Ultrastructural Changes in Brain Tissue in Drug-Resistant Mesial Temporal Lobe Epilepsy in Humans: A Mini-Review

Darya Sitovskaya; Yulia Zabrodskaya

doi:10.37871/jbres1831

ISSN: 2766-2276

Medicine Group. 2023 November 17;4(11):1570-1574. doi: 10.37871/jbres1831.

Subject area(s)

Neurological Disorders
Brain Disorders

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Mini Review

Ultrastructural Changes in Brain Tissue in Drug-Resistant Mesial Temporal Lobe Epilepsy in Humans: A Mini-Review

Darya Sitovskaya^1,2* and Yulia Zabrodskaya^1,3

¹Polenov Neurosurgical Institute, Branch of Almazov National Medical Research Centre, 197341 St. Petersburg, Russia
²Department of Pathology with a course of forensic medicine named after D.D. Lochov, St. Petersburg State Pediatric Medical University, 194100 St. Petersburg, Russia
³Department of Pathology, Mechnikov North-West State Medical University, 191015 St. Petersburg, Russia

*Corresponding author: Darya Sitovskaya, Polenov Neurosurgical Institute, Branch of Almazov National Medical Research Centre, 197341 St. Petersburg, Russia E-mail:

Received: 03 November 2023 | Accepted: 13 November 2023 | Published: 17 November 2023

How to cite this article: Sitovskaya D, Zabrodskaya Y. Ultrastructural Changes in Brain Tissue in Drug-Resistant Mesial Temporal Lobe Epilepsy in Humans: A Mini-Review. J Biomed Res Environ Sci. 2023 Oct 17; 4(11): 1570-1574. doi: 10.37871/jbres1757, Article ID: jbres1757

Keywords

Drug-resistant epilepsy
Temporal lobe
Electron microscopy
Ultrastructure

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Abstract

Epilepsy is a group of chronic neurological diseases of the brain characterized by a persistent predisposition to epileptic seizures, affecting more than 70 million people worldwide. Drug-resistance is a key problem in the theory and practice of epileptology. The literature contains many publications devoted to ultrastructural changes in brain tissue in experimental animal models, but the features of ultrastructural changes in human brain tissue in drug-resistant mesial Temporal Lobe Epilepsy (TLE) remain unknown. This brief review presents the current state of the art of problems devoted to the study of the ultrastructure of neurons, glia, and blood vessels in patients with drug-resistant mesial TLE.

Introduction

Epilepsy is a group of chronic neurological diseases of the brain characterized by a persistent predisposition to epileptic seizures that affects more than 70 million people worldwide [1], and seizures are the main symptom of epilepsy. Epileptogenesis is a pathogenic process by which physiological and structural changes are induced in the brain, resulting in increased susceptibility to seizures and an increased likelihood of recurrent spontaneous seizures [2]. Currently, drug-resistance is a key problem in the theory and practice of epileptology [3]. There are many factors that can contribute to the development of drug resistance, including genetic, epigenetic, neurological, immunological, and environmental factors that can affect the concentration of the drug in the brain or the response to antiepileptic drugs [4-5]. One of the most common causes of drug-resistant epilepsy is focal cortical dysplasia. Focal Cortical Dysplasia (FCD), specifically malformations of the cerebral cortex, is one of the most common causes associated with DRE [6]. FCD is characterized by focal abnormalities in cortical cytoarchitecture and is closely linked to DRE, particularly in children and young adults [7]. However, ultrastructural changes in brain tissue have been described mainly in experimental animal models; the results of studies of human brain tissue are not sufficiently presented in the literature. Also in the literature there are numerous publications devoted to storage diseases [8] and lesions in genetic syndromes [9-13], in particular, through electron microscopy Yang F, et al. [14] revealed mitochondrial swelling and hyperproliferation in hippocampal pyramidal neurons upon mTOR hyperactivation as a result of loss of Tsc2 in a Mitf-M-derived cell line, which led to a dramatic increase in sensitivity and aberrant synchronization of hippocampal networks and disruption of intracellular calcium dynamics [14]. However, the question of the features of ultrastructural changes in human brain tissue in drug-resistant mesial Temporal Lobe Epilepsy (TLE) remains open.

Neurons

Tóth EZ, et al. [15] showed how Parvalbumin (PV) and Cannabinoid type 1 Receptor (CB1R)-positive perisomatic interneurons innervate pyramidal cell bodies. At the same time, the general somatic inhibitory inputs PV+ and CB1R+ remained unchanged in focal cortical epilepsy; however, in epileptic samples, in regions generating synchrony, on the contrary, the size of PV-colored synapses increased and their number decreased. Because PV+ cells have a stronger influence on shaping population activity in epileptic samples, they may predispose a cortical region to generate or participate in hypersynchronous events [15]. In addition, Ábrahám H, et al. [16] found in the molecular layer of the hippocampus a strong sprouting of parvalbumin-immunoreactive axons that terminate on proximal and distal dendritic shafts, as well as dendritic spines of granule cells, contributing to the known synaptic remodeling in TLE [16]. Using high-resolution ultrastructural immunocytochemistry in animals, the presence of GABA in the synaptic vesicles of the endings of mossy fibers was revealed, indicating a possible modulating role of GABA in synaptic transmission between mossy fibers and the target cell [17]. In humans, an imbalance of Glutamate- and GABAergic neuronal systems has been observed [18].

Vannini E, et al. [19] showed in their study that epileptic networks exhibit an early onset of active zone elongation at inhibitory synapses together with a delayed spatial reorganization of recycling vesicles at excitatory synapses. They also found that the altered arrangement of transmitter vesicles capable of release represents a novel feature of epileptic networks [19].

In addition, when studying neurons ultrastructurally, the authors found neurons at different stages of apoptosis. The early manifestations of apoptosis were signs of DNA fragmentation, based on the presence of heterochromatin clots distributed throughout the karyoplasm. At the later stages of apoptosis, nuclear disintegration was detected, along with irreversible degenerative changes in the cytoplasm, pronounced perinuclear pockets, sharply dilated tubules of the endoplasmic reticulum, and cisterns of the Golgi apparatus, which were often combined into huge vacuoles [20].

Glia and fibers

Perisynaptic astroglia are critical for the normal development and function of synapses. Reactive astrogliosis is a common pathology in epilepsy in both animals and humans, and recent work has shown that even in the absence of other pathology, reactive astrogliosis may be sufficient to cause the development of epilepsy [21]. In animal models of epilepsy, for example, it has been shown that intense whisker stimulation causes astrocytes in the barrel cortex of rats to increase the coverage of excitatory synapses [22]. Clarkson, et al. [23] focused their attention on the ultrastructural properties of the tripartite synapse in the CA1 region of the hippocampus, where they found increased astrocyte coverage around both presynaptic and postsynaptic elements. In addition, scientists identified decreased expression of the synaptic AMPA receptor subunit and perisynaptic astrocytic GLT-1, as well as an increase in the number of docked vesicles at the presynaptic terminal, suggesting that potential drug targets should be expanded to include all components of the tripartite synapse. Witcher MR, et al. [24] using human material, they revealed the loss of multisynaptic spines by astrocytes in the structures of the hippocampus, the number of which depended on the severity of hippocampal sclerosis. Moreover, connections between astroglial processes were more frequent in moderate damage than in mild cases but were hidden by densely packed intermediate filaments in astroglial processes in severe cases. The scientists also showed that, as in the adult rat hippocampus, perisynaptic astroglial processes were predominantly associated with larger synapses in mild to moderate cases, but rarely penetrated the cluster of axonal boutons surrounding multisynaptic processes. Because the synaptic perimeters were only partially surrounded by astroglial processes, all synapses had partial access to substances in the extracellular space, like the hippocampus of adult rats.

Ultrastructural changes in oligodendrogliocytes in DRE have been less studied; however, it has been shown that these cells are most susceptible to apoptotic death [25], with the formation of Lewy bodies in the cytoplasm.

In addition, researchers found destruction of the myelin sheaths of nerve fibers and progressive demyelination of the white matter of the brain [20].

Vessels

Some authors have suggested that increased blood vessel density is another indicator of drug-resistant epilepsy, based on interpretation of staining markers associated with both the breakdown of the blood-brain barrier and the formation of new blood vessels [26-27]. However, using electron microscopy, Alonso-Nanclares, et al. [28] studied the hippocampus and showed that many of these "blood vessels" are in fact atrophic vascular structures with reduced or virtually absent lumen, and are often filled with processes of reactive astrocytes. Thus, the "normal" vasculature in the CA1 sclerotic field is dramatically reduced. Since this reduction is consistently observed in human sclerotic CA1, this feature can be considered another key pathological indicator of hippocampal sclerosis associated with temporal lobe epilepsy.

During an ultrastructural study, researchers discovered a pronounced thickening of the basement membrane in combination with the growth of collagen fibers into it, the accumulation of calcifications and fibrosis, as well as an uneven expansion of the basement membrane with a tendency to grow into the brain parenchyma [29].

Technological advances and regulatory and ethical considerations

The integration of Artificial Intelligence (AI) and machine learning algorithms in healthcare has the potential to greatly improve data analysis. These technologies could quickly analyze large data sets and identify subtle patterns, which can be particularly useful in the morphometric assessment of electron microscopy, analysis of large volumes of ultramicrographs, and interpretation of Magnetic Resonance Imaging (MRI) results [30]. For instance, AI algorithms can analyze patient data to accurately identify lesions on high-Tesla MRI scans based on ultrastructural changes, reducing the number of MRI-negative cases of epilepsy.

However, as we delve further into the realm of personalized medicine [31,32], where the ultrastructural profile of the epileptic focus is taken into consideration, it is crucial to also address the ethical and regulatory implications associated with it. Issues such as data privacy and fair distribution of personalized testing and treatment must be carefully considered.

Conclusion

In conclusion, ultrastructural changes in drug-resistant mesial temporal lobe epilepsy in humans have not been sufficiently studied; however, they could improve the understanding of epileptogenesis and treatment options in these patients.