EFFICACY OF ANTICONVULSANT ADMINISTRATION AS A SEIZURE
PROPHYLACTIC THERAPY IN TRAUMATIC BRAIN INJURY PATIENTS
Filipo David Tamara
Fakultas Kedokteran Universitas Tarumanagara,
Jakarta, Indonesia
|
KEYWORDS |
ABSTRACT |
|
traumatic brain injury, anticonvulsant, prophylactic
therapy. |
Traumatic brain injury (TBI) is a non-degenerative,
non-congenital disorder of the brain that occurs due to external mechanics
that can cause permanent or temporary impairment of cognitive, physical and
psychosocial functions. Based on the 2018 Basic Health Research (Riskesdas)
data, the prevalence of head injuries in Indonesia is 11.9%. Seizures after
head injury result in secondary brain damage and seizure prophylaxis is only
recommended in patients with TBI during the first seven days. This study was
designed to assess the efficacy of anticonvulsants as prophylactic therapy in
patients with TBI in Indonesia. The research method used was a literature
review that was searched using Google Scholar, Pubmed, Medline, Ebsco,
Hindawi, ScienceDirect, and Cochrane, published in the last ten years. After
obtaining the appropriate literature, the manuscript is written. The results
showed that prophylactic anticonvulsants such as Phenytoin could reduce the
incidence of early posttraumatic seizures (PTS) in patients with TBI compared
to placebo. Another study also stated that giving anticonvulsants
(Carbamazepine, Phenobarbital, Phenytoin, Levetiracetam and Valproate) in
preventing early PTS showed effective results in TBI when compared to
placebo. So, it can be concluded, based on the literature search conducted,
anticonvulsants are proven to be able to prevent PTS, with the recommendation
of drug choice being Phenytoin. |
|
DOI: 10.58860/ijsh.v2i6.54 |
|
Corresponding
Author: Filipo David Tamara
E-mail: davidtamara017@gmail.com
INTRODUCTION
Traumatic brain injury (TBI) is a non-degenerative,
non-congenital disorder of the brain that occurs due to external mechanics that
can cause permanent or temporary impairment of cognitive, physical and
psychosocial functioning (Dawodu,
2021). Traumatic brain injury can be caused by a collision, blow
or jolt to the head or a penetrating head injury that disrupts the brain's
normal function (Capizzi et al., 2020). The Centers for Disease Control and Prevention (CDC) stated that 2014
there were 2.53 million emergency room visits with TBI cases. Adults aged 75
years and over had the highest rate of TBI-related Emergency Room visits (1682
per 100,000 people), followed by young children aged 0 to 4 years (1618.6 per
100,000 people) and lastly followed by adolescents and young adults aged 15 to
24 years (1010.1 per 100,000 people) (Capizzi et al., 2020). An epidemiological study by Dewan et al. states that an estimated
sixty-nine million people suffer from TBI from all causes yearly, with the
Southeast Asia and West Pacific regions experiencing the most significant
overall disease burden (Dewan et al., 2018). Basic Health Research 2018 The prevalence of head injuries in
Indonesia is 11.9%, with the highest prevalence in Papua (16.5%) and the lowest
in South Kalimantan (8.6%) (Ministry of Health, 2018). Everyone has a risk of developing TBI, but certain groups are more
vulnerable, such as older adults, women exposed to intimate partner violence,
the homeless population, prisons and workers in high-risk jobs (Mollayeva et al., 2018).
The Brain Trauma Foundation and the American Academy of
Neurology recommend prophylactic use of anticonvulsants to reduce the incidence
of early posttraumatic seizures within seven days after TBI. This
recommendation is based on the literature showing that prophylaxis with
Phenytoin effectively reduces the risk of early posttraumatic seizures but may
not effectively reduce the risk of late posttraumatic seizures (PTS) (Zimmermann et al., 2016). Research conducted by Kirmani et al. also stated that Phenytoin be the
anticonvulsant of choice because it is widely studied and researched compared
to other anticonvulsants, but further prospective clinical trials are needed
regarding Phenytoin to prove its efficacy as a first-line agent in PTS (Kirmani et al., 2016). This study aimed to assess the efficacy of anticonvulsants as
prophylactic therapy in patients with TBI in Indonesia, sehingga dapat
diketahui langkah yang tepat untuk pemberian profilaksis pada pasien traumatic
brain injury.
METHODS
The research design used in writing this journal is to
use a literature review method related to the definition, epidemiology, predisposition,
or risk factors for traumatic brain injury with the keywords traumatic brain
injury, anticonvulsant, and prophylactic therapy. The literature sources that
the authors use include Google Scholar, Pubmed, Medline, Ebsco, Hindawi,
ScienceDirect, and Cochrane, which were published in the last ten years. We restricted the included studies to English language and
adults post traumatic brain injury after undergoing hospitalized. Any types of
articles were included, except an abstract-only publication and those that did
not report the outcome of interest. Based on the search results, journal
selection was carried out, and journals that met the criteria were obtained.
The author then reviews each journal that meets the criteria and then writes
literature.
RESULTS AND DISCUSSION
Traumatic Brain Injury
Traumatic Brain Injury is a non-degenerative, non-congenital disorder of
the brain that occurs due to external mechanics that can cause permanent or
temporary impairment of cognitive, physical and psychosocial functioning (Dawodu,
2021). Traumatic Brain Injury is
divided into two categories, namely penetration and non-penetration.
Penetrating traumatic brain injury occurs when an object penetrates the brain
and enters the brain tissue. At the same time, non-penetrating TBI is caused by
an external force strong enough to cause trauma to the part of the brain inside
the skull (National
Institute of Neurological Disorders and Stroke, 2023).
Traumatic Brain Injury is a case that is often found in the emergency
room. Based on data from the CDC, in 2014 there were around 288,000 cases, and
56,800 of them died. Adults aged 75 years and over had the highest TBI-related
ED visit rate (1682 per 100,000 people), followed by young children aged 0 to 4
years (1618.6 per 100,000 people) and lastly followed by adolescents and young
adults aged 15 to 24 years (1010.1 per 100,000 people) (Capizzi
et al., 2020). An epidemiological study by
Dewan et al. states that an estimated sixty-nine million people suffer from TBI
from all causes yearly, with the Southeast Asia and West Pacific regions
experiencing the largest overall disease burden (Dewan
et al., 2018). Basic health research in
2018, the prevalence of head injuries in Indonesia is 11.9%, with the highest
prevalence in Papua (16.5%) and the lowest in South Kalimantan (8.6%) (Ministry
of Health, 2018). Everyone has a risk of
experiencing TBI, but groups of adults, women who experience domestic violence,
the homeless population and workers in high-risk jobs are at greater risk of
experiencing TBI (Mollayeva
et al., 2018).
The most common complication of TBI is the occurrence of posttraumatic
seizures. As many as 20% of patients in the Intensive Care Unit (ICU) and 25%
-50% outside the ICU have post-TBI seizures (Zimmermann
et al., 2016). Posttraumatic seizures are
classified into early onset, which occurs from 0-7 days after trauma, and
late-onset, which occurs after seven days post-trauma, usually occurring in
patients with moderate or severe TBI (Wat
et al., 2019). A theory explains the
mechanism of post-TBI seizures using animal models. The first
posttraumatic day occurs with microRNA disruption, facilitating the transition
to seizure activity. Disrupted microRNA exacerbates glutamate-mediated
excitotoxicity after trauma. The induction of glutamate toxicity can be
regulated by releasing iron from damaged blood cells that diffuse across the
disturbed blood-brain barrier. The remaining neurons will participate in
functional and structural adaptations, such as axonal growth, to increase the
risk of subsequent hyperexcitability. Concomitant with changes in glutamate, a
substantial reduction in GABA-releasing interneurons in the hippocampus leads
to enhanced disinhibition time early posttraumatic (Lucke-Wold et al.,
2015).
Another theory suggests that after TBI, the
neuroinflammatory response is initiated rapidly, and the neuroinflammatory
response has a pro-epileptogenic role in developing PTE. In general, after TBI,
inflammatory cytokines, chemokines and complement proteins are rapidly
released. This immune response signals various cellular mediators and initiates
the acute phase response. Following this signal, astrocytes and microglial
cells are induced to become active, multiply and migrate to the site of injury.
Peripheral immune cells are also known to travel to the brain in response to
TBI. Once this immune or neuroimmune response is activated to re-establish
tissue homeostasis, these immune cells remove remnants and identify signalling
potential pathogens. While the most intense neuroinflammatory responses occur
relatively early (within hours and days after the trauma), low-grade
neuroinflammation often persists chronically. Several early neuropathology
reports acknowledged that progressive gliosis at the site of brain trauma is a
significant component of the development of an epileptogenic focus (Mukherjee et al.,
2020).
Days after injury, the damaged brain area can initiate
a response consisting of a series of injury cascades that interrupt normal
homeostasis. Part
of this response depends on the mechanistic target of rapamycin (mTOR) which is thought to
contribute to tissue damage and subsequent excitotoxicity. Mechanistic targets of rapamycin, in particular, have been
implicated in PTE pathology. Acute neuroinflammation activates Akt, which
phosphorylates mTOR and contributes to cell death. Toll-ligands and toll-like
receptors mediate another critical subacute response. Toll-like receptors
trigger the innate immune system and regulate non-NMDA glutamate channels.
Following trauma, activation of this toll-like receptor can lead to glutamate
excitotoxicity that persists for several weeks. Toll-like receptor four is
associated with temporal lobe spasms after trauma (Lucke-Wold
et al., 2015).
Anticonvulsant as Seizure
Prophylaxis in TBI Patients
Seizures after
head injury result in secondary brain damage, which includes increased
intracranial pressure, increased brain metabolic demands after head trauma and
excessive release of neurotransmitters resulting in more severe damage. The use
of anticonvulsants is to minimize brain damage by preventing early onset PTS (Kirmani
et al., 2016). The Brain Trauma Foundation
and the American Academy of Neurology for the Management of Severe TBI state
that seizure prophylaxis is only recommended for patients who experience TBI
during the first seven days (Zimmermann
et al., 2016). The recommended seizure
prophylaxis for TBI patients is Phenytoin. Phenytoin is more effective than
other anticonvulsants in preventing the risk of early-onset PTS. However, it
may not effectively reduce the risk of late-onset PTS (Wat
et al., 2019).
Other anticonvulsants,
such as Phenobarbital, Valproate and Carbamazepine, have not been extensively
studied. Considering their side effect profile and pharmacodynamic properties,
it can be concluded that there is no advantage of using these agents compared
to Phenytoin (Torbic et al., 2013). Anticonvulsants that have a neuroprotective effect
(Phenytoin) work by blocking voltage-dependent membrane sodium channels, which
are responsible for increasing the action potential. Through this way of
working, anticonvulsants can block the positive feedback that maintains
high-frequency recurrence, thereby preventing seizures (Gupta
& Tripp, 2022).
Relationship of
Anticonvulsants as Seizure Prophylaxis in Traumatic Brain Injury Patients
The study
conducted by Wang et al. of 11 studies of 2450 patients, comparing various
anticonvulsants prophylaxis to prevent early and late PTS in patients
with TBI, it was found that Phenytoin can reduce early PTS compared to placebo (Wang
et al., 2022). This is in line with
Thomson et al., who states that the administration of anticonvulsants (Carbamazepine,
Phenobarbital, Phenytoin, Levetiracetam and Valproate) in preventing early PTS
showed effective results in TBI when compared to placebo and effectively
reduced the occurrence of early PTS after head injury compared to placebo. No
statistically significant differences were observed when Phenytoin and
anticonvulsants were administered to others (Thompson
et al., 2015).
A study conducted
by Kumar et al. stated that prophylactic anticonvulsant therapy with Phenytoin
for 21 days was no more effective than prophylactic therapy with Phenytoin
given for seven days to reduce the frequency of seizures in TBI patients (Kumar
et al., 2022). This is similar to Kirmani
et al., who revealed that anticonvulsants have proven beneficial in the first
seven days after injury, where Phenytoin remains the anticonvulsant of choice
because treatment with Phenytoin is effective as a prophylaxis for seizures in
TBI patients (Kirmani
et al., 2016).
The study
conducted by Wat et al. recommends Phenytoin as prophylaxis in early PTS in
severe TBI even though early PTS is not associated with a poor prognosis and
prophylaxis with anticonvulsant drugs is not recommended as a prevention of
late PTS (Wat
et al., 2019). This aligns with Torbic et
al., who recommended using Phenytoin
for early PTS prophylaxis and stated that Valproate had shown similar efficacy
to Phenytoin. However, its use may increase mortality (Torbic et al., 2013). The study by Khan et al. stated that the administration of Phenytoin
could indicate an early PTS event which had to be given only for the first
seven days (Younus et al., 2018).
CONCLUSION
Traumatic Brain Injury is a non-degenerative,
non-congenital disorder of the brain that occurs due to external mechanics that
can cause permanent or temporary impairment of cognitive, physical and
psychosocial functions. One of the complications of TBI is PTS. The use of
anticonvulsants with Phenytoin as a recommendation has been shown to prevent
the occurrence of PTS in early-onset seizures in patients with TBI.
REFERENCES
Capizzi,
A., Woo, J., & Verduzco-Gutierrez, M. (2020). Traumatic Brain Injury: An
Overview of Epidemiology, Pathophysiology, and Medical Management. Medical
Clinics of North America, 104 (2), 213238.
https://doi.org/10.1016/J.MCNA.2019.11.001
Dawodu,
ST (2021). Traumatic Brain Injury (TBI) - Definition, Epidemiology,
Pathophysiology: Overview, Epidemiology, Primary Injury. Physical Medicine
and Rehabilitation.
Dewan,
MC, Rattani, A., Gupta, S., Baticulon, RE, Hung, YC, Punchak, M., Agrawal, A.,
Adeleye, AO, Shrime, MG, Rubiano, AM, Rosenfeld, JV, & Park, K.B. (2018).
Estimating the global incidence of traumatic brain injury. Journal of
Neurosurgery, 130 (4), 10801097.
https://doi.org/10.3171/2017.10.JNS17352
Gupta,
M., & Tripp, J. (2022). Phenytoin. Encyclopedia of Toxicology: Third
Edition, pp. 895897. https://doi.org/10.1016/B978-0-12-386454-3.00771-5
Ministry
of Health. (2018). RISKERDAS Main Results 2018. Republic of Indonesia
Ministry of Health.
Kirmani, BF, Robinson, DM, Fonkem, E., Graf, K., &
Huang, JH (2016). Role of anticonvulsants in the management of
posttraumatic epilepsy. Frontiers in Neurology, 7, 32.
https://doi.org/10.3389/FNEUR.2016.00032/BIBTEX
Kumar,
S., Bharti, A., Prasad, R., Kumari, S., Singh, A., & Yadav, G. (2022).
Efficacy of Phenytoin for seven days versus 21 days as a prophylactic
anticonvulsant in traumatic brain injury patients - A comparative study. Journal
of Family Medicine and Primary Care, 11 (8), 4805.
https://doi.org/10.4103/JFMPC.JFMPC_486_22
Lucke-Wold,
BP, Nguyen, L., Turner, RC, Logsdon, AF, Chen, YW, Smith, KE, Huber, JD,
Matsumoto, R., Rosen, CL, Tucker, ES, & Richter, E. ( 2015). Traumatic
brain injury and epilepsy: Underlying mechanisms leading to seizures. Seizure, pp. 33,
1323. https://doi.org/10.1016/J.SEIZURE.2015.10.002
Mollayeva, T., Mollayeva, S., & Colantonio, A. (2018).
Traumatic brain injury: sex, gender and intersecting
vulnerabilities. Nature Reviews Neurology 2018 14:12, 14 (12),
711722. https://doi.org/10.1038/s41582-018-0091-y
Mukherjee,
S., Arisi, G., Mims, K., Hollingsworth, G., O'Neil, K., & Shapiro, LA
(2020). Neuroinflammatory mechanisms of posttraumatic epilepsy. Journal of
Neuroinflammation 2020 17:1, 17 (1), 111.
https://doi.org/10.1186/S12974-020-01854-W
National
Institute of Neurological Disorders and Stroke. (2023). Traumatic Brain
Injury (TBI).
Thompson,
K., Pohlmann-Eden, B., Campbell, LA, & Abel, H. (2015). Pharmacological
treatments for preventing epilepsy following traumatic head injury. The
Cochrane Database of Systematic Reviews, 2015 (8).
https://doi.org/10.1002/14651858.CD009900.PUB2
Torbic,
H., Forni, A., Anger, K., Degrado, JR, & Greenwood, BC (2013). Use of
antiepileptics for seizure prophylaxis after traumatic brain injury. American
Journal of Health-System Pharmacy, 70 (9), 759766.
https://doi.org/10.2146/AJHP120203
Wang,
BC, Chiu, HY, Luh, HT, Lin, CJ, Hsieh, SH, Chen, TJ, Wu, CR, & Chen, PY
(2022). Comparative efficacy of prophylactic anticonvulsant drugs following
traumatic brain injury: A systematic review and network meta-analysis of
randomized controlled trials. PLoS One, 17 (3).
https://doi.org/10.1371/JOURNAL.PONE.0265932
What,
R., Mammi, M., Paredes, J., Haines, J., Alasmari, M., Liew, A., Lu, VM,
Arnaout, O., Smith, TR, Gormley, WB, Aglio, LS, Mekary, RA, & Zaidi, H.
(2019). The Effectiveness of Antiepileptic Medications as Prophylaxis of Early
Seizure in Patients with Traumatic Brain Injury Compared with Placebo or No
Treatment: A Systematic Review and Meta-Analysis. World Neurosurgery, 122,
433440. https://doi.org/10.1016/J.WNEU.2018.11.076
Younus,
SM, Basar, S., Ahmed Gauri, S., Ahmed Khan, A., Imran, M., Abubakar, S.,
Sheikh, D., Shehbaz, N., & Ashraf, J. (2018). Comparison of Phenytoin
versus Levetiracetam in Early Seizure Prophylaxis after Traumatic Brain Injury,
at a Tertiary Care Hospital in Karachi, Pakistan Original Article. Asian
Journal of Neurosurgery, p. 1096. https://doi.org/10.4103/ajns.AJNS_125_17
Zimmermann, LL, Diaz-Arrastia, R., & Vespa, PM (2016).
Seizures and the Role of Anticonvulsants After Traumatic
Brain Injury. Neurosurgery Clinics of North America, 27 (4),
499508. https://doi.org/10.1016/J.NEC.2016.06.001
|
|
©
2023 by the authors. It was submitted for possible open-access publication
under the terms and conditions of the Creative Commons Attribution (CC BY SA) license (https://creativecommons.org/licenses/by-sa/4.0/). |
