Abstract
Introduction
Traumatic brain injury (TBI) constitute the greatest cause of death and disability globally among all trauma related injuries. 1 Around 5.48 million people are estimated to suffer from severe TBI each year. 2 Post traumatic seizures (PTS) and post traumatic epilepsy (PTE) are a potential sequela of TBI with an overall incidence of about 3%–5%.3, 4 PTE accounts for about 10%–20% of symptomatic epilepsy in general population. 5 PTS are usually divided into immediate seizures, early seizures, and late seizures. 6 Seizures that occur at or within minutes of the impact are immediate seizures. Early seizures are those occurring within one week and late seizures occur after one week. Early PTS appear to increase mortality and morbidity in early stage of TBI and will also increase the risk of development of late PTE.7, 8 However, there is no uniform consensus among doctors regarding management issues like, indication for anti-epileptic drugs (AEDs), choice of drugs, duration of treatment, criteria for stopping treatment, and so on. Management of PTS and PTE has not been straightforward and it encompasses different aspects stretching across cognitive, social, economic and medicolegal domains. Here we report the results of an online global survey that was conducted to assess the different practices adopted by clinicians in the management of PTS and PTE.
Methods
An online survey was conducted. The participants consisted of Neurosurgeons and Neurologists dealing with PTS and PTE round the world. A questionnaire which consisted of 16 questions was set up using google forms and sent to the concerned doctors through e-mail, WhatsApp, Facebook messenger, or Telegram. Data were collected and entered in the Statistical Package for the Social Sciences (SPSS) version 16 (IBM, Chicago, Illinois, USA). The categorical variables were expressed as percentages. Differences between categories were assessed by Chi-square test and p value less than 0.05 were taken as significant. The questionnaire is given in Table 1.
Survey Questionnaire.
Results
Demographics
There were a total of 220 responses from 72 countries. Maximum number of responses were from India (n = 58; 26.5%%), followed by Egypt (n = 13; 5.9%), and Mexico (n = 10; 4.6%) (Figure 1). Low-income countries and low middle-income countries constituted 63.6% (140) of responses, and high-income countries and high middle-income countries constituted 80 responses (36.3%). Most of the responses were from teaching institutes (n = 151; 68.6%) (Figure 2). Among the responders 80.9% (n = 179) were from Neurosurgeons and 18.7% (n = 41) were from Neurologists. Responders were having different work experiences (Figure 3).
Heat Map of Responders Countries.
Institute of Responders.
Experience of Responders.
Prophylaxis of Post Traumatic Seizures
Among the 220 responders, 202 (91.8%) will start a prophylactic AED to prevent PTS; 18 responders (8.18%) opined that they would not start a prophylactic AED in TBI (Figure 4). Among those who do not start prophylactic AEDs, 10 (55.5%) are not certain about the indications, 4 (22.2%) of them think it is ineffective and 4 (22.2%) believed that the side effects outweighed the anticipated benefits. Most of the clinicians (n = 161; 79.7%) start prophylactic AEDs based on GCS and CT scan findings. While 26 responders (12.87%) started AED prophylaxis based on CT scan findings only, 14 clinicians (6.9%) start prophylactic AEDs to all TBI patients irrespective of the GCS and CT findings.
Response to the Question will you Start Prophylactic AED for all TBI Patients.
Regarding the choice of first line AED majority preferred to give Phenytoin (n = 98; 48.5%) followed by Levetiracetam (n = 78; 38.6%). Phenobarbitone was the first line drug for 13 (6.4%) clinicians, and 9 (4.45%) chose sodium valproate as their first preference; 3 responders (1.48%) preferred newer AEDs (Figure 5).
Regarding the use of double AEDs, 6 (2.9%) practitioners will routinely start two AEDs for all TBI patients. The remaining group of people (n = 196) started double AEDs depending up on the situation. Among them, previous history of seizure was the commonest indication 59 (30.1%), followed by severe head injury 45 (22.9%), temporal lobe injury 35 (17.8%), alcoholism 29 (14.7%), craniotomy 15 (7.6%).
Among those who were using double anti-epileptic prophylaxis, a combination of phenytoin and levetiracetam was the most preferred one (n = 63; 32.1%), followed by Phenytoin and sodium valproate (n = 21; 10.7%).
Regarding the duration of prophylactic treatment for PTS, 50 clinicians (24.7%) responded that they will continue up to 7 days after TBI, 49 (24.2%) will continue for 14 days, 28 (13.8%) will continue for 1 month, while 38 (18.8%) will stop prophylactic treatment only after 3 months. Also, 20 clinicians (9.9%) rely on radiological resolution of traumatic lesion for stopping anti-epileptic prophylaxis, while 17 clinicians (8.4%) would take an EEG and make sure that there are no epileptic foci, before stopping anti-epileptics.
Regarding the management of complications of AEDs, 17 clinicians (8.4%) say that they will continue anti-epileptic prophylaxis in lower dose, in the event of any drug reaction; 117 people (57.9%) will switch over to another AED and continue prophylactic treatment; 43 clinicians (21.28%) will completely stop the anti-epileptic treatment, in such a scenario; 24 clinicians (11.8%) will seek a specialist opinion before stopping the prophylactic treatment.
The opinion of 159 clinicians (78.7%) were that there was no need for prophylactic AEDs in mild head injury with normal CT findings, while 39 responders (19.3%) opined in favor of starting an AED.
Treatment of Post Traumatic Seizures
Most of the clinicians (n = 160; 72.7%) managed PTE with single drug like Phenytoin (n = 69; 31.3%) or Levetiracetam (n = 67; 30.4%). Sodium valproate was used by 14 (6.3%) people and Phenobarbitone by 8 (3.6%) responders. Clobazam was the preferred drug by 2 (0.9%), while 60 (27.7%) responders used multiple AEDs to treat PTS. Among these, 32 (53%) responders treated PTE with combination of Phenytoin and Levetiracetam, 11 responders (18.3%) prefer Levetiracetam and Sodium valproate, and 4 clinicians (6.6%) used Phenytoin and Sodium valproate. Phenobarbitone and Sodium valproate were preferred by 4 clinicians (6.6%).
Regarding the duration of AED treatment for the PTE, most of the clinicians (n = 192; 87.2%) preferred a treatment duration of less than one year and some responders (n = 28; 13.8%) treat for more than one year. Among the former groups, 26 (13.5%) clinicians stopped AEDs after one month of seizure free period, 61 (31.7%) stopped after 3 months, and 75 (39%) clinicians would stop after 6 months of seizure free period. While 30 (15.6%) clinicians used AEDs up to one year of seizure free period.
Most of the clinicians (n = 180; 89.1%) agreed that there were no guidelines followed in their institutions for the prophylaxis and management of PTS; 38 (18.8%) responders said that they were following institute guidelines for the management of PTS. Some among them suggested their guidelines in the survey.
Discussion
A conspectus of our survey findings would indicate that there is uncertainty and lack of uniformity round the globe with regard to the management of PTS and PTE. These varying practices would spread across all aspects of management, namely the starting of anti-epileptics, the choice of drugs, duration of treatment, criteria for stoppage of drugs. This randomness in practice could be seen among experienced clinicians also, irrespective of their specialty and patient turnover. A recent survey conducted in the UK and Ireland among clinicians demonstrated the inconsistencies that revolved around this aspect among them. 9 In our survey 91.8% of people were giving AED for seizure prophylaxis in TBI, while 8.18% were not at all using any drugs. A generally accepted practice guidelines are laid down by American Academy of Neurology 10 and the Brain Trauma Foundation 11 (BTF). The BTF 4th edition recommend phenytoin to decrease the incidence of early PTS (within 7 days of injury), when the overall benefit is felt to outweigh the complications associated with such treatment although prophylactic use of phenytoin or valproate is not recommended for preventing late PTS. They have identified a group of patients at risk for developing early PTS which include Glasgow Coma Scale (GCS) score of ≤10; immediate seizures; post traumatic amnesia lasting longer than 30 minutes; linear or depressed skull fracture; penetrating head injury; subdural, epidural, or intracerebral hematoma; cortical contusion; age ≤65 years; or chronic alcoholism.
What is the rationale for routine seizure prophylaxis in TBI? BTF 4th edition says that there is insufficient evidence to support level 1 recommendations on this topic. The incidence of PTS in general has been reported to be anywhere from 4% to 53%. 6 Early PTS increase the morbidity and mortality in the early stages of TBI. 8 It will also increase the risk of developing PTE. 7 Individuals with TBI were more likely to die of seizures. 12 The cumulative incidence of PTE in the first 3 years after discharge, after adjusting for loss to follow-up, was 4.4 per 100 persons over 3 years for hospitalized mild TBI, 7.6 for moderate, and 13.6 for severe. 13 Though it would be intuitive to start AEDs in all moderate to severe TBI, the adverse effects including allergic reactions, cognitive effects, costs, and so on, has to be considered; 79.7% of our responders opined that they would start an anti-epileptic based on a CT scan and Glasgow Coma Scale. Out of the responders of a survey conducted in the UK, 60% expressed uncertainty regarding the routine use of seizure prophylaxis in TBI and 53% among them do not routinely use seizure prophylaxis.
Literature is rife with discordant results regarding the use of AED for prophylaxis of PTE and PTS. AEDs has been classically prescribed to reduce the incidence of early PTS.10, 14, 15, 16 Logically it would seem that the long-lasting high risk of epilepsy after brain injury might get reduced if prophylactic AEDs are administered. Temkin et al. have randomly assigned 404 eligible patients with serious head trauma to treatment with phenytoin or placebo for one year in a double-blind fashion. They have concluded that Phenytoin exerts a beneficial effect by reducing seizures only during the first week after severe head injury. This study might have formed the basis of recommendation of AED for prevention of early PTS.
These studies, which support AED prophylaxis for early PTS however do not recommend it for late PTS or PTE. All studies do not support the routine use of AEDs in early PTS also. 17, 18, 19 Bhullar et al. has observed that Phenytoin prophylaxis may not decrease early PTS and may suppress functional outcome after blunt TBI. This does not apply to penetrating trauma. The use of AEDs are often associated with a worse rehabilitation outcome, independently of the onset of epilepsy during treatment which cautions against the generic use of prophylactic therapy to prevent PTE in patients with TBI. 20 A recently conducted systematic review and meta-analysis has shown only modest evidence regarding the effectiveness of AEDs as prophylaxis for early PTS. 21
Choice of anti-epileptic is another area where a consensus is lacking in literature. Though Phenytoin has been classically recommended for early PTS, levetiracetam is also being used widely due to its superior side effect profile. Phenytoin was the drug used by 48.5% of our responders, and Levetiracetam by 38.6%. The increased use of Phenytoin in developing countries, may be attributed to the fact that it is cheap when compared to Levetiracetam. The Glasgow outcome scale score at six months was better for patients treated with intravenous levetiracetam when compared with phenytoin. 22 Yang et al. has conducted a systematic review and meta-analysis on this matter where they came to a conclusion that Levetiracetam does not appear to be superior to phenytoin in efficacy or safety with regard to early or late seizure prophylaxis following TBI. 23 The heterogenous nature of TBI has always been a challenge to our understanding of the mechanism of epileptogenesis and developing newer drug targets. The optimal duration of AEDs and criteria for stoppage of drugs are also not clear in literature. This lack of clarity is reflected in our survey also. Majority of our respondents stopped AEDs in 14 days. Double anti-epileptics are generally not widely used.
The limitations of our survey must however be acknowledged. Since the number of responses were low, the conclusions derived cannot be deemed to represent the practices of Neurological community in general. The wide variations in the practice patterns even in such a small sample is the point which we would like to highlight.
Conclusion
Our study would throw light up on the arbitrariness in the management of PTS and PTE by clinicians globally. There is obviously a pressing need to develop clear clinical practice recommendations on this important topic. Further robust studies with large samples size are required to provide class 1 evidence to help the development of the same.
Footnotes
Abbreviation
Acknowledgement
Authors’ Contribution
Statement of Ethics
Declaration of Conflicts of Interest
Funding
ORCID iD
