Water diffusion in the human hippocampus in epilepsy

doi:10.1016/S0730-725X(98)00153-2

Magnetic Resonance Imaging

Volume 17, Issue 1, February 1999, Pages 29-36

https://doi.org/10.1016/S0730-725X(98)00153-2 Get rights and content

Abstract

The hippocampus plays a central role in the generation and propagation of seizures in patients with complex partial seizures. Hippocampal sclerosis (HS) is a common structural abnormality in patients with refractory epilepsy. The aim of this study was to quantify diffusion in the hippocampus in patients with epilepsy to evaluate the diffusion changes associated with HS. We scanned 20 subjects (14 patients and 6 controls) with a 1.5T magnetic resonance (MR) system using a cardiac-gated, navigated spin-echo diffusion-weighted sequence. Hippocampal ADC measurements were performed on maps of the ADC measured in three orthogonal directions labeled x, y, and z. The mean ADC (ADC_av) and an anisotropy index (AI) were calculated. Hippocampi which fulfilled the MR criteria for HS had a higher ADC_av (p < 0.001) and a lower AI (p = 0.04) than normal appearing hippocampi in patients and hippocampi in controls. These results imply a loss of structural organization in sclerotic hippocampi and an expansion of the extracellular space. Quantitative measurements of diffusion can be used as an independent parameter for the identification and characterization of abnormal hippocampi in epilepsy.

Introduction

Diffusion weighted imaging (DWI) allows the quantitative measurement of diffusion and diffusion anisotropy of water molecules. The apparent diffusion coefficient (ADC), and anisotropy index (AI), can be calculated.1, 2, 3, 4 The ADC is a measurement of the magnitude of diffusion and AI is a measurement of the directionality of diffusion. Both parameters are independent of T1- and T2-relaxation and directly reflect intrinsic characteristics of tissue microstructure and microdynamics.5 Microstructural changes associated with pathological processes including neuronal swelling, shrinkage or widening of the extracellular space, or the loss of tissue organization, all result in transient or permanent changes of diffusion and diffusion anisotropy.6, 7 ADC changes occur in human acute and chronic brain ischemia,8, 9, 10, 11, 12 in multiple sclerosis13, 14 and in brain tumours.15, 16 Loss of anisotropy has been reported in diseases affecting the white matter such as MS plaques and Pelizaeus Merzbacher disease.17, 18

Transient decreases in ADC have also been observed in experimental status epilepticus,19, 20, 21, 22, 23, 24 after electroshocks25 and in spreading depression.26 The most likely explanation is that a flux of sodium followed by a shift of water from the extracellular to the intracellular space27 results in a net reduction of the ADC. In human prolonged focal status a similar decrease in the cortical ADC associated with an increase in the subcortical ADC has been observed.28 Animal models of chronic epilepsy following status have demonstrated that persistent ADC changes can also develop.29 These persistent ADC changes are likely to reflect the microstructural damage in such animals which include widened extracellular space, low neuronal densities, reduced dendritic branching and loss of cellular organization.

In humans, the hippocampus plays a central role in the generation and propagation of seizures in complex partial seizures. Hippocampal sclerosis (HS) is a common structural abnormality in patients with refractory temporal lobe epilepsy.30, 31

The aim of this study was to investigate diffusion in the hippocampus in epilepsy during the interictal stage. To evaluate the diffusion changes associated with HS in epilepsy we established a normal range, and performed measurements in patients with and without the MR criteria of HS.

Section snippets

Subjects

Seventeen patients and six control subjects without a history of neurological disease were scanned. Three patients had to be excluded from further analysis because of severe motion artefacts resulting in fourteen patients (4 female, 10 male, mean age 33 years, range 20–50 years) and six controls (2 female, four male, mean age 31 years, range 29–36 years). Patients were recruited from a tertial referral centre for epilepsy, were investigated with EEG and standard MR imaging, and were interviewed

Control subjects

The mean ADC_av was 0.91 × 10⁻³mm²/s, the SD 0.03 × 10⁻³ mm²/s, the coefficient of variation (COV) 4%. The mean AI in the hippocampus was 0.09 (SD 0.04, COV 46%). The mean AI in the corpus callosum was 0.55 (SD 0.10, COV 18%), in the water phantom (theoretically 0) the mean AI was <0.01. The mean hippocampal T2-relaxation time was 85.5 ms (SD 1.59 ms, COV 2%). The mean hippocampal volume corrected for intracranial volume was 2941 mm³ (SD88 mm³, COV 3%). Figure 1 shows ADC maps in a control

Discussion

Our measurements showed that water diffusion is frequently abnormal in hippocampi of patients with epilepsy. We found a positive correlation of hippocampal T2-relaxation time and ADC_av, and a negative correlation of hippocampal volume and ADC_av Fig. 3, Fig. 4. This is in keeping with the observed trend of Zhong et al.42 We also found a negative correlation of T2-relaxation time and AI, and a positive correlation of hippocampal volume and AI. However, correlations for AI were weak, and the

Acknowledgements

This research has been kindly funded by a European Community Fellowship (U.C.W.), by the National Society for Epilepsy (M.R.S + K.D.B.), the Brain Research Trust (C.A.C. + M.R.S.) and the Multiple Sclerosis Society of Great Britain and Northern Ireland (G.J.B.). We would like to thank Dr. BE Kendall and Dr. JM Stevens for their helpful comments. We thank Dr. JS Duncan for permission to study his patients.

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Previous studies have demonstrated lateralized, elevated ADC intensities in the temporal lobe areas ipsilateral to the seizure onset zone in patients with intractable mTLE (Hugg et al., 1999; Lee et al., 2004; Nagy et al., 2016; O’Brien et al., 2007; Yoo et al., 2002). Additionally, the elevated ADC signals were negatively associated with hippocampal volume (Wieshmann et al., 1999), which was attributed to tissue changes from hippocampal sclerosis and recurrent seizures (Latour et al., 1994; Wieshmann et al., 1999). It remains unclear whether regions high in ADC intensity constitute the seizure onset zone that harbors the primary epileptogenic focus.
Magnetic resonance-guided laser interstitial thermal therapy (MRgLiTT) is becoming a first-line surgical therapy for mesial temporal lobe epilepsy (mTLE) due to good seizure control and low complication risk. However, seizure outcomes after MRgLiTT remain highly variable and there is a need to improve patient selection and post-operative prognostication. In this retrospective study, we investigated whether the pre-operative MRI-derived apparent diffusion coefficient (ADC), used as a marker of tissue pathology in the mesial temporal structures could help predict seizure outcome.
Thirty-five patients who underwent MRgLiTT at our institution between 2014 and 2019 were included in the study. Demographic and clinical data were retrospectively collected. Seizure outcome was defined as good (ILAE Class I-II) and poor (ILAE Class III-VI). Volumetrics were performed on pre-ablation hippocampus and amygdala. Ablation volumes, and the proportion of ablated hippocampus and amygdala calculated via their respective mean voxel-wise ADC intensities were quantified from pre-operative and intra-operative post-ablation MRIs and statistically compared between the two outcome cohorts. Univarate and multivariate regression analysis was performed to identify demographic, clinical, and radiographic predictors of seizure outcome.
Mean age at LiTT was 36 years and 14 (40 %) were female. Mean follow-up duration was 1.90 ± 0.17 years. Twenty-seven (77 %) patients had mesial temporal sclerosis. There was no significant difference in the ablation volumes and proportion of ablated volume of hippocampus and amygdala between the two outcome groups. Patients with good seizure outcome had significantly higher normalized ADC intensities in the ablated mesial temporal structures compared to those with poor outcome (0.01 ± 0.08 vs.−0.29 ± 0.06; p = 0.015).
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1) Characterize the evolution of microstructural changes in the contralateral, non-operated hippocampus—using longitudinal diffusion tensor imaging (DTI)—following surgery for temporal lobe epilepsy (TLE). 2) Characterize the downstream extra-hippocampal volumetric changes of the fornix and mammillary bodies after TLE surgery. 3) Examine the relationship between these measures and seizure/cognitive outcome.
Serial structural and DTI brain MRI scans were collected in 25 TLE patients pre- and post-surgery (anterior temporal lobectomy, ATL – 13; selective amygdalohippocampectomy, SelAH – 12) and in 12 healthy controls. Contralateral hippocampal fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were computed with manual hippocampal tracings as volumes of interest following co-registration to anatomical images. Fornix and mammillary body volumetry was performed by manual segmentation.
After surgery, the non-resected hippocampus showed significant postoperative decline in FA (p = 0.0001), with increase of MD (p = 0.01) and RD (p = 0.0001). In contrast to the timing of our previously reported volume changes where atrophy is observed in the first week, diffusion changes occurred late, taking 1–3 years to develop and are not significant at one week after surgery. Diffusion changes are accompanied by delayed limbic circuit volume loss in the mammillary bodies (35%; p < 0.0001) and fornix (24%; p < 0.0001) compared to baseline. There was no correlation between postoperative diffusion or structural changes and memory score nor did the degree of postoperative change in hippocampal DTI parameters, mammillary body volume or fornix volume vary significantly based on seizure outcome.
Differences observed in the timing of postoperative volume (first week) and FA/MD (one year) changes would suggest that early contralateral hippocampal atrophy is not secondary to fluid shifts (dehydration) while the late DTI changes suggest ongoing microstructural changes extending beyond the early postoperative period. Postoperative hippocampal diffusion changes are accompanied by delayed mammillary body and fornix volume loss which did not differ when stratified by seizure outcome nor was correlated with degree of hippocampal diffusion change. Finally, we did not identify any significant correlation between postoperative diffusion parameter change and memory performance.
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However, it has been reported that FA can detect structural abnormality more sensitively than conventional MRI (Liacu et al., 2010). Thus, decreased hippocampal anisotropy indicates the presence of hippocampal sclerosis (Wieshmann et al., 1999; Liacu et al., 2010). Our previous studies demonstrated the decrease of unilateral hippocampal volume and FA in FSECs, compared to control cats (Mizoguchi et al., 2015, 2017).
The familial spontaneous epileptic cat (FSEC) is thought to be a good genetic model of mesial temporal lobe epilepsy. In the current study, cerebral diffusion and perfusion magnetic resonance imaging (MRI) were used to confirm the functional deficit zone in the FSEC and evaluate the effect of a single seizure on different brain regions.
Six FSECs and six healthy control cats were used in this study. MRI was performed in the interictal state (resting state for control) and postictal state immediately after the vestibular stimulation-induced generalized epileptic seizure (control cats received the same stimulation as the FSECs). The apparent diffusion coefficient (ADC), fractional anisotropy and perfusion parameters (i.e., relative regional cerebral blood volume (rCBV), relative regional cerebral blood flow (rCBF), and relative regional mean transit time (rMTT)) were measured in the hippocampus, amygdala, thalamus, and gray and white matter.
In the interictal state, the rCBV and rMTT in the hippocampus was significantly decreased in FSECs, compared to the control. In the postictal state, FSECs had a significantly decreased ADC and an increased rCBV, rCBF, and rMTT in the hippocampus, and an increased rMTT in the amygdala, compared to the interictal state.
This study showed that FSECs had interictal hypoperfusion in the hippocampus, and postictal hypodiffusion and hyperperfusion in the hippocampus and/or amygdala. These findings suggested that the hippocampus and/or amygdala act as the functional deficit and expanded seizure-onset zones in FSECs.
DTI-based response-driven modeling of mTLE laterality
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Citation Excerpt :
The related microstructural changes can be detected using segmentation or fiber tracking (FT) with DTI data. Most previous studies have reported bilateral alterations of fractional anisotropy (FA) and mean diffusivity (MD), as indices of fiber integrity and overall diffusivity, respectively (Nazem-Zadeh et al., 2012a; Pierpaoli et al., 2001) as a way to differentiate the DTI-based structural changes in subjects with unilateral mTLE from those in nonepileptic controls (Concha et al., 2004, 2009, 2010; Gross et al., 2006; Hugg et al., 1999; Kim et al., 2008, 2010; Liacu et al., 2012b; Rugg-Gunn et al., 2001; Thivard et al., 2005; Wieshmann et al., 1999; Yogarajah and Duncan, 2008). Some have reported upon the capability of DTI to lateralize mTLE by comparing variations among patients with mTLE and nonepileptic subjects (Ahmadi et al., 2009; Focke et al., 2008; Nazem-Zadeh et al., 2014b; Yoo et al., 2002), but most have not applied DTI to lateralize epileptogenicity in individual mTLE patients, and none have reported its capability to differentiate bilateral from unilateral cases.
To develop lateralization models for distinguishing between unilateral and bilateral mesial temporal lobe epilepsy (mTLE) and determining laterality in cases of unilateral mTLE.
mTLE is the most common form of medically refractory focal epilepsy. Many mTLE patients fail to demonstrate an unambiguous unilateral ictal onset. Intracranial EEG (icEEG) monitoring can be performed to establish whether the ictal origin is unilateral or truly bilateral with independent bitemporal ictal origin. However, because of the expense and risk of intracranial electrode placement, much research has been done to determine if the need for icEEG can be obviated with noninvasive neuroimaging methods, such as diffusion tensor imaging (DTI).
Fractional anisotropy (FA) was used to quantify microstructural changes reflected in the diffusivity properties of the corpus callosum, cingulum, and fornix, in a retrospective cohort of 31 patients confirmed to have unilateral (n = 24) or bilateral (n = 7) mTLE. All unilateral mTLE patients underwent resection with an Engel class I outcome. Eleven were reported to have hippocampal sclerosis on pathological analysis; nine had undergone prior icEEG. The bilateral mTLE patients had undergone icEEG demonstrating independent epileptiform activity in both right and left hemispheres. Twenty-three nonepileptic subjects were included as controls.
In cases of right mTLE, FA showed significant differences from control in all callosal subregions, in both left and right superior cingulate subregions, and in forniceal crura. Comparison of right and left mTLE cases showed significant differences in FA of callosal genu, rostral body, and splenium and the right posteroinferior and superior cingulate subregions. In cases of left mTLE, FA showed significant differences from control only in the callosal isthmus. Significant differences in FA were identified when cases of right mTLE were compared with bilateral mTLE cases in the rostral and midbody callosal subregions and isthmus. Based on 11 FA measurements in the cingulate, callosal and forniceal subregions, a response-driven lateralization model successfully differentiated all cases (n = 54) into groups of unilateral right (n = 12), unilateral left (n = 12), and bilateral mTLE (n = 7), and nonepileptic control (23).
The proposed response-driven DTI biomarker is intended to lessen diagnostic ambiguity of laterality in cases of mTLE and help optimize selection of surgical candidates. Application of this model shows promise in reducing the need for invasive icEEG in prospective cases.
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ADC can also be used as a complementary tool for lateralizing epileptogenic lesions in patients with refractory TLE, especially in those with a normal MRI [35–39]. There are reports of a significant ADC increase in patients with hippocampal sclerosis and TLE that is refractory to medical treatment [40,41]. Yoo et al. studied 18 patients with refractory TLE and 19 healthy controls.
The objective of part one of this review is to present the structural neuroimaging techniques that are currently used to evaluate patients with temporal lobe epilepsy (TLE), and to discuss their potential to define patient eligibility for medial temporal lobe surgery. A PubMed query, using Medline and Embase, and subsequent review, was performed for all English language studies published after 1990, reporting neuroimaging methods for the evaluation of patients with TLE. The extracted data included demographic variables, population and study design, imaging methods, gold standard methods, imaging findings, surgical outcomes and conclusions. Overall, 56 papers were reviewed, including a total of 1517 patients. This review highlights the following structural neuroimaging techniques: MRI, diffusion-weighted imaging, tractography, electroencephalography and magnetoencephalography. The developments in neuroimaging during the last decades have led to remarkable improvements in surgical precision, postsurgical outcome, prognosis, and the rate of seizure control in patients with TLE. The use of multiple imaging methods provides improved outcomes, and further improvements will be possible with future studies of larger patient cohorts.

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Original ContributionsWater diffusion in the human hippocampus in epilepsy

Abstract

Introduction

Section snippets

Subjects

Control subjects

Discussion

Acknowledgements

Use of spin-echo pulsed magnetic field gradient to study anisotropic restricted diffusion and flow

J Chem Phy

The spatial mapping of translational diffusion by the NMR imaging technique

Phys Med Biol

MR imaging of intravoxel incoherent motionsapplication to diffusion and perfusion in neurologic disorders

Radiology

Water diffusion and acute stroke

Magn Reson Med

MR imaging of anisotropically restricted diffusion of water in the nervous system: Technical, anatomic, and pathologic considerations

J Comput Assist Tomogr

Effects of osmotically driven cell volume changes on diffusion-weighted imaging of the rat optic nerve

Magn Reson Med

Cytotoxic brain edema: Assessment with diffusion-weighted MR imaging

Radiology

Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging

Ann Neurol

Navigated diffusion imaging of normal and ischemic human brain

Magn Reson Med

Clinical utility of diffusion-weighted magnetic resonance imaging in the assessment of ischemic stroke

Ann Neurol

Enlargement of human cerebral ischemic lesion volumes measured by diffusion-weighted magnetic resonance imaging

Ann Neurol

Acute and chronic stroke: Navigated spin-echo diffusion-weighted MR imaging

Radiology

Apparent diffusion coefficients in benign and secondary progressive multiple sclerosis by nuclear magnetic resonance

Magn Reson Med

Increased water self-diffusion in chronic plaques and in apparently normal white matter in patients with multiple sclerosis

Acta Neurol Scand

MR imaging of high-grade cerebral gliomas: Value of diffusion-weighted echoplanar pulse sequences

AJR

Diffusion-weighted MR imaging of the brain: Value of differentiating between extraaxial cysts and epidermoid tumors

AJNR

Brain parenchyma apparent diffusion coefficient alterations associated with experimental complex partial status epilepticus

Magn Reson Imag.

Diffusion-weighted MR in experimental sustained seizures elicited with kainic acid

AJNR

MR spectroscopic imaging and diffusion-weighted MRI for early detection of kainate-induced status epilepticus in the rat

Magn Reson Med

Postictal alteration of sodium content and apparent diffusion coefficient in epileptic rat brain induced by kainic acid

Epilepsia

Changes in water diffusion and relaxation properties of rat cerebrum during status epilepticus

Magn Reson Med

Barbiturate-reversible reduction of water diffusion coefficient in flurothyl-induced status epilepticus in rats

Magn Reson Med

Reversible, reproducible reduction of brain water apparent diffusion coefficient by cortical electroshocks

Magn Reson Med

Spreading waves of decreased diffusion coefficient after cortical stimulation in the rat brain

Magn Reson Med

Original Contributions
Water diffusion in the human hippocampus in epilepsy