Current Pharmaceutical Design - Volume 23, Issue 42, 2017

An archaic surgical procedure, the skull trepanning, was introduced in ancient Greece to treat brain derangement, and endured until the 18th century with the same use. Hippocrates recognized epilepsy as a common entity and categorized it as a brain disorder, removing any divine origin. He proposed that the excess of black bile and mucus is due to the infiltration of air inside the blood circulation (veins). For him it was a hereditary disease that could be cured. Thus, he suggested a non-invasive treatment based on herbal potions, and a surgical treatment by using the most advanced operation of the era, the open brain drilling, known as trepanning, or trephination, setting the beginning of neurosurgery.

Epilepsy has been known since antiquity and trepanation has been documented as a therapeutic option. The Greek born physician Aretaeus of Cappadocia (2nd century BC) was the first to recommend trepanation for the treatment of refractory epilepsy to drugs, pointing out the efficacy of the method (Fig. 1). Trepanation was practiced throughout the Middle Ages, as it is proved by the book of “Quattuor Magistri” and during Renaissance as well. In 19th century, Sir Victor Alexander Horsley (1857-1916), combining analysis of clinical presentation with cortical stimulation, performed a series of craniotomies for the treatment of epilepsy Fig. 2. In the following years the advent of electrophysiology and neurosurgery provided a fertile ground for further progress in epilepsy surgery such as the preoperative use of electroencephalography (EEG) to determine the epileptogenic zone by Otfrid Foerster (1873–1941); the research of Wilder Graves Penfield (1891–1976) in Montreal Neurological Institute and the use of stereoelectroencephalography (SEEG) by the neurosurgeon Jean Talairach (1911–2007) and the neurologist Jean Bancaud (1921–1994)) Fig. 3. Nowadays, epilepsy surgery remains a valuable therapeutic option in cases of drug resistant epilepsy.

Recurrent, spontaneous seizure activity caused by abnormal neuronal firing in the brain is a hallmark of epilepsy, a common chronic neurological disorder. Recent research that has expanded the knowledge of the cellular and molecular mechanisms that modulate neuronal excitability and network activity in the brain provides the development and discovery of antiepileptic drugs (AEDs). AED therapy starts with the selection of the most appropriate drug for individual patient according to a strategic decision based on the risk-benefit ratio. Beyond three generations of AEDs developed over the last 40 years, more effective, better tolerated, disease-modifying pharmacological therapies are still needed to improve seizure outcome and reduce the safety burden. In this review, we aim to provide a special focus on epilepsy with an overview of underlying pathophysiological mechanisms that may contribute to seizure generation and propagation. Besides, knowledge of principle pharmacological properties of current AEDs which are essential for rational drug therapy is considered. Limited safety data are available especially for recent AEDs, we also discussed their safety profiles concerning major adverse effects, teratogenicity and their use in pregnancy and lactation. Epilepsy is a chronic disorder which needs special knowledge and experience during AED treatment with meticulous follow-up of patients to avoid short and long-term adverse effects with the best possible seizure controlled outcome and high quality of life.

We now get benefit from more than 20 antiepileptic drugs (AEDs) in the care of people with epilepsy. Newer generation of AED is associated with a more favourable tolerability profile than older generation AEDs which makes them easier to use, despite similar efficacy. In order to define the place of newer generation AEDs in the therapy, we review here the main current guidelines about their use for a special issue concerning antiepileptic drugs in neurosurgical practice. We also discuss how to tailor the treatment with newer generation AEDs according to the patient's needs and comorbid conditions. We review different common setting that may require specific therapeutic considerations, i.e. elderly, pregnancy, HIV infection, tumours and hospital/critical care use. We also discuss the current evidence regarding the use of newer generation AEDs in the neurosurgical practice. We present the most recent commercially available newer AEDs (ezogabine, perampanel, brivacetam, everolimus), describing their mechanism of action, adverse effects and indication according to the type of seizure. We finally describe the promising AEDs that are currently under development or testing. This article is a special issue concerning antiepileptic drugs in neurosurgical practice.

Seizure control is a critical component of care in many neurosurgical conditions. The development of seizures in patients without a previously identified seizure disorder occurs in a significant proportion of traumatic brain injury, subarachnoid hemorrhage, and brain tumor patients. In this literature review and synthesis, we will discuss the incidence of seizures in selected conditions, indications and evidence for the initiation of antiepileptic drugs (AEDs), suggested duration of usage for AEDs, and current AED guidelines by the American Academy of Neurology (AAN), Congress of Neurological Surgeons (CNS), American Academy of Neurological Surgeons (AANS) and international committees.

Antiepileptic drugs (AEDs) possess diverse mechanisms of action – enhancement of GABA-mediated events, inhibition of glutamate-mediated excitation, blockade of voltage-dependent sodium or calcium channels being the most frequently shared. They are not only used for the symptomatic management of epilepsy but in the treatment of psychiatric or neurologic disorders (e.g. bipolar disorder, neuropathic pain, prophylaxis of migraine). Generally, this group of drugs is also widely used in neurosurgery patients for the prevention of seizure activity and their effectiveness in this regard has been evaluated in this review. There is no controversy as to whether continue AEDs in patients with epilepsy scheduled for neurosurgery. A question arises on whether AEDs may be recommended to non-epileptic neurosurgical patients for the prevention of post-surgery early or late seizures. There are some positive examples indicating that AEDs may reduce the occurrence of preferably early seizures, some results also being positive in the case of late seizure activity. However, there are also many negative data in this regard. The existence of serious adverse effects and a possibility of pharmacokinetic interactions with the concomitant therapy may further complicate the decision on whether to start the prophylactic use of AEDs. In general, the existing evidence does not support the prophylactic use of AEDs, especially in patients who underwent craniotomy/craniectomy for the inhibition of late seizure activity.

Traumatic brain injury (TBI) is an important public health concern plagued by high rates of mortality and significant long-term disability in many survivors. Post-traumatic seizures (PTS) are not uncommon following TBI, both in the early (within 7 days post-injury) and late (after 7 days post-injury) period. Due to the potential of PTS to exacerbate secondary injury following TBI and the possibility of developing post-traumatic epilepsy (PTE), the medical community has explored preventative treatment strategies. Prophylactic antiepileptic drug (AED) administration has been proposed as a measure to reduce the incidence of PTS and the ultimate development of PTE in TBI patients. In this topical review, we discuss the pathophysiologic mechanisms of early and late PTS and the development of PTE following TBI, the pharmacodynamic and pharmacokinetic properties of AEDs commonly used to prevent post-traumatic seizures, and summarize the available clinical evidence for employing AEDs for seizure prophylaxis after TBI.

Chronic subdural hematoma (CSH) is an accumulation of blood within the intracranial subdural space. It is associated with minor traumatic events and affects mostly the elderly. CSH can be effectively treated surgically with good outcomes, although the recurrence rate is high. Epileptic seizures are one of the major complications associated with CSH, either in the pre or postoperative period. The incidence rate of new onset seizures after CSH diagnosis ranges between 3% and 23%. However, the benefit of using prophylactic antiepileptic drugs in these patients is controversial with significant variations in clinical practice. It ranges from routine to total absence of use in this clinical context. The best current evidence does not allow any firm conclusion on whether such prophylactic treatment is effective, that is if it prevents the development of epileptic seizures. Furthermore, these drugs are associated with important adverse events. A systematic literature review found no controlled randomized trials evaluating the risk/benefit of the prophylactic use of anticonvulsants for people with CSH and retrospective studies showing contradictory results. Moreover, these observational studies are outdated and do not evaluate new generation drugs. Herein, we discuss the evidence for the use of antiepileptic drugs for preventing seizures in patients with CSH, with a particular focus on the subgroup of people most likely to benefit (such as the elderly and alcohol abusers), as well as the possible safety advantages of the new antiepileptic drugs.

Aneurysmal subarachnoid hemorrhage (aSAH) and spontaneous intracranial hemorrhage (ICH) are frequently associated with epileptic complications. The use of anti-epileptic drugs (AEDs) for seizure prophylaxis, however, is controversial. In patients with aSAH, nonconvulsive status epilepticus has been associated with poor outcome. Effect of other forms of less severe epileptiform activity on clinical outcome remains unclear. Evidence on efficacy of AEDs in reducing seizure incidence is also mixed. However, increasing number of studies suggest that AEDs may have significant adverse effects on outcome, especially with phenytoin. Similarly, in patients with ICH, the impact of seizures that do not progress to status epilepticus on clinical outcome is controversial, and whether prophylactic AED use has independent effects on outcome remains ambiguous. Currently, there are no large scale randomized control trials investigating the efficacy and safety of AED prophylaxis in patients with hemorrhagic stroke. There are also no trials comparing the efficacy and safety of the different AEDs. Survey based studies have found a wide range of prescribing patterns across treatment centers and clinicians for seizure prophylaxis in patients with hemorrhagic stroke. The lack of clear guidelines and recommendations also highlights the paucity of good quality evidence in this area. In conclusion, a well-designed randomized, double blinded, and appropriately powered trial is needed to evaluate the incidence as well as clinical outcomes in patients with aSAH and ICH who received AED prophylaxis versus controls. The results will be extremely valuable in providing evidence to establish management guidelines for patients with hemorrhagic stroke.

Background: Antiepileptic treatment strategy plays an important role in the management of intracranial vascular malformations. The intracranial vascular malformations can be divided into cavernous hemangiomas, arteriovenous malformations, developmental venous anomalies and capillary telangiectasias. Seizures and hemorrhage are among their most common clinical manifestations. Objective: The aim of this article is to review the current literature on the antiepileptic treatment in the setting of intracranial vascular malformations and offer an updated view on when antiepileptic drug treatment should be employed for each type of vascular malformation. Methods and Materials: Current literature has been reviewed on cavernous malformations, arteriovenous malformations, developmental venous anomalies and capillary telangiectasias. Epidemiological features, epileptogenesis, clinical presentation and antiepileptic treatment have been analyzed. Results: A variety of treatment modalities exist for the management of intracranial vascular malformations, including antiepileptic treatment, microsurgery, radiosurgery and embolization. The decision-making process is different for each type of intracranial vascular malformation. Moreover, a plethora of other clinical factors needs to be taken into consideration during the decision-making process, such as the patient's age and comorbidities, the risk of hemorrhage the need for definitive treatment of the malformation, the seizure rates after the definitive treatment, the efficacy and side effects profile of antiepileptic drugs. Conclusion: Antiepileptic treatment strategy is a multifactorial decision that should be individualized and ideally be made by multidisciplinary teams.

In cancer, epilepsy can be the manifestation of a primary brain tumour, metastatic disease, vascular or surgical complications, opportunistic infection or secondary to anti-tumour therapy. Seizures are frequently the first symptom of a brain tumour. The epilepsy is related to elevated extracellular glutamate stimulating NMDAand AMPA-receptors and to the formation of D-2HG which resembles glutamate in IDH1 mutated gliomas. Epilepsy as presenting sign is associated with a longer survival in low- and high- grade gliomas, particularly with the IDH1 mutation. Anti-tumour treatment by surgery, radiotherapy or chemotherapy strongly contributes to seizure control. Symptomatic management of brain tumour-related epilepsy (BTE) by evidenced-based anti-epileptic drugs (AEDs) as indicated for focal epilepsy depends on individual patient factors including age, sex, weight, co-morbidity and cotherapy. Levetiracetam followed by lacosamide or valproic acid are the agents of choice. Both can be combined with levetiracetam in case monotherapy is inactive or produces side-effects. Lamotrigine, perampanel, zonisamide or clobazam are other good choices. On seizure prophylaxis, there is some evidence for its application in the peri-operative period. The most prevalent side-effects of AEDs in neuro-oncology are cognitive dysfunction, bone marrow toxicity and skin hypersensitivity. Combining anti-epileptic drugs with chemotherapy, tyrosinekinase inhibitors or steroids increases the risks of drug-drug interactions. Plasma monitoring of AEDs for detecting drug insufficiency, interactions or toxicity helps in choosing the proper dose regimen. For practical use, tables on drug interactions between AEDs and cancer therapy are added together with a guideline on the medical management of seizure control including dose regimens.

Background: Epileptic seizures are a relatively common problem in pediatric neurosurgery that can have physical, mental and/or behavioral implications. Pediatric neurosurgery is involved in the treatment of secondary epilepsy, which is mainly associated with brain tumors, traumatic brain injury and intracranial vascular malformations. Objective: The aim of this article is to review the current literature for commonly used antiepileptic drugs in pediatric neurosurgery and offer an updated view on epilepsy treatment with antiepileptic drugs in the most commonly encountered neurosurgical entities in the pediatric population. Methods and Materials: Current literature has been reviewed for epilepsy, antiepileptic drugs and common neurosurgical conditions in children that cause seizures and/or epilepsy. Epidemiological features, epileptogenesis and treatment have been thoroughly examined. Conclusion: The most common neurosurgical conditions that cause seizures and/or epilepsy in the pediatric population are brain tumors and traumatic brain injury. Newer antiepileptic drugs are powerful instruments in the management of epilepsy and they improve the quality of life of patients as well as decrease the epilepsy associated morbidity.

Post-epilepsy surgery antiepileptic drug discontinuation (AED) practices remain unclear and little evidence about the optimum timing exists. In the present study, we reviewed the types of surgery for epilepsy and their outcome. The current concepts for discontinuation of AED after surgery are presented and all contributing factors that should be taken into consideration are discussed.

Surgery for epilepsy dates back to 1886 and has undergone significant developments. Today it is considered a key treatment modality in patients who are resistant to pharmacological intervention. It improves seizure control, cognition and quality of life. New technologies, advances in surgical technique and progress in scientific research underlie the expansion of surgery in epilepsy treatment. Effectiveness of surgical treatment depends on several factors including the type of epilepsy, the underlying pathology and the localisation of the epileptogenic zone. Timely referral to an experienced epilepsy surgery centre is important to allow the greatest chance of seizure control and to minimise associated morbidity and mortality. Following referral, patients undergo thorough presurgical investigation to evaluate their suitability for surgery. The commonest form of epilepsy treated by surgery is mesial temporal lobe sclerosis and there is Class I evidence for the medium-term efficacy of temporal lobe resection from two randomised control trials. Various other forms of epilepsy are now considered for resective and neuromodulatory surgical intervention due to favourable results. In this article, the authors review the current status of surgical treatment for epilepsy including the presurgical evaluation of patients, surgical techniques and the future directions in epilepsy surgery.

Background: Epilepsy is a common condition with up to 1% prevalence in the general population. In the perioperative course of neurologic surgery patients, the use of prophylactic and therapeutic antiepileptic drugs is a common practice. Nonetheless, there is limited evidence supporting the use of prophylactic antiepileptics to prevent perioperative seizures and there are no guidelines for which anesthetic technique is preferred. Objective: To discuss the seizurogenic potential of anesthetic drugs and to discuss intraoperative seizures in neurosurgical patients. Method: We performed a search of the literature available in PubMed and Ovid MEDLINE. We also included articles identified in the review of the references of these articles. Results: The incidence of seizures is heterogenic among neurosurgical patients. Seizure prophylaxis is widely administered despite limited available evidence of its effectiveness. In epileptic patients, the recommendation is to continue antiepileptic drugs in the perioperative setting. In these patients, anesthesiologists may also limit the use of medications that alter the seizure threshold and avoid medications that pose significant pharmacological interaction with antiepileptic drugs. Conclusion: In conclusion, a knowledgeable multidisciplinary perioperative team is essential to avoid, identify and treat intraoperative seizures competently. In patients with a history of epilepsy it is recommended to continue antiepileptic therapy. Therefore, clinical judgment should guide the decision of administering seizure prophylaxis in neurosurgery patients according to an individual assessment of potential risk for seizures. Furthermore, there is a need for randomized controlled trials that support new protocols and/or guidelines for anesthetic and perioperative regimens to prevent and treat intraoperative seizures.

The etiology of seizures in the Neurosurgical/Neurological Intensive Care Unit (NICU) can be categorized as emanating from either primary brain pathology, at either macro- or microscopic level, or from physiological derangements of critical care illness such as toxic or metabolic abnormalities. Particular etiologies at risk for seizures include ischemic or hemorrhagic stroke and traumatic brain injury. The use of prophylactic antiepileptic drug administration remains controversial in many situations, with most of the larger studies having used older antiepileptic drugs prophylactically. If seizures do occur, patients are typically treated with parenteral antiepileptic drugs. The duration of treatment is unknown in most situations, but it should be individualized depending on acute and monophasic injury versus chronic process. Late seizures, which occur after the first 2 weeks from the insult, have a more ominous risk for subsequent epilepsy and should be treated for extended periods of time or indefinitely. Electrolyte and glucose abnormalities and medications at high or low levels, when corrected, usually lead to seizure control. This review discusses the risk for seizures with commonly encountered types of brain injuries in the NICU and ends by examining the treatment algorithms for simple seizures and status epilepticus and the role newer antiepileptics may potentially play.