged 14-60 months. No statistically significant differences were found between the two sides, and six of the subjects showed 10% larger right HCV than the left side. The hippocampal volumes are both age and gender-dependent and larger with increasing age and tend to be larger in males.

In a study conducted by Aravind Narayan Mohandas et al.⁷, it was found that the mean HV was 2.411 cm3, with the mean RHV as 2.424 cm3 and the mean LHV as 2.398 cm3. A small but statistically significant association between gender and HV is detected, with males having slightly larger volumes than females, similar to our study.

In our study, of the 40 children with positive clinical history, 12.5% of patients have shown a mean left hippocampal volume of 2.0+/-.35 cc3 and of right hippocampal volume 2.1+/-.35 cc3, which is decreased compared to the control population. According to a study by Quigg M et al.⁸, most patients with MTLE have some degree of bilateral, asymmetric hippocampal pathology. According to another study by Luby et al.⁹, comprising 49 patients undergoing anteromedial temporal lobe resection for medically intractable temporal lobe seizures, 89% of MTS cases had significant volumetric atrophy of the ipsilateral hippocampus.

The volume reduction witnessed in TLE is the result of neuronal cell death. Lee et al.¹⁰ compared MRI hippocampal volumes before anterior temporal lobectomy with quantitative neuronal density measurements in resected hippocampal specimens and found evidence for a significant correlation of MR-derived hippocampal volume with neuronal density in the CA1, CA2, and CA3 subfields of the hippocampus. This finding has been confirmed by Luby et al. ^nine and Briellmann et al.^11, who found that the ipsilateral hippocampal volume best predicted the neuronal cell count in the dentate gyrus, whereas the T2 relaxation time, on the other hand, best predicted the glial cell count in the dentate gyrus (Kuzniecky et al.¹²).

In a study by Daley et al.¹³, which compared hippocampal volume in children with cryptogenic epilepsy, all of whom had complex partial seizures with normal children, the children with complex partial seizures had significantly smaller total hippocampal volumes than the normal children. Bartzokis et al.¹⁴ have compared the volumetry of different brain structures at 0.5 and 1.5 T and demonstrated good interscanner reliability. Although images acquired on the 0.5 T scanner were acquired using a similar sequence, they differed in quality and tissue T2 relaxation times.¹⁵ Similarly, although measurement error is lower and measurement reliability is improved at 3 T due to increased tissue contrast, this is not significantly different from that at 1.5 T and does not dramatically increase at 3 T; the increased field strength does not significantly affect the volume measurement.¹¹

Comparison of the standard non-volumetric epilepsy-specific MR imaging protocol with quantitative MR imaging for the detection of HA was deemed necessary because the standard MR imaging protocol represents what is available in the majority of clinical settings.

The detection of MR imaging signs of HS can help to define seizure aetiology and indicate surgical treatment for patients with drug-resistant MTLE. We demonstrated here that even in 3T MRI analysed in tertiary centres by epilepsy experts, hippocampal volume and signal quantification could significantly improve the detection of signs of HS in patients with otherwise normal MRI findings by using an epilepsy protocol. MR imaging has significantly improved the detection of pathologies related to epilepsy. It is safe, noninvasive, and widely available in epilepsy centres. However, a variable but significant number of patients with focal epilepsies have normal MRI findings and unknown seizure aetiology. Today, these MR imaging quantification methods are easily available and not very time-consuming, and they could be used as routine diagnostic tools for patients with drug-resistant focal epilepsies and visually normal MRI findings after further validation for clinical use.

In conclusion, seizures are a significant neurological issue in childhood, with mesial temporal sclerosis (MTS) being the most common lesion in surgically eligible epileptic patients. MTS is always associated with clinical seizures and is more prevalent in males, though without significant gender predilection. It is more commonly found on the left side, possibly due to the naturally larger right hippocampus. Unilateral hippocampal sclerosis (HS) is the most frequent pathological finding in temporal lobe epilepsy (TLE). The use of 3 Tesla MRI, particularly with hippocampal volume quantification, significantly enhances the detection of hippocampal sclerosis, especially in cases without signal changes. The normal hippocampal volume ranges are 2.6±0.35 cc³ on the right and 2.5±0.35 cc³ on the left, with volume loss observed in patients with MTS. MRI remains the ideal imaging modality due to its non-invasive and non-radiating nature.

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