Epilepsia, 44(Suppl. 10):21–26, 2003 Blackwell Publishing, Inc.  C International League Against Epilepsy

Overview of Studies to Prevent Posttraumatic Epilepsy Ettore Beghi Epilepsy Center, University of Milano-Bicocca, Monza, and Istituto “Mario Negri,” Milano, Italy

Summary: Purpose: Prevention of posttraumatic epilepsy (PTE) is of primary importance to reduce the degree of functional morbidity following traumatic brain injury (TBI). However, the effects of antiepileptic drugs (AEDs) in patients with TBI must be assessed separately in terms of prevention and control of provoked seizures (which include immediate and early posttraumatic seizures) and prevention of subsequent unprovoked seizures (late posttraumatic seizures or PTE). Methods: Potential mechanisms for prevention of epileptogenesis as well as reports and systematic reviews were evaluated to determine strategies and results of attempts to reduce or prevent the development of epilepsy following TBI. Results: In observational studies, after a period ranging from 6 months to 13 years, the proportion of cases developing seizures was 0-10% in patients receiving treatment compared to 2–50% in those who were left untreated. In randomized clinical trials, the difference between active treatment [phenytoin (PHT), phenobarbital, or carbamazepine (CBZ)] and placebo was less remarkable after a follow-up ranging from 3 to 60 months and was virtually lacking for the prevention of PTE. In a Cochrane

systematic review of 890 patients from 10 RCTs assessing PHT or CBZ, the pooled relative risk (RR) for prevention of early seizures was 0.33 (95% CI 0.21–0.52). By contrast, the RR for prevention of late seizures was 1.28 (95% CI 0.90–1.81). Mortality and neurological disability were similar in the two treatment groups. The use of PHT was followed by an increased (nonsignificant) risk of skin rashes. In addition, cognitive performance was significantly affected by PHT in severely injured patients at 1 month and treatment withdrawal was followed by improvement in cognitive function. Conclusions: The failure to influence the risk of PTE in studies of patients with TBI are similar to findings of meta-analysis of randomized clinical trials on seizure prevention in other conditions, such as febrile seizures, cerebral malaria, craniotomy, and excessive alcohol intake. For these reasons, the prophylactic use of AEDs should be short-lasting and limited to the prevention of immediate and early seizures. Chronic treatment should be considered only after a diagnosis of PTE. Key Words: Epilepsy—Prophylaxis—Brain injury—Anticonvulsant drug— Clinical trial.

Traumatic brain injury (TBI) is one of the most common events occurring in civilian life. The overall incidence of TBI in developed countries is ∼200 per 100,000 population per year (1–3), with a significant proportion of cases resulting in lifelong disability (4). Moderate-tosevere TBI is a frequent cause of epileptic seizures. The overall risk of seizures after TBI ranges from ∼2 to 5% in civilian populations (1,5); it ranges from 7 to 39% in patients with cortical injury and neurologic sequelae (6), and ≤57% with dural penetration (6). Prevention of posttraumatic epilepsy (PTE) is thus of primary importance to reduce the degree of functional morbidity after TBI. However, to improve our understanding of the indications and efficacy of drug treatment for the prevention of PTE, we must clearly define the risk of provoked and unprovoked seizures after TBI, along with the factors influencing that risk. The risk of epilepsy after TBI and the most common risk factors are discussed in detail elsewhere in this issue (7) and will be only briefly summarized here.

DEFINITIONS Epilepsy can be defined as the occurrence of repeated unprovoked seizures (8). An unprovoked seizure is a seizure occurring in the absence of one or more precipitating factors. By contrast, a provoked (acute symptomatic) seizure is a seizure occurring in close temporal relation with an acute systemic, toxic, or metabolic insult (including TBI), which is expected to be the underlying cause. Unprovoked seizures include events occurring in patients with antecedent stable (nonprogressing) CNS insults, including TBI (remote symptomatic seizures). After TBI, the difference between provoked and unprovoked seizures is relevant to the assessment of the indications for and effects of treatment. By definition, seizures occurring within 24 h of TBI (immediate seizures) and seizures occurring between the first 24 h and the first 7 days after injury (early posttraumatic seizures) are provoked seizures, whereas seizures seen after 7 days (late posttraumatic seizures) are unprovoked seizures (9). Based on these definitions, the effects of antiepileptic drugs (AEDs) in patients with TBI must be assessed separately in terms of prevention and control of provoked seizures (which include immediate

Address correspondence and reprint requests to Dr. E. Beghi at Istituto “Mario Negri,” Via Eritrea, 62 – 20157, Milano, Italia. E-mail: [email protected]

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E. BEGHI TABLE 1. Laboratory models: effect of classic and new drugs on epileptogenesis

Drug

Model

Carbamazepine Diazepam Ethosuximide Felbamate Lamotrigine Levetiracetam Phenobarbital

Phenytoin

Tiagabine Topiramate Valproate

Vigabatrin

Effect

Amygdala-kindled rats Amygdala-kindled cats Pentylenetetrazol-induced kindling in rats Amygdala-kindled rats Pentylenetetrazol-induced kindling in rats Pentylenetetrazol-induced kindling in rats Amygdala-kindled rats Homocysteine thiolactone administration Amygdala-kindled rats Amygdala-kindled rats Corneally kindled rats Pentylenetetrazol-induced kindling in rats Amygdala-kindled rats Amygdala-kindled cats Hippocampal injection of penicillin in cats Hippocampal injection of penicillin in rats Alumina-gel injection in monkeys Amygdala-kindled rats Amygdala-kindled cats Homocysteine thiolactone administration Flurothyl seizures in mice Kindling induced by cortical penicillin in rats Alumina-gel injection in monkeys Amygdala-kindled rats Amygdala-kindled rats Amygdala-kindled rats Pentylenetetrazol-induced kindling in rats Flurothyl seizures in mice Rat brain slice Amygdala-kindled mice Amygdala-kindled rats Corneally kindled rats

Ineffective Weakly attenuated Ineffective Attenuated Attenuated Attenuated Weakly attenuated Ineffective Ineffective Attenuated Protected Attenuated Attenuated Attenuated Attenuated Attenuated Ineffective Raises seizure threshold but ineffective in preventing epileptogenesis Ineffective Attenuated Attenuated Attenuated Mixeda Attenuated Ineffective Markedly attenuated Attenuated Attenuated, retarded reorganization Mixedb Attenuated Ineffective Attenuated

a Attenuated b Attenuated

with high dose; enhanced with standard dose. if applied within 20 min; ineffective if applied ≥30 min. Adapted from ref. 13, with permission.

and early posttraumatic seizures) and prevention of subsequent unprovoked seizures (late posttraumatic seizures or PTE). THE RISK OF SEIZURES AFTER TBI AND THE RISK FACTORS In unselected patients with TBI, the incidence of early posttraumatic seizures is ∼2% (1). About 2% of patients tend also to develop late posttraumatic seizures (1). Approximately one half to two thirds of patients with TBI will experience one or more seizures within the first 12 months, and ≤80%, by the end of the second year (10). The cumulative probability of seizures after TBI is significantly correlated to the severity of the injury. In a populationbased study (11), the 5-year probability of seizures was 0.7% in patients with mild injuries (loss of consciousness or posttraumatic amnesia for 24 h). Epilepsia, Vol. 44, Suppl. 10, 2003

In this population, the presence of early seizures, which was found by univariate analysis affecting the risk of PTE, lost significance when assessed by multivariate analysis. Early seizures did not affect the risk of epilepsy in mild TBI. Multivariate analysis showed brain contusion and subdural hematoma as being the strongest risk factors for PTE, followed by older age. RATIONAL BASIS FOR THE ANTIEPILEPTOGENIC ACTION OF THE ANTICONVULSANT DRUGS In recent years, a marked increase has occurred in the understanding of epileptogenesis at the cellular and molecular levels. However, although critical events involve the potentiation of excitatory synapses and the depression of inhibitory pathways, the exact mechanisms of epileptogenesis are poorly understood. The deposition of iron liberated from hemoglobin may be a key factor in the pathogenesis of epilepsy after TBI (12). Several animal models have been developed to investigate epileptogenesis. These include kindling (i.e., repeated subconvulsive electrical or chemical brain stimulations), status

OVERVIEW OF STUDIES TABLE 2. Observational studies of prophylaxis of posttraumatic seizures Reference Drug(s) 14 15 16 17 18 19

PB, PHT PHT PHT PB PB VPA

No. of Follow-up Treated Untreated cases (mo) (% seizures) (% seizures) 168 62 84 83 390 143

8–156 6–72 12 24 12 24

2a 10a 6a 2 2 0

25(a ) 50(a ) 2–31(a ) – 7–16 15–55

PB, phenobarbital; PHT, phenytoin; VPA, valproate. a Late seizures only. Adapted from ref. 20, with permission.

epilepticus induced by chemicals (e.g., picrotoxin or bicuculline), and application of alumina gel, iron compounds, or penicillin to the brain. The effects on epileptogenesis of old and new AEDs in laboratory models are summarized in Table 1 (13). Based on animal experiments, the antiepileptogenic effect can be considered definite for some AEDs [diazepam, levetiracetam, phenobarbital (PB), tiagabine, and valproate (VPA)]. The effect is possible for other compounds [phenytoin (PHT), topiramate, vigabatrin] and absent or unknown for others [carbamazepine (CBZ), felbamate, gabapentin, oxcarbazepine]. However, based on the results of animal studies, these differences should be considered only speculative, as they require confirmation by clinical trials in humans with TBI. RESULTS OF OBSERVATIONAL STUDIES AND CLINICAL TRIALS FOR THE PROPHYLAXIS OF POSTTRAUMATIC SEIZURES A number of observational studies have been published from various countries comparing treated and untreated patients with TBI to assess the occurrence of seizures during follow-up (14–19) (Table 2). The drugs used were, in decreasing order, PHT, PB, and VPA. After a period ranging from 6 months to 13 years, the proportion of cases developing seizures was 0–10% in patients receiv-

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ing treatment compared with 2–50% in those who were left untreated. In randomized clinical trials, the difference between active treatment (PHT, PB, or CBZ) and placebo was less remarkable after a follow-up ranging from 3 to 60 months (20–30) (Tables 3 and 4). A significant difference regarding the incidence of early seizures was found between placebo and PHT or CBZ in two of four studies. By contrast, only one study (of 11) showed a significant effect of PHT in preventing late seizures. However, this was an unblinded study. In three studies, the incidence of PTE was actually higher in patients receiving PHT or PB. In one of these studies (24,25), propylene glycol, a diluent used in the intravenous placebo treatment, was noted to possess potential anticonvulsant activity, which might have accounted in part for lack of difference between treatments. Based on a qualitative assessment of the randomized clinical trials, AEDs are thought to reduce the rate of occurrence of early seizures, but they do not seem to exert a significant effect on the prevention of PTE.

A SYSTEMATIC REVIEW OF RANDOMIZED CLINICAL TRIALS To assess the overall efficacy and safety of prophylaxis of early and late seizures in patients with TBI, a Cochrane systematic review of randomized clinical trials (shown in Tables 5–9) was recently performed (31,32). In this review, a trial was included if done in patients with a clinically definite TBI of any severity assigned to active treatment or control (placebo or no drug) by random or quasi random allocation. Excluded were trials in which treatment was started >8 weeks after injury. Ten randomized controlled trials were identified, for a total of 2,036 patients. Based on the assessment of 890 available patients, the pooled relative risk (RR) for prevention of early seizures was 0.33 [95% confidence interval (CI), 0.21–0.52; Table 5). With the exclusion of the articles by Young et al. (24,25), in all the eligible studies, patients receiving active treatment were at lower risk of early seizures than were untreated

TABLE 3. Randomized clinical trials of prophylaxis for posttraumatic seizures

Reference

Drug(s)

No. of cases

Treatment/ follow-up (mo)

21,22 Brackett et al.b Brackett et al.b 23 Marshall et al.b Locke et al.b

PHT PB, PHT PB, PHT PHT PB, PHT PB, PHT

100 125 49 164 154 303

48/>48 18/36 6/18 12/24 6/18 6/18

Activea (% seizures)

Placeboa (% seizures)

6 23 14 10c 24 4

51 13 39 9c 16 12

PB, phenobarbital; PHT, phenytoin. a Early and late seizures combined. b Quoted by ref. 20. c Early seizures only. Adapted from ref. 20, with permission.

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E. BEGHI TABLE 4. Randomized clinical trials of prophylaxis for posttraumatic seizures

Drug(s)

No. of cases

Treatment/ follow-up (mo)

PHT PHT CBZ PB PHT VPA (1 and 6 mo) PHT (1 wk)

244 404 139 126 86 379

18/18 12/24 24/24 24/60 3–12/24 1 4 –6/24

Reference 24,25 26 27 28 29 30

Early seizures (% Active/placebo)

Late seizures (% Active/placebo)

4/4 4/14a 10/25a -/6–24 1 (PHT)/4 (VPA)

12/11 27/21 27/33 16/11 6/42a 15 (PHT) 16 (VPA 1 month) 23 (VPA 6 months)

CBZ, carbamazepine; PB, phenobarbital; PHT, phenytoin; VPA, valproate. a p < 0.01. Adapted from ref. 20, with permission.

controls. Based on the number-needed-to-treat estimate, 100 patients should be treated to have10 seizure-free individuals. By contrast, in 1,218 examined patients, the RR for prevention of late seizures was 1.28 (95% CI, 0.90– 1.81; Table 6). In none of the four eligible studies did the RR achieve significance. Mortality (of all causes) at the end of follow-up was available in 1,054 patients and was similar in the two treatment groups, with no studies providing evidence for a positive effect of treatment on patient survival (Table 7). Although neurologic disability [measured in two studies (26,27) by the Glasgow Coma Outcome Scale] was unaffected by treatment, conflicting results were provided on the effects of treatment on death or severe disability (Table 8). In the study by Glotzner et al. (27), a worse outcome (severe disability, vegetative state, or death) was detected in patients receiving treatment. However, a likely explanation given by the authors (use of CBZ) is contended by the complex therapeutic regimen (CBZ oral load or intravenous PHT in patients in whom oral intake was impossible), which prevents any inference on the risk attributable to the investigated drug. The use of AEDs was followed by an increased (although nonsignificant) risk of skin rashes in the two studies reporting adverse treatment effects (23,26) (Table 9). On this basis, four expected skin rashes were found for every 100 patients assigned to active treatment. In addition,

TABLE 5. Meta-analysis of prophylaxis for posttraumatic early seizures Reference

Drug (Sz/N)

Control (Sz/N)

OR

95% CI

27 28 26 25 Total

8/75 2/37 7/208 5/136 22/456

22/76 13/54 26/196 4/108 65/434

0.37 0.22 0.25 0.99 0.34

0.18–0.78 0.05–0.94 0.11–0.57 0.27–3.61 0.21–0.54

Sz, no. of cases with seizures; OR, odds ratio; 95% CI, 95% confidence interval. Adapted from ref. 31, with permission.

Epilepsia, Vol. 44, Suppl. 10, 2003

in the only randomized trial examining neurobehavioral effects of PHT versus placebo in PTE, performance was significantly affected by active treatment in severely injured patients at 1 month, and treatment withdrawal was followed after improvement in several cognitive functions (33). Based on the results of randomized clinical trials and meta-analysis, the prophylactic use of PHT or CBZ is effective in reducing the risk of early posttraumatic seizures, whereas late seizures, disability, and/or death seem unaffected by active treatment. However, adverse treatment events (mostly rashes and neurobehavioral abnormalities) are expected to some extent among PHT users. PROBLEMS WITH TRIALS ON THE PROPHYLAXIS OF PTE One major problem with the prophylaxis of PTE is the safety profile of the drugs used for the treatment of epilepsy. AEDs possess a high potential of adverse treatment effects, which can be enhanced by the presence of brain injury (34). Adverse events have been reported in 22% of patients receiving AEDs in monotherapy in clinical practice (35). Adverse treatment events may require drug withdrawal or substitution in ≤30% of cases (36,37). TABLE 6. Meta-analysis of prophylaxis for posttraumatic late seizures Reference

Drug (Sz/N)

Control (Sz/N)

OR

95% CI

28 24 26 25 27 29 Total

8/71 8/84 36/208 13/136 14/75 2/34 81/608

8/98 7/80 26/196 8/108 20/76 22/52 91/610

1.38 1.09 1.30 1.29 0.71 0.14 1.28

0.54–3.50 0.41–2.86 0.82–2.08 0.56–3.00 0.39–1.30 0.03–0.55 0.90–1.81

Sz, no. of cases with seizures; OR, odds ratio; 95% CI, 95% confidence interval. Adapted from ref. 31, with permission.

OVERVIEW OF STUDIES TABLE 7. Meta-analysis of prophylaxis for posttraumatic seizures: deaths at end of follow-up Reference

Drug (Sz/N)

Control (Sz/N)

OR

95% CI

27 24 29 26 25 Total

27/75 5/84 2/37 47/208 14/136 95/540

20/76 2/80 3/54 40/196 13/108 78/514

1.37 2.38 0.97 1.05 0.86 1.15

0.84–2.22 0.48–11.92 0.17–5.54 0.74–1.49 0.42–1.74 0.89–1.51

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TABLE 9. Meta-analysis of prophylaxis for posttraumatic seizures: patients with skin rash Reference

Drug (Sz/N)

Control (Sz/N)

OR

95% CI

24 26 Total

5/84 25/208 30/292

1/80 17/196 18/276

3.77 1.43 1.63

0.74–19.14 0.76–2.71 0.90–2.95

Sz, no. of cases with seizures; OR, odds ratio; 95% CI, 95% confidence interval. Adapted from ref. 32, with permission.

Sz, no. of cases with seizures; OR, odds ratio; 95% CI, 95% confidence interval. Adapted from ref. 31, with permission.

Cognitive and behavioral abnormalities are common findings in patients with head injury. AEDs have negative cognitive effects, although differences were found when comparing old and new compounds, the latter displaying lesser or no effects on cognition (38). The clinically observed neurobehavioral consequences of AEDs are confirmed by the results of animal studies (39). Randomized clinical trials for seizure prevention have a number of methodologic limitations, which have been carefully outlined in recent reviews (13,20). A first limitation is the variability of the risk of unprovoked seizures across patients with TBI (see Tables 3 and 4), which indicates that the patients enrolled in the clinical trials are heterogeneous and have different propensities to develop PTE. A second limitation is the prolonged period required for the occurrence of PTE in several individuals, which may affect patient compliance. In the largest published study (26), the cumulative probability of late seizures at 12 months was 22% among patients receiving placebo and 16% among PHT users. By that time, about one fourth of patients taking PHT required stopping treatment (placebo, 17%). A third limitation is the uncertainty about the diagnosis of epilepsy in patients observed for the occurrence of a first clinical event, which may not necessarily be a tonic–clonic seizure. Uncertain seizures were reported by 83 of 397 patients admitted to a randomized clinical trial at the time of a first tonic–clonic seizure (40). A fourth limitation is the confounding effect of a long-term treatment started in patients developing seizures during the TABLE 8. Meta-analysis of prophylaxis for posttraumatic seizures: deaths or severe disability Reference

Drug (Sz/N)

Control (Sz/N)

OR

95% CI

27 26 Total

44/75 67/208 111/283

30/76 66/196 96/272

2.14 0.94 1.20

1.14–4.05 0.62–1.42 0.85–1.70

treatment period, which may lessen the difference seen after the study drug is discontinued. A fifth limitation is the significant heterogeneity of the study designs, which was documented by the systematic review (31,32), and which might prevent comparisons and any inference from data pooling. The last (but not least) limitation is the use of a limited number of active principles among those with a definite antiepileptogenic effect. Based on these findings, AED prophylaxis seems to control provoked seizures in patients with TBI, but it does not seem to prevent the subsequent development of PTE, and it can be poorly tolerated and even detrimental to cognitive and behavioral functions. The results of studies in patients with TBI are confirmed by a meta-analysis of other randomized clinical trials on seizure prevention (41). In several clinical conditions, including febrile seizures, cerebral malaria, craniotomy, and excessive alcohol intake, AEDs have shown effective results for the control of provoked seizures. By contrast, no drug (among those examined) has been shown to be effective for the prevention of subsequent unprovoked seizures. For these reasons, the prophylactic use of AEDs should be brief and limited to the prevention of immediate and early seizures. Prolonged treatment should be considered only after a diagnosis of PTE. Further studies are awaited to test other compounds, chosen among those shown to possess definite antiepileptogenic effects. In this respect, as shown in Table 1, several drugs have been found to be effective against experimentally induced epileptogenesis. However, several of these compounds also have been shown to impede recovery of function after brain damage in animals (39). Thus, the identification of antiepileptogenic drugs should be made through interdisciplinary research and communication between clinical and basic scientists. In addition, in a future randomized trial on the prophylaxis of PTE, the potential benefits of a drug should be weighed against its safety and the monetary costs at patient and societal levels. REFERENCES

Sz, no. of cases with seizures; OR, odds ratio; 95% CI, 95% confidence interval. Adapted from ref. 32, with permission.

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