Epilepsy (Seizure Disorder) is a disorder characterized by recurrent epileptic seizures (convulsions) often of unknown cause. Autoimmune pathologies are associated with epileptic seizures, additionally; autoimmune and inflammatory disorders such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Type-1 Diabetes (T1DM) have been suggested as risk factors for the development of convulsions. The hidden autoimmune pathogenesis in such disorders usually involve the production of auto-antibodies that target the Blood-brain barrier (BBB), leading to the loss of integrity and function. Moreover, this further aggravates clinical features due potential gush of pro-inflammatory cytokines specifically, TNF-, and IL-1. These pro-inflammatory cytokines have also been associated in breakdown of the tight junctions between neurons and the basement membranes (matrix metalloproteinase) that could further impact the electrical activities in the brain leading to periodic convulsions.  Additionally, such pathologies may co-exist and may reflect common genetic risk factors, for instance, RA have been associated with increased risk of seizures. The familial association studies have suggested there may be autoimmune genes and conduits that could represent among various CNS pathologies. It calls out for a pressing need to understand the disease course to next level, specifically adolescents with seizures and their associations. Treatment and clinical evaluation need to be further studied and proposed for fresh protocols.

Anti epileptics (AEDs) are known to configure resistance against the treatment protocols or when administered for longer periods (lack of patient track), causing relapsing episodes.  One major contributing factor to this is the loss of integrity within the BBB. The BBB is a semi-permeable membrane, consisting of cellular and extracellular matrix components that work as a physical barrier to various chemicals/drugs. This protection is regulated by the movement of molecules, ions, and immune cells between the blood and the brain parenchyma. The integrity withstands in conjunction with proteins between cells, called the tight junctions (e.g. Claudin-5 and Occludin) that selectively restrict the passage. The BBB leakage, which is associated with an increase in the chemical messenger glutamate, has been suggested in the process of developing epilepsy. Moreover, deregulation of electrical activity would possibly degrade the tight junctions.  Therefore, better understanding the cause of seizure-induced BBB leakage in epilepsy could be important for developing targeted treatment for the patients suffering with epilepsy and for increasing effectiveness of AEDs.

The association between the BBB leakage and convulsions has been considered a “puzzle of the chicken and the egg” (1). In new onset seizures and iatrogenic acute seizures, the role of the BBB may be easier to establish. Long-term cognitive impairment does document EEG changes. Intra-and post-ischaemic stroke insult can result into significant new onset convulsions. This could be in relation to the breakage of the BBB during or after hypoperfusion insult in the brain leading to abnormal opening of the barrier (2). During acute phase reactions considering the opening of the BBB, there is an evident increase in proinflammatory cytokines and cerebrovascular dysfunction, gliosis, and reactive microglia occur as a part of the same proinflammatory reaction. This finding now waves off the orthodox concept that brain cells are the sole players in the inflammatory process leading to seizures. This is perhaps not surprising; inflammation consists of increased vascular permeability and extravasation of serum components. Glial and microglial cells respond to seizures by expressing cytokines and chemokine. Toll-like receptors (e.g., TLR-4) and High-mobility group protein B1 (HMGB1) immune-reactivity was found in the hippocampi of patients with temporal lobe epilepsy and in animal models of seizure. TLR-4 also plays an important role in the innate immune system, recognizing xenopathogens, and it is expressed by circulating monocytes/macrophages, myeloid dendritic cells, mast cells, and B lymphocytes (3). Acute seizures may also result from poorly controlled diabetes or blood osmolality changes. Moreover, BBB insult has been associated with long standing hyperglycaemia. Activation of blood leukocytes and BBB damage is one of the mechanisms of drug induced seizures. For e.g. lithium is known to activate circulating leukocytes, which in turns causes BBB disruption.

The literature so far supports that the symptoms of epilepsy and seizures are not only initiated by CNS cells but can also be caused by altered immune responses in the periphery. Furthermore, seizures may promote activation of the hypothalamic-pituitary-adrenal axis, in turn triggering peripheral leukocyte activation which further promotes the production of pro-inflammatory cytokines. These activated leukocytes are known to exacerbate BBB damage and such brain-to-periphery crosswalk. Nevertheless, under these circumstances the role of BBB remains crucial, since it resides at the anatomic interface between the periphery and the brain, responding to modification imminent from both sides. For e.g. Leukocyte–BBB interactions have been known facilitate seizures, leukocyte pathogenesis are similar to sequel of events describing this interaction (leukocyte rolling, tethering) is almost identical to the pathogenesis underlying multiple sclerosis and ischaemic stroke.

Before any conclusion can be made, a systematic radiologic evaluation of BBB damage in patients with drug-resistant epilepsy needs to be performed; this would demand the urge for new BBB restoration drugs. Magnetic Resonance Imagining could detect brain oedema which could explain BBB damage and parenchymal cellular dysfunction clinically. Moreover, serum markers of BBB damage may constitute a viable surrogate for detecting BBB damage. However, T2-DWI and FLAIR are mostly performed on patients affected by drug-resistant seizures, status epilepticus, or traumatic brain injury, and not in patients presenting with a new onset, low frequency or drug-respondent seizures. Understandably, severe hypertension and vasogenic oedema are the accepted mechanisms in inflammatory reactions. BBB damage (can be detected by T2-FLAIR) represents a risk during the triggering iatrogenic seizures. The use of BBB protective drugs should be tailored to specific epilepsies and, most likely, not all patients with epilepsy may benefit from this therapeutic approach. BBB drugs are likely to be most effective when used as an add-on to available AEDs, therefore targeting both BBB cells and neurons. Specific ion channel fragments may access the systemic circulation by way of a leaky BBB, triggering the production of auto-antibodies; the latter may re-enter the brain parenchyma and cross the brain barriers, thereby exacerbating symptoms.

A corollary of the BBB hypothesis of epilepsy is the fact that activated leukocytes sustain BBB dysfunction and seizures. Moreover, associated hypoperfusion can further defame the integrity. Therefore, if BBB-leakage associated inflammation is a target to treat seizures, then new anti-inflammatory drugs may not require penetration into the brain. If conversely, the main targets are glial and microglia cells or extravasated leukocytes, then drug brain penetration needs to be taken into account. Finally, the selective targeting of altered proangiogenic processes occurring in the epileptic brain represents an attractive avenue for the development of new therapeutics aimed at preserving BBB functions and reducing seizures. BBB dysfunction represents a hallmark of seizures and epilepsy. Although the importance of the BBB continues to grow, therapeutic options targeting the dysfunctional BBB are being tested in animal models and, in some cases, administrated to cohort of selected patients. BBB drugs may represent an add-on therapeutic option and could be administrated in association with available neuronal antiepileptic drugs. The continuous refinement of experimental models, new molecules, and imaging techniques is shaping this field of research, creating new possibilities to better control drug resistant forms of epilepsy.

In conclusion, pharmacologic intervention targeting the BBB may therefore be an important tool to prevent acute, comorbid seizures occurring after TBI, stroke, and iatrogenic vascular interventions. Furthermore, hypothesis such as mild hypothermia (35℃) elongating the BBB leakage interval during and after the neuronal damage that could stand out as an additional therapeutic window with the AEDs. We clinicians do need to regulate a constant upsurge in epilepsy treatment guidelines. Thereby, collective in-vitro and in-vivo detailed research are extremely crucial. There is a definitive need to educate pandemic areas of seizure disorders in terms of disease process and treatment outcomes.

References

1. Friedman A. Blood–brain barrier dysfunction, status epilepticus, seizures, and epilepsy: a puzzle of a chicken and egg? Epilepsia. 2011;52(Suppl. 8):19–20. doi: 10.1111/j.1528-1167.2011.03227.
2. Mathur M, Bayraktutan U (2022) Hypothermia as a Treatment Option for Intra and Post Ischemic Stroke. J NeurolNeurosci Vol.13 No.2:411
3. Rivest S, Lacroix S, Vallieres L, Nadeau S, Zhang J, Laflamme N. How the blood talks to the brain parenchyma and the paraventricular nucleus of the hypothalamus during systemic inflammatory and infectious stimuli. Proc Soc Exp Biol Med. 2000;223:22–38. doi: 10.1046/j.1525-1373.2000.22304.

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