by Benedetta Bodini
This interesting session covering the mechanisms and the best strategies to treat epilepsy resulting from stroke, brain infection, and traumatic brain injury, started with a lecture by Prof Pitkänen from Finland, who discussed post-stroke and post-traumatic epileptogenesis. She started her lecture with a reminder that one of the major challenges in epilepsy research is the development of effective treatments to prevent epileptogenesis and epilepsy progression in subjects at risk. A few studies on relatively small populations of patients have investigated the genetic risk factors of post-traumatic and post-stroke epileptogenesis, which is a developing field of research. Dr Pitkänen indicated that the majority of patients develop epileptic seizures in the first few years after a brain trauma or a stroke but underlined that epileptogenesis progresses at a variable speed in different patients. Animal models of traumatic brain injury have recently shown that post-traumatic epileptic activity can be detected early after the traumatic event, even without a clinical correlate, and this early epileptiform activity significantly predicts the development of post-traumatic epilepsy. Recent studies have shown that specific abnormalities detected in the first EEG after a stroke are significantly correlated with the development of post-stroke epilepsy. Prof Pitkänen then provided a very interesting overview of all the proof-of-concept studies testing antiepileptogenesis treatments in different animal models of brain traumatic injury, which proved effective in reducing seizure frequency or duration, but did not show any significant effect in preventing epileptogenesis. She then showed a very recent meta-analysis which demonstrated that the use of statins was associated with a lower risk of post-stroke epilepsy and a remarkable reduction of early post-stroke seizures. In the last part of her lecture, Prof Pitkänen presented new research data on novel diagnostic and prognostic biomarkers of post-traumatic epileptogenesis. In particular, studies conducted on animal models showed that the shortening of N3-REM transition sleep spindles was a significant biomarker for post-traumatic epilepsy, while pathologic high-frequency oscillations were diagnostic biomarkers of seizure onset zone. Studies focused on the investigation of serum and plasma biomarkers of post-stroke epileptogenesis, including a very recent study on S-Neuropeptide Y, also provided very promising results.
In the second lecture of the session, Prof von Oertzen from Austria focused on post-stroke epilepsy. He first underlined that the risk of developing epilepsy after a vascular accident increases in older people and is higher following ischaemic than haemorrhagic strokes (90% of post-stroke epilepsy results from ischaemic vascular accidents). Early post-stroke seizures (occurring less than 7 days after stroke onset) occur in 3-6% of ischaemic and 10-16% of haemorrhagic strokes, and the risk of developing these early seizures is higher following total anterior circulation strokes, strokes with a severe neurological impairment and those characterised by a haemorrhagic transformation. Importantly, early post-stroke seizures are associated with a worse functional outcome and a higher mortality. Late post-stroke seizures (occurring more than 7 days after stroke onset) are associated with a very high risk (more than 70%) of developing subsequent unprovoked seizures. Dr von Oertzen then moved on to discussing proven risk factors for post-ischaemic stroke epilepsy, which include stroke severity at admission, large-artery atherosclerosis, early seizures, cortical involvement, and the involvement of the middle cerebral artery territory. Instead, risk factors for post-haemorragic stroke epilepsy are age, heavy drinking, early seizures, volume of intracerebral haemorrhage and cortical involvement. Moreover, the detection of epileptic activity on EEG after acute stroke has been shown to significantly contribute to the prediction of clinical outcome at 3 months, and of the overall clinical prognosis. Dr von Oertzen then indicated that novel biomarkers and genetic factors are currently being investigated to improve the stratification of stroke patients who are at higher risk of developing early/late seizures, or post-stroke epilepsy. He then provided important insights into the management of acute symptomatic seizures: while it is recommended not to treat acute post-stroke seizures as the recurrence rate is rather low, in common clinical practice antiseizure medications are frequently introduced early after a stroke. Dr van Oertzen suggested that, in this case, antiseizure medications should be used only temporarily and then withdrawn, as there is no evidence for effective prevention of post-stroke epilepsy. As far as the management of post-stroke epilepsy is concerned, he indicated that the antiseizure treatment should be chosen based on seizure type and frequencies, but also on comorbidities and concomitant medications. Overall, lamotrigine is better tolerated than levetiracetam which, in turn, is better tolerated than carbamazepine. In the last part of his lecture, Dr van Oertzen discussed the evidence shown by several studies of a significant effect of statins introduced within 3 days post-stroke in lowering the risk of early post-stroke seizures and post-stroke epilepsy.
In the third lecture of the session, Dr Koepp from the UK provided a comprehensive overview of CNS infections resulting in epilepsy. He started indicating that infections are among the most common preventable risk factors for acquired epilepsy, particularly in low and medium income countries. He then described the main mechanisms involved in epileptogenesis following CNS infections, which include direct pathogen-mediated effects but also a prolonged stimulation of proinflammatory signals leading to a residual pathological state, characterised by damage of the blood-brain barrier, neuronal death and persistent neuronal hyperexcitability. In particular, he indicated that following bacterial infections, the pathogenesis of both acute symptomatic seizures and acquired epilepsy involves arteritis, ischaemia, infarction, and inflammatory changes. CNS tuberculosis, both in the form of subacute meningitis and intraparenchymal tubercolomas, is highly associated with epilepsy, which is frequently drug resistant. Almost all parasitic infections can be associated with seizures and epilepsy, resulting from a diffuse encephalitis or encephalopathy, or from the intracerebral location of the parasite. Epileptogenesis in neurocysticercosis, which is the major risk factor for acquired epilepsy in endemic regions, involves inflammation, oedema, gliosis, but is also influenced by genetic factors. Epilepsy following cerebral malaria infections is probably the result of vascular lesions and of the release of interleukins involved in the inflammatory reaction to the infection. Toxoplasmosis and fungal infections can be causes of acute seizures and epilepsy among immune-compromised subjects. Different virus infections can result in direct neuronal damage and in the release of pro-inflammatory cytokines with the subsequent activation of the innate and then the adaptive immune response, and can trigger post-infectious encephalitis and encephalomyelitis. Dr Koepp then indicated the main risk factors of developing seizures after a cerebral infection, which relate to the type of pathogen, the degree of cortical involvement, the degree of maturation of the brain, the genetic makeup, and the citokyne-mediated inflammatory response. He concluded his lecture suggesting that the prevention of CNS infections through immunisation and the eradication of parasitic infections by increasing public awareness and improving sanitation is the only effective approach that will reduce the burden of post-infectious epilepsy.
In the final lecture of the session, Dr Bjork from Norway focused on post-traumatic epilepsy, which is responsible for 20% of symptomatic epilepsies. Post-traumatic epilepsy is defined as the occurrence of epilepsy seizures after the first week following a traumatic brain injury. Dr Bjork underlined that the severity of brain injury is the main risk factor for post-traumatic epilepsy, with the risk of post-traumatic epilepsy raising to 12.9% in severe brain injuries and dropping down to 2.6% in mild brain injuries. She added that focal cerebral injuries resulting from depressed skull fractures, penetrating injuries and intracranial hematomas, and those involving temporal lobes are associated with an increased risk of post-traumatic epilepsy. Dr Biork then moved onto the analysis of the main mechanisms linking brain injuries with post-traumatic seizures. She indicated that early post-traumatic seizures result from mechanims such as cortical contusion, axonal shearing and diffuse vascular injury, which develop in the first seconds, hours or early days following the trauma, while post-traumatic epilepsy results from different mechanisms, including hypoxia, edema, exitotoxicity, oxidative stress, neuroinflammation, neurodegeneration and mossy fiber sprouting, which develop over days, months and even years following the traumatic event. Antiepileptic treatments have proven effective in preventing early post-traumatic seizures, but not in treating epileptogenesis and preventing post-traumatic epilepsy. The most recent guidelines for the management of severe brain injury (2017) suggest the use of phenytoin to prevent symptomatic brain seizures within 7 days of severe brain injury, as these may aggravate brain damage. However, despite these recommendations, and although no univocal indication emerges from comparative studies, in real world practice levetiracetam is often preferred to phenytoin in these patients, as it is easier to manage. Several drugs, including anakinra, rapamycin, gabapentin, statins and ceftriaxone, have demonstrated some effects in reducing post-traumatic epilepsy in animal models, but none of these medications has been tested in clinical trials so far. Dr Bjork reminded that the first line choice medications for focal epilepsy are levetiracetam, zonisamide and carbamazepine according to ILAE guidelines, and lamotrigine and carbamazepine according to NICE guidelines, but neurologists should choose the best medication considering the vulnerability of brain injured individuals to negative psychotropic effects and sedation. She concluded her lecture mentioning that surgery for post-traumatic epilepsy should only be considered for carefully selected patients, such as those with temporal focus who usually have good post-surgery outcomes.
