Clinical Approach to Posttraumatic Epilepsy
Clinical Approach to Posttraumatic Epilepsy
The neurologic community has come a long way since the days when trephination was the mainstay of treating PTE. There is growing awareness of the clinical heterogeneity of PTE, and optimal treatment can involve pharmacological and surgical options. Medical treatment is usually pursued first, and clinicians must therefore decide when to treat and with which drug. Unnecessary treatment with AEDs may impair neurorehabilitation after TBI, and patients with post-TBI PNES should be treated with antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), and/or cognitive–behavioral therapy (CBT) rather than AEDs. After the diagnosis of PTE is confirmed, the necessity of pharmacotherapy depends on the temporal relationship between onset of seizures and the inciting TBI.
Convulsions are reasonably common in the immediate aftermath of concussive head trauma, and the pathogenesis may relate to brainstem dysfunction secondary to biomechanical forces inducing transient functional decerebration. In a cohort of 22 Australian rugby players, concussive convulsions did not result in development of PTE over a mean follow-up of 3.5 years. The prognosis is therefore thought to be universally excellent, and there is widespread agreement that AED therapy is not indicated.
Chronic AED treatment is indicated after a first late seizure due to the high risk of recurrence. Principles of AED selection in PTE mirror those for other patients with epilepsy, and standard AEDs should all be effective. In many cases, given the paucity of evidence for superior efficacy of one AED over another, AEDs are primarily selected based on consideration of the patient's comorbidities and the drug's spectrum of activity, anticipated side effects, titration rate, dosing schedule, cost, and potential for drug-drug interactions. There is no doctrine on duration of AED therapy, and much depends on a patient's age, personal preference, and drug tolerability. However, as a rule of thumb, AED withdrawal can be considered after at least 2 years of seizure-freedom, though waiting up to 4 years has been suggested as well.
Despite the development of over 15 third-generation AEDs since the 1980s, 30 to 40% of patients with epilepsy have seizures that are incompletely controlled with medications alone. Medical intractability is predicted after failure of two antiepileptic drugs, and poor prognostic factors include the presence of structural cerebral abnormalities, such as can be seen in PTE. In some medically refractory patients, surgical resection of the epileptogenic tissue is highly effective, and recent evidence supports early consideration of surgical treatment. A patient's candidacy for resective surgery hinges on precise seizure localization by cVEEG and neuroimaging, and the likelihood of seizure-freedom depends on temporal versus extratemporal ictal onset and on the presence or absence of an identifiable lesion. Although epilepsy surgery remains underutilized overall, the frequent presence of focal cerebral pathology in patients with PTE often prompts consideration of surgical options. For example, mesial temporal sclerosis (MTS) is a common pathology in PTE despite the presence of multifocal injury. Rates of seizure freedom in selected patients with mesial temporal lobe epilepsy (MTLE) who undergo temporal lobectomy can be as high as 80 to 90%, and patients with posttraumatic MTLE may therefore be particularly good candidates for epilepsy surgery. Indeed, surgical outcomes for MTLE are comparable between traumatic and nontraumatic patient populations. Patients with PTE of neocortical origin are less ideal surgical candidates, but those with focal encephalomalacia can have good outcomes with electrocorticography-guided resections.
Enthusiasm for surgical resection in patients with medically refractory PTE should be tempered by several considerations: (1) As a group, patients with PTE have seizure foci that are difficult to localize accurately, partly due to technical issues related to prior craniotomies and breach rhythms and because of frequent involvement of the frontal lobes; (2) TBI frequently produces diffuse cerebral injury, which can result in multifocal epilepsy and/or seizure-onset zones that overlap with eloquent brain regions; and (3) scar tissue and adhesions related to the inciting trauma can increase the risk for surgical complications.
For patients with medically refractory PTE who are poor candidates for definitive resection, vagus nerve stimulation (VNS) should be considered for adjunctive treatment. Vagus nerve stimulation involves a device implanted in the neck for open-loop peripheral stimulation of the vagus nerve, which is thought to provide indirect seizure control via retrograde brain inhibition. Although prospective clinical trial data in patients with PTE are lacking, one case-control study found that VNS was associated with greater reduction in seizure frequency in patients with PTE than in patients with non-PTE at 2 years of follow-up (78% vs. 61% of patients with > 50% reduction in seizure frequency).
More recently, a direct form of neuromodulation, called responsive neurostimulation (RNS), has emerged as a promising therapy for patients with medically refractory epilepsy. Unlike VNS, the RNS system functions in a closed-loop manner, detecting incipient seizure activity with implanted intracranial electrodes and then counterstimulating to terminate seizures via a small, programmable neurostimulator seated in a skull cassette. Optimal candidates for RNS are adults with multifocal seizure onsets and/or seizure foci that are not amenable to surgical resection due to overlap with eloquent brain regions. Over 2 years of follow-up, more than half of patients with RNS experienced at least a 50% reduction in seizure frequency. A related technology, deep brain (anterior thalamic nucleus) stimulation, has been approved in several countries and may soon be available in the United States. Although not without controversy, neurostimulation for epilepsy continues to evolve rapidly, expanding the clinician's armamentarium for treating medically refractory PTE. A strategy for navigating the various diagnostic and treatment options in PTE is outlined in Fig. 1, which expands upon a previously proposed algorithm.
(Enlarge Image)
Figure 1.
An algorithm for the management of posttraumatic epilepsy. AED, antiepileptic drug; CBT, cognitive–behavioral therapy; CT, computed tomography; cVEEG, continuous video-electroencephalography; LEV, levetiracetam; MRI, magnetic resonance imaging; PHT, phenytoin; PNES, psychogenic nonepileptic spell; PTE, posttraumatic epilepsy; RNS, responsive neurostimulation; SSRI, selective serotonin reuptake inhibitors; TBI, traumatic brain injury; VNS, vagus nerve stimulation.
Management
The neurologic community has come a long way since the days when trephination was the mainstay of treating PTE. There is growing awareness of the clinical heterogeneity of PTE, and optimal treatment can involve pharmacological and surgical options. Medical treatment is usually pursued first, and clinicians must therefore decide when to treat and with which drug. Unnecessary treatment with AEDs may impair neurorehabilitation after TBI, and patients with post-TBI PNES should be treated with antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), and/or cognitive–behavioral therapy (CBT) rather than AEDs. After the diagnosis of PTE is confirmed, the necessity of pharmacotherapy depends on the temporal relationship between onset of seizures and the inciting TBI.
Convulsions are reasonably common in the immediate aftermath of concussive head trauma, and the pathogenesis may relate to brainstem dysfunction secondary to biomechanical forces inducing transient functional decerebration. In a cohort of 22 Australian rugby players, concussive convulsions did not result in development of PTE over a mean follow-up of 3.5 years. The prognosis is therefore thought to be universally excellent, and there is widespread agreement that AED therapy is not indicated.
Chronic AED treatment is indicated after a first late seizure due to the high risk of recurrence. Principles of AED selection in PTE mirror those for other patients with epilepsy, and standard AEDs should all be effective. In many cases, given the paucity of evidence for superior efficacy of one AED over another, AEDs are primarily selected based on consideration of the patient's comorbidities and the drug's spectrum of activity, anticipated side effects, titration rate, dosing schedule, cost, and potential for drug-drug interactions. There is no doctrine on duration of AED therapy, and much depends on a patient's age, personal preference, and drug tolerability. However, as a rule of thumb, AED withdrawal can be considered after at least 2 years of seizure-freedom, though waiting up to 4 years has been suggested as well.
Despite the development of over 15 third-generation AEDs since the 1980s, 30 to 40% of patients with epilepsy have seizures that are incompletely controlled with medications alone. Medical intractability is predicted after failure of two antiepileptic drugs, and poor prognostic factors include the presence of structural cerebral abnormalities, such as can be seen in PTE. In some medically refractory patients, surgical resection of the epileptogenic tissue is highly effective, and recent evidence supports early consideration of surgical treatment. A patient's candidacy for resective surgery hinges on precise seizure localization by cVEEG and neuroimaging, and the likelihood of seizure-freedom depends on temporal versus extratemporal ictal onset and on the presence or absence of an identifiable lesion. Although epilepsy surgery remains underutilized overall, the frequent presence of focal cerebral pathology in patients with PTE often prompts consideration of surgical options. For example, mesial temporal sclerosis (MTS) is a common pathology in PTE despite the presence of multifocal injury. Rates of seizure freedom in selected patients with mesial temporal lobe epilepsy (MTLE) who undergo temporal lobectomy can be as high as 80 to 90%, and patients with posttraumatic MTLE may therefore be particularly good candidates for epilepsy surgery. Indeed, surgical outcomes for MTLE are comparable between traumatic and nontraumatic patient populations. Patients with PTE of neocortical origin are less ideal surgical candidates, but those with focal encephalomalacia can have good outcomes with electrocorticography-guided resections.
Enthusiasm for surgical resection in patients with medically refractory PTE should be tempered by several considerations: (1) As a group, patients with PTE have seizure foci that are difficult to localize accurately, partly due to technical issues related to prior craniotomies and breach rhythms and because of frequent involvement of the frontal lobes; (2) TBI frequently produces diffuse cerebral injury, which can result in multifocal epilepsy and/or seizure-onset zones that overlap with eloquent brain regions; and (3) scar tissue and adhesions related to the inciting trauma can increase the risk for surgical complications.
For patients with medically refractory PTE who are poor candidates for definitive resection, vagus nerve stimulation (VNS) should be considered for adjunctive treatment. Vagus nerve stimulation involves a device implanted in the neck for open-loop peripheral stimulation of the vagus nerve, which is thought to provide indirect seizure control via retrograde brain inhibition. Although prospective clinical trial data in patients with PTE are lacking, one case-control study found that VNS was associated with greater reduction in seizure frequency in patients with PTE than in patients with non-PTE at 2 years of follow-up (78% vs. 61% of patients with > 50% reduction in seizure frequency).
More recently, a direct form of neuromodulation, called responsive neurostimulation (RNS), has emerged as a promising therapy for patients with medically refractory epilepsy. Unlike VNS, the RNS system functions in a closed-loop manner, detecting incipient seizure activity with implanted intracranial electrodes and then counterstimulating to terminate seizures via a small, programmable neurostimulator seated in a skull cassette. Optimal candidates for RNS are adults with multifocal seizure onsets and/or seizure foci that are not amenable to surgical resection due to overlap with eloquent brain regions. Over 2 years of follow-up, more than half of patients with RNS experienced at least a 50% reduction in seizure frequency. A related technology, deep brain (anterior thalamic nucleus) stimulation, has been approved in several countries and may soon be available in the United States. Although not without controversy, neurostimulation for epilepsy continues to evolve rapidly, expanding the clinician's armamentarium for treating medically refractory PTE. A strategy for navigating the various diagnostic and treatment options in PTE is outlined in Fig. 1, which expands upon a previously proposed algorithm.
(Enlarge Image)
Figure 1.
An algorithm for the management of posttraumatic epilepsy. AED, antiepileptic drug; CBT, cognitive–behavioral therapy; CT, computed tomography; cVEEG, continuous video-electroencephalography; LEV, levetiracetam; MRI, magnetic resonance imaging; PHT, phenytoin; PNES, psychogenic nonepileptic spell; PTE, posttraumatic epilepsy; RNS, responsive neurostimulation; SSRI, selective serotonin reuptake inhibitors; TBI, traumatic brain injury; VNS, vagus nerve stimulation.
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