History

Post-traumatic epilepsy (PTE) was recognized in ancient India several thousand years ago. Epilepsy was mentioned using the terms Apasmara or Apasmrti in many Ayurvedic texts dating to 2500 BC and earlier.¹ There have been three factors commonly implicated for the etiology of Apasmara: endogenous factors (genetic, congenital and enzymatic disturbances); exogenous factors (intake of unwholesome and unhygienic foods, worms and other environmental factors including trauma); and psychological factors (excessive worry, anger and anxiety).² According to ancient literature the aggravated vata dosa (one of the life-forces which govern flow and motion in the body) due to brain trauma spreads throughout the body through nerves, leading to manifestation of post-traumatic seizures in the form of shaking limbs (akshepaka) or episodes of brief unconsciousness without shaking (apatantraka).² The ancient literature also concludes that PTE can only be controlled with medications and can sometimes be incurable and will remain uncontrolled.

Burden

Traumatic brain injury (TBI) is the one of the leading cause of death especially in younger people in many developing countries.³ Health systems in low and middle income countries are not prepared well to tackle the post-traumatic consequences including PTE. The data on epidemiology, financial costs and the social impact of PTE is sparse.⁴ Increased incidence of road traffic accidents, combined with poor healthcare services, as well as lack of knowledge of the causes and consequences are underlying causes for the disproportionately high burden of PTE in those countries.⁵

Epidemiology

Epidemiological data on incidence, prevalence and mortality of PTE is particularly important for optimal health care delivery and prevention of this condition. Poverty and poor national health resources are major reasons for the inadequate number of neuro-epidemiological studies in the developing world where more than half of the world’s population resides. Inaccuracy of death certification is another reason for unreliability of the mortality data for PTE in these areas. Lack of a universal definition on PTE also contributes to lack of epidemiological data. Starting anti-epileptic drugs (AEDs) as prophylaxis following TBI and prescribing AEDs for acute symptomatic seizures may lead to methodological flaws. In contrast to developed countries, lack of centralized reporting systems or national disease registries together with inadequate population-based studies makes obtaining reliable statistics on PTE a daunting task.

Epidemiology of TBI

The leading causes for TBI in most of the developing world are road traffic accidents, assaults and accidental falls.⁶ Almost two-thirds of TBI cases occur due to traffic accidents, and the other onethird of cases are mainly due to violence/assault and accidental falls.

Road Traffic Accidents

Road traffic injury is a leading cause of death and disability among adolescents and young adults in many developing countries. It is estimated more than 85% of all deaths due to motor vehicle crashes occur in developing countries.⁷ There are multiple reasons for dramatic increase in traffic-related case fatalities. The recent growth in numbers of motor vehicles without infrastructure development is a major cause for rising fatalities from traffic-related injuries in poor countries. Extensive use of public transport and prevalence of poor quality vehicles which often carry more people than their authorized capacity are two main factors contributing to comparatively higher proportion of death toll in these countries.⁸ There are number of other factors associated with increased incidence of motor vehicle crashes, such as poor practice of road safety measures, high speed driving, low level of vehicle ownership and inadequate public health infrastructure.^{9, 10} The highest burden of morbidity and mortality is borne disproportionately by poor people, as pedestrians, passengers of public transport and cyclists are more vulnerable. It is estimated that urban pedestrians account for around two-third of deaths.^{11, 12}

Violence

Many developing countries suffer or have suffered large-scale war and violence. Both civilians and security personnel residing near war zones are more prone to develop TBI as well as other life-threatening injuries.¹³ Increased use of improvised explosive devices results in high number of blast injuries and closed head injuries.¹⁴ TBI often goes unnoticed when it occurs without any signs of external injuries.

Higher prevalence of alcohol consumption due to increasing availability without proper regulation contributes to increased rate of violence (with or without weapons) in those countries.¹⁵ In some countries around quarter of TBI occurred under influence of alcohol. It is estimated that morbidity and disability due to TBI are almost twice the rate than in those who were not under the influence of alcohol.¹⁶

Falls

Around 424,000 fall-related fatalities occur globally each year.¹⁷ It is estimated that more than 80% of those fatalities occur in developing countries.¹⁸ Around 20% to 30% of fallers sustain TBI.¹⁹ People at the extremities of age are more vulnerable to fall-related injuries. It is imperative to have better understanding of unique contributors of falls in the elderly and in children.

The elderly population continues to rise in many developing countries. Around two-thirds of the hospitalizations due to injuries in elders are due to falls.²⁰ Elders in these countries are more vulnerable to falls and fall-related injuries due to malnutrition, hazards at home, environmental risk factors, lack of accessible transportation and inadequate health services.²¹ The cost of fall-related injuries and their burden on health care systems are disproportionately high in low income countries.

Most fall-related injuries in pediatric population occur while playing either at home or school. Children are often unattended without adequate safety measures. Lack of knowledge and appreciation by parents further increases the chances for falls.²² A study from China revealed that for every pediatric death from a fall, there were four children with a permanent disability and 37 requiring hospitalization.²³

Occupational health hazards are the main contributing factors to falls in the middle-age population.²⁴ Worker safety remains an important health problem in many low and middle income countries. Financial constrains lead to unsafe work practices. Falls from height at construction sites are a common cause of TBI, leading to higher mortality and morbidity.²⁵

Epidemiology of Post-traumatic Epilepsy

As post-traumatic epilepsy (PTE) is the one of the common complications of TBI, rising rate of TBI has resulted in increased incidence of PTE in many developing countries. However, studies on incidence of PTE in developing countries are very rare. Available small-scale studies reported incidence of PTE ranging from 2.5% to 5%.

In a cohort of 520 TBI patients in India, overall 11.4% developed post-traumatic seizure (PTS). Most of them (8.9% of the whole cohort) developed seizures within a week of TBI.²⁶ Independent risk factors for PTS were severity of TBI at presentation, associated medical comorbidities and fall from height. During the median follow-up of 386 days, 32.2% of patients with PTS developed recurrence seizures. The recurrence was higher in patients with late-onset seizures, while multiple early seizures were not associated with long-term recurrence.

In a Chinese cohort of 2,826 TBI patients, the incidence of PTE was 5% during the first 3 years after the trauma.²⁷ In addition to the severity of TBI, other factors associated with increased incidence of PTE were older age, abnormal neuroimaging and surgical interventions. In contrast to the Indian study, around 66.7% of the victims with acute and early seizures developed PTE.

In another multicenter Chinese study, the overall incidence of PTS was 9.8% among 3,093 patients during the 2-year follow up²⁸; 35.1% developed seizures while they were in hospital. More than half (59.9%) of them were diagnosed as having PTS at 6 months. Only 21.9% developed PTS after 1 year. Severity of TBI, frontal-temporal lobar contusion and linear fracture are risk factors for PTS.

A survey of 163 Iranian war veterans with intractable epilepsy revealed that the PTS occurred earlier in patients with penetrating trauma (78% developed within 1 year) in comparison with blunt trauma cases (only 38% had seizure within 1 year).²⁹ In addition, seizure frequency and duration of unconsciousness were higher in veterans who sustained penetrating trauma.

As there are differences in sample size, study setting, mechanisms and severity of the injury, it is not possible to draw any reliable conclusion from the studies described here.

Mechanisms of PTE

The pathophysiology of PTE is not simple and involves both primary and secondary brain injury mechanisms. It may differ between penetrating injuries and closed head injuries.

The Vietnam Head Injury study confirm the association between penetrating TBI and PTS. Out of the 421 veterans who suffered TBI, 53% developed PTE.³⁰ The majority of cases developed within a year of TBI and almost half of them were still experiencing seizures 15 years after their TBI. Focal neurological signs, large lesions and presence of hematoma and retained metal fragments were associated with increased risk of developing PTE. Only lesions in some parts of brain, such as left temporal gray matter/hippocampus, right vertex gray matter, significantly predicted seizure occurrence.

An animal model of penetrating TBI in rats closely resembles the many aspects of war-time TBI.³¹ A computer operated hydraulic pressure generator was used to simulate the two aspects of a high-energy bullet injury to brain: a permanent injury tract created by the path of the bullet and the large temporary cavity generated by energy dissipation of the penetrating bullet. Up to 70% of rats developed one or more seizures 72 hours after injury, and the frequency and duration of epileptic events correlated with the severity of the injury. Pathological examination revealed a penumbral zone of injury surrounding the core zone of injury susceptible to secondary injury.

The Fluid Percussion Injury model (FPI) mimics the pathophysiology of closed head injury by reproducing both destructive processes and regenerative inflammatory processes.³² Conventionally, injury is induced by rapid fluid injection through a craniotomy combined with a hammer swung on a pendulum. A group of researchers from China recently evaluated an advanced device for FPI in rats.³³ The device was software controlled and delivered more reliable fluid percussion pulses. FPI-induced electrographic as well as clinical seizures.

Management of PTE

Access to appropriate treatment for PTE is poor in developing countries. PTE in many developing countries is often managed by general physicians due to lack of specialist neurologists or epileptologists. Such specialists are often concentrated in urban areas giving rise to a large treatment gap in rural areas. In addition to the lack of specialists, high costs of treatment, increased distance to health care facilities, inadequate knowledge about PTE and stigmatization also contribute to unacceptably high treatment gap.

The diagnosis of PTE is made on clinical grounds. Diagnostic tests such as electroencephalography (EEG), computed tomography (CT) scan and magnetic resonance imaging (MRI) scan may assist in the assessment of patients with PTE.³⁴ In the acute setting, a CT scan is effective in the assessment of moderate to severe TBI, but MRI is the imaging modality of choice for mild TBI and for patients with PTE. Even though MRI is available in many developing countries, its accessibility is limited to private health care facilities in larger cities. Long-term video EEG monitoring is not available in many low income countries. Furthermore, interpretation of EEG can be challenging in the absence of adequate number of specialists.

The American Academy of Neurology recommends prophylactic treatment with phenytoin for first 7 days for patients with severe TBI (typically with prolonged loss of consciousness or amnesia, intracranial hematoma or brain contusion on CT scan and/or depressed skull fracture).³⁵ Although phenytoin has been shown to decrease the incidence of early PTS, this treatment does not protect against late PTS or PTE.³⁶ In a retrospective analysis in China, effectiveness of sodium valproate for the prevention of early PTS was evaluated.³⁷ Out of 87 severe TBI patients, 6 patients in the control group developed early PTS whereas no patient from the sodium valproate cohort developed early seizures. The authors concluded that sodium valproate was effective in decreasing the risk of early seizures in severe TBI. However, the difference was not statistically significant. Furthermore, a previous randomized trial in Washington revealed tend toward a higher mortality rate among TBI patients treated with sodium valproate.³⁸

A small scale single blinded randomized trial showed that use of levetiracetam may be associated with better cognitive outcome in comparison with phenytoin.³⁹ Many second generation antiepileptic drugs including levetiracetam are not available in many resource-limited countries. Despite having a better safety profile, many patients in poor countries do not receive newer antiepileptic medications suitable for their needs and comorbidities.⁴⁰