POST-TRAUMATIC SEIZURES AND EPILEPSY: THERAPEUTIC CONSIDERATIONS

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2 POST-TRAUMATIC SEIZURES AND EPILEPSY: THERAPEUTIC CONSIDERATIONS NATHAN D. ZASLER, MD, FAAPM&R, FACRM, FIAIME, DAIPM, CBIST CEO AND MEDICAL DIRECTOR, CCCV, LTD. AND TOLS, INC. AFFILIATE PROFESSOR, DEPARTMENT OF PM&R, VCU, RICHMOND, VIRGINIA ASSOCIATE PROFESSOR, DEPARTMENT OF PM&R, UVA, CHARLOTTESVILLE, VIRGINIA 2016 AAPM&R ANNUAL CONFERENCE

3 DISCLOSURES Dr. Zasler is CEO and Medical director of the Concussion Care Centre of Virginia, LTD and Tree of Life Services Inc. in Richmond, Virginia and receives a salary as well as distributions from same. He also engages in consultative work including both educational and medicolegal. On scientific advisory board of Intendu, Inc. CEO of Tremorless, Inc.

4 PTE AND TBI: THERAPEUTIC CONSIDERATIONS Although, we as neurorehabilitationists regularly encounter patients after TBI with PTE there is often a lack of understanding regarding various aspects of management. There remain controversies and unanswered questions germane to PTE and TBI. Guidelines for management are lacking for most aspects of care. Most therapeutic decisions are modeled based on data derived from general epilepsy populations.

5 PTE AND TBI: THERAPEUTIC CONSIDERATIONS Ultimately, we need to be able to choose drugs that are best at controlling epilepsy while optimizing compliance and minimizing adverse side-effects. Understanding each drug and its pros and cons is important when recommending treatment. There is a need for knowing what labs may be relevant dependent on the medication being used. Newer treatment approaches that go beyond drug therapy must also be appreciated.

6 THERAPEUTIC CONSIDERATIONS Drugs for PTE is there a drug of choice? Patient profiling when prescribing AEDs after TBI what should you consider? Duration of AED therapy is there ever a safe time to stop? Lab testing with AED therapy when, what and why.

7 THERAPEUTIC CONSIDERATIONS When is AED drug resistance diagnosed? How many is too many AEDs? What adjutant therapies should be considered for PTE? What are other treatment options for PTE?

8 DRUGS FOR PTE: IS THERE A DRUG OF CHOICE? There is no drug of choice for PTE acute or otherwise. DPH and LTR most studied for early prophylaxis. Efficacy comparisons of AEDs have shown no clear advantage for one therapy over another in long term management of epilepsy in general. Cannot predict whether a given AED will be effective in a particular patient. Emphasis should be on tolerability and safety.

9 DRUGS FOR PTE: IS THERE A DRUG OF CHOICE A meta-analysis by Zafar et al (2012) found that there was no drug that was superior in preventing early seizures. GBP may have a neuroprotective effect and may also decrease excitatory synapse formation (Li et al, 2012). Choose a drug with a spectrum of activity, side-effect and interaction profile that has the potential to produce seizure freedom without long term adverse effects and allow for optimal compliance.

10 NEWER AEDs: ARE THEY BETTER? Newer AEDs have shown no better efficacy than the older generation agents in controlling epilepsy. Newer agents are easier to use and have better pharmacokinetic profiles. Newer agents have fewer drug interactions and less teratogenicity. Newer agents have demonstrated less hypersensitivity reactions.

11 NEWER AEDs: ARE THEY BETTER? Newer agents have less long-term side effects. Newer agents generally don t require hematological, hepatic or drug level laboratory monitoring. Research has indicated that newer agents for adjunctive treatment of epilepsy have not really made any substantive difference in overall degree of seizure control in management of epilepsy regardless of mechanism of action.

12 INITIAL MONOTHERAPY RECOMMENDATIONS Based on consensus, symptomatic localization-related epilepsies and symptomatic generalized tonic-clonic seizures are best treated with carbamazepine, oxcarbazepine, with lamotrigine and/or levetiracetam usually appropriate as well. Symptomatic localization related epilepsies with complex partial seizures are best treated by carbamazepine, lamotrigine and oxcarbazepine with levetiracetam usually being appropriate as well. Women who are pregnant or trying to conceive should be treated with lamotrigine as should the elderly (can also consider levetiracetam or gabapentin in elderly).

13 PATIENT PROFILING WHEN PRESCRIBING AEDs AFTER TBI Is the seizure a neurogenic event? Is it focal or generalized in onset? Were there obvious precipitant(s)? What behavioral or affective issues,if any, are also present? What is the patient s cognitive status? Is pain an issue? Is dyssomnia an issue? Is obesity an issue?

14 PATIENT PROFILING WHEN PRESCRIBING AEDs AFTER TBI Lamotrigine is not a good choice if there is a history of rash or hypersensitivity reaction. Cross sensitivity exists between phenytoin and carbamazepine. Levetiracetam, gabapentin, pregabalin and valproate have low risk of hypersensitivity.

15 PATIENT PROFILING WHEN PRESCRIBING AEDs AFTER TBI Valproate, gabapentin, pregabalin, carbamazepine and ezogabine have weight gain risk. Topiramate and zonisamide may cause weight loss. Levetiracetam, gabapentin and pregabalin are exclusively renally cleared. Existing data does not seem to support consideration of MOAs as a criterion for choosing an AED whether with monotherapy or as an add-on therapy

16 DURATION OF AED THERAPY: IS THERE EVER A SAFE TIME TO STOP? If a patient with TBI has a late seizure it is likely they will have another one. Risks for seizure recurrence: Multiple or clustered seizures Abnormal cerebral imaging Abnormal EEG (epileptiform discharges) Abnormal interictal neurological exam Status epilepticus at onset Partial seizures Missile injury Mixed seizure types Medication non-compliance

17 STOPPING AEDS Good control with AEDs does not indicate that one can safely cease AED treatment. Patients in long-term remission have a fairly high rate of relapse in the first 2 years after cessation of treatment in general epilepsy studies. The more severe and long lasting a patient s active epilepsy was before remission the greater the risk of relapse.

18 STOPPING AEDs General rule of thumb is patient should be seizure free for 2-5 years depending on the type of epilepsy. Preference is for a normalized EEG prior to withdrawal. If someone is driving would recommend avoiding driving for 3 months while discontinuation taking place.

19 STOPPING AEDs Discontinuation should last 6-12 months No good data per se for PTE specifically. May also opt to wean medication even in a patient with established epilepsy if: pregnancy is an issue side effects are intolerable patient unable to find a job while on AEDs *consider alternative treatments including surgery.

20 TO TREAT OR NOT TO TREAT Treat if acute or remote symptomatic seizure as with history of TBI, clinically unstable patient and/or with seizure related complications such as aspiration. Recommend treatment when risk of recurrence is likely, second seizure may be dangerous, and/or benefits to patient outweigh risk of having seizure as related to driving clearance, work maintenance, etc. No treatment if patient/guardian refuse and have understanding of potential consequences or low risk for recurrence.

21 LAB TESTING WITH AED THERAPY: WHEN, WHAT AND WHY With most newer agents lab testing is not necessary. Certain agents including phenytoin and carbamazepine related compounds have been associated with hyponatremia. Lab testing may still be indicated to assure lack of relative toxicity and/or medication compliance. With drugs that are hepatically metabolized LFT panel should be done at least annually. Physicians should be aware of uncommon side effects with AEDs such as hyperammonemia with valproic acid.

22 AED DRUG RESISTANCE Traditionally, therapeutic failure was historically defined as failure of three sequential AED trials. Several prospective case series have shown that a high likelihood of medical intractability is associated with two unsuccessful trials. With each AED failure, likelihood of successful treatment with other drugs diminishes. Assumes AED appropriately chosen and administered, whether as monotherapy or in combination.

23 AED DRUG RESISTANCE Most PTE can be controlled with medication. A switch to a second agent for those not controlled on the first achieves success in only a minority of patients. A switch to a third AED in those not controlled on the first two has a low rate of controlling PTE.

24 AED DRUG RESISTANCE Drug resistance can usually be assessed within 6-12 months. Average time to epilepsy surgery after diagnosis of drug resistance is 15 years based on recent studies. Risk of SUD is about 1 in per year in association with persistent uncontrolled epilepsy. Risk of recurrent TBI increases with uncontrolled PTE.

25 HOW MANY IS TOO MANY AEDs TO CONTROL PTE? General epilepsy literature shows that addition of a second AED may further improve seizure control. Adding a third agent has minimal benefit for additional seizure control Adding a fourth agent has little to no benefit in improving seizure control.

26 GENERAL GUIDELINES FOR POLYTHERAPY General rule of thumb is to initiate patient on AED monotherapy and if that fails a second monotherapy should be tried. If the second monotherapy fails, then expert consensus is divided between trying a third monotherapy or attempting a combination therapy with 2 drugs. By consensus, failure at that stage requires moving to a dual therapy regimen. If dual therapy regimen fails then there is a lack of consensus on how to proceed.

27 RATIONAL POLYTHERAPY First consider AED to AED interactions: Valproate and Lamotrigine (Lamotrigine level may triple although synergism in combination has been reported). Topiramate, Lamotrigine or Zonisamide with enzyme inducers such as carbamazepine where dose needs to be higher due to increased clearance as a result of enzyme induction. Try to avoid combinations of AEDs with similar side effects. Will often need to reduce the original dose of one of the AEDs for better tolerance of the combination.

28 RATIONAL POLYTHERAPY When epilepsy proves refractory in some cases polypharmacy is inevitable. Eliminate drugs which are deemed ineffective to allow increased dosing of newer agents, avoidance of drug drug interactions and reduction in her overall drug burden. Withdrawal of ineffective agents should always be done slowly and after new drug has been uptitrated. Even ineffective drug withdrawal can trigger seizures or status epilepticus.

29 POLYTHERAPY IN EPILEPSY AND PTE There is a wide range of combinations of 2 or perhaps 3 AEDs that can be effective in some patients with epilepsy including PTE Given the number of individual AEDs currently available on the market, there are more than 200 possible dual therapies and more than 1000 triple therapy regimens. Recent literature suggests that approximately 5% more patient s per year will be seizure free with polytherapy.

30 POLYTHERAPY IN EPILEPSY AND PTE The majority of seizure-free patient s on polytherapy were: On 2 antiepileptic drugs Most common dual therapy that has shown efficacy was with lamotrigine and sodium valproate Most successful regimens involving 3 agents include: Lamotrigine plus topiramate plus sodium valproate Levetiracetam plus lamotrigine plus sodium valproate

31 POLYTHERAPY VS. MONOTHERAPY Surprisingly, adverse effects do not seem to differ between monotherapy and polytherapy patients. Adverse effects do not seem to correlate with AED load questionably secondary to physician intervention in individualizing treatment regimens. Adverse effects of AEDs seemed to be determined more by individual susceptibility, type of AED used and physician skills.

32 ADJUTANT THERAPY: LIFESTYLE CHANGES Minimize stress and anxiety. Avoid heavy drinking. Avoid illicit drug use. Avoid prescription medicines such as antidepressants, antipsychotic medication that may lower seizure threshold. Get good restorative sleep. Eat regular meals to avoid low blood sugar. Avoid physiological and psychological stressors as possible.

33 ADJUTANT THERAPY: DIETARY CHANGES The ketogenic diet is a special high-fat, low-carbohydrate diet that helps to control seizures in some people with epilepsy. Doctors usually recommend the ketogenic diet for children whose seizures have not responded to several different seizure medicines. The typical ketogenic diet, called the "long-chain triglyceride diet," provides 3 to 4 grams of fat for every 1 gram of carbohydrate and protein. Several studies have shown that the ketogenic diet does reduce or prevent seizures in many children whose seizures could not be controlled by medications.

34 ADJUTANT THEAPY: DIETARY CHANGES Doctors usually recommend the ketogenic diet for children whose seizures have not responded to several different seizure medicines. It is particularly recommended for children with the Lennox-Gastaut syndrome. The diet is usually not recommended for adults, mostly because the restricted food choices make it hard to follow. Yet, studies done on the use of the diet in adults show that it seems to work just as well.

35 ADJUTANT THERAPY: DIETARY CHANGES The modified Atkins diet (often abbreviated in the literature as MAD ) is a change to the traditional classic ketogenic diet to make it less restrictive. Along with the MCT (medium chain triglyceride) diet and LGIT (low glycemic index treatment), it is one of three alternative diets used to treat patients with epilepsy. The low glycemic index treatment (LGIT) for epilepsy was developed in 2002 as an alternative to the ketogenic diet (KD) for treatment of intractable epilepsy. The LGIT monitors not only the total amount of carbohydrates consumed daily, but focuses on carbohydrates that have a low Glycemic Index.

36 WHAT ARE OTHER TREATMENT OPTIONS FOR PTE? Neuromodulation: VNS RNS/CRS TNS DBS Stem cell transplantation??? Neurosurgical interventions

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38 VAGAL NERVE STIMULATION Vagus nerve stimulation (VNS Therapy ) is designed to prevent seizures by sending regular, mild pulses of electrical energy to the brain via the vagus nerve. These pulses are supplied by a device something like a pacemaker. The VNS device is sometimes referred to as a "pacemaker for the brain." It is placed under the skin on the chest wall and a wire runs from it to the vagus nerve in the neck. The vagus nerve is part of the autonomic nervous system, which controls functions of the body that are not under voluntary control, such as the heart rate. The vagus nerve passes through the neck as it travels between the chest and abdomen and the lower part of the brain.

39 VAGAL NERVE STIMULATION The physician programs the strength and timing of the impulses according to each patient's needs. The settings can be programmed and changed by placing a wand which is connected to a handheld computer over the generator on the left side of the chest. For all patients, the device is programmed to go on (give stimulation) for a certain period and then to go off for another period. The device is set to give stimulation at regular intervals during the day, usually with 30 seconds of stimulation alternating with 5 minutes of no stimulation.

40 VAGAL NERVE STIMULATION The patient is usually not aware that it's operating. Holding a special magnet near the implanted device (generator) triggers the device to deliver another burst of stimulation, outside of the programmed intervals. For people with warnings (auras) before their seizures, activating the stimulator with the magnet when the warning occurs may help to stop the seizure. The battery for the stimulator lasts approximately 5-10 years, depending on the settings used. The VNS implant devices are built by LivaNova

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42 RESPONSIVE NEUROSTIMULATION Responsive neurostimulation is a new approach to treating medically uncontrolled partial onset seizures. The RNS System is the first device to provide responsive neurostimulation, automatically monitoring brain signals and providing stimulation to abnormal electrical events just when it is needed. The system is approved by the U.S. Food and Drug Administration (FDA) as an adjunctive treatment for adults with medically refractory partial seizures that come from one or two seizure targets identified by the treating doctor. The RNS Neurostimulator is placed under the scalp and within the skull by a surgeon. One or two leads are then placed at the seizure target and connected to the neurostimulator.

43 RESPONSIVE NEUROSTIMULATION After the scalp heals, the neurostimulator should not be noticeable to others. The neurostimulator continuously monitors the brain s activity and is programmed by the epilepsy doctor to detect and record specific patterns that could lead to a seizure. When these patterns are detected, the neurostimulator responds with brief pulses of stimulation intended to disrupt the abnormal brain activity before a seizure occurs. Detection and stimulation settings are individualized for each patient s patterns and so that stimulation is not felt. Each patient gets a take-home monitor so that brain activity data can be sent to the epilepsy doctor between office visits.

44 RESPONSIVE NEUROSTIMULATION Although not a cure for epilepsy, treatment with the RNS System reduces seizures in most patients. Prospective clinical trials have demonstrated median seizure frequency reductions of 44% at one year, 53% at two years, and seizure reductions ranging from 60 to 66% three to six years post-implant. The RNS System is manufactured by NeuroPace, Inc.

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46 EXTERNAL TRIGEMINAL NERVE STIMULATIOIN External Trigeminal nerve stimulation is a non-invasive neuromodulation therapy. External Trigeminal nerve stimulation has been shown to associated with significant within-groups improvements in seizure control and also with significant improvements in mood, as measured by the Beck Depression Inventory (p = 0.03, Wilcoxon). NeuroSigma, the exclusive licensee and manufacturer of the Monarch TM etns TM System, has received European approval for the treatment of epilepsy in adults and children 9 years and older, as well as Canadian approval. etns is still investigational in the USA.

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48 DEEP BRAIN STIMULATION Deep brain stimulation (DBS) is a medical therapy in which an implanted device delivers electrical stimulation to regions deep in the brain. The use of DBS to treat epilepsy is in the early stages of research. A programming computer allows the doctor to adjust the stimulation intensity and rate, along with other settings, from outside the body. Settings are adjusted to maximize benefit and minimize any side effects related to the stimulation.

49 DEEP BRAIN STIMULATION Evidence from animal studies shows that the delivery of electrical stimulation to certain brain targets can sometimes stop seizure related electrical hyperactivity. ending seizure symptoms. The target areas for stimulation involve the cerebellum, caudate, thalamus, mamillary nuclei, anterior nucleus of the thalamus, and subthalamic nucleus. Most of the evidence supporting DBS to treat epilepsy is derived from uncontrolled studies, Research on DBS in humans with epilepsy that has targeted the centromedian nucleus of the thalamus, the anterior nucleus of the thalamus, and the subthalamic nucleus has shown that some reduction in the severity or frequency of seizures.

50 NEUROSURGICAL INTERVENTIONS Resection techniques including lesionectomy, lobectomy, hemispherectomy and corticectomy generally yield the best surgical results for epilepsy. Disconnection techniques including callosotomy, subpial transection and augmentation (cerebellar and vagal stimulation) techniques remain worthwhile considerations. Primary objective of most epilepsy surgical procedures is to accurately localize and then completely excised the epileptogenic focus without causing cognitive or neurologic deficit.

51 NEUROSURGICAL INTERVENTIONS A major factor in assessing surgery risk is the relationship of the lesion to functionally important for eloquent brain regions because injury to these areas can cause irreversible neurologic impairment. Pre-and intraoperative techniques to optimize surgical resection while minimizing risk of injury to functional cortex are utilized including cortical mapping, subdural grid electrodes, intraoperative stimulation, somatosensory evoked potentials, functional MRI, magnetoencephalography, positron emission tomography.

52 NEUROSURGICAL INTERVENTIONS A sub-pial resection approach is utilized using suction or cavitron so that the pia remains intact over the adjacent gyri with the intent to form a nonscarring barrier preserving blood supply to the remaining cortex. Some centers use post-resection cortical EEG recordings and may carry out further surgical intervention if considerable epileptic activity remains at the resection margins.

53 CONCLUSIONS PTE managment is complex and rife with unanswered questions that require further formal prospective, blinded studies. Clinicians working with patient s post-tbi should take the time to familiarize themselves with PTE management and its many facets.

54 CONCLUSIONS It is critical to stay up to date with PTE literature given the potential significant disability associated with this episodic neurological disorder. All clinicians working with patients with TBI should be aware of treatment options including non-pharmacological ones and know where to refer patients for same.

55 Thank You NATHAN ZASLER, MD