By Megan E. Barra, PharmD, BCPS, BCCCP, Brian L. Edlow, MD
The efficacy of pharmacologic stimulant therapy in patients with severe traumatic brain injury (TBI) was demonstrated in a 2012 randomized controlled trial that provided Level I evidence for using amantadine to accelerate subacute recovery.1 Amantadine therapy is now recommended for patients with post-traumatic disorders of consciousness in the 2018 Disorders of Consciousness management guideline.2 Although prescribing trends in stimulant use after the 2012 amantadine trial have yet to be fully characterized, it appears that stimulant use is increasing for patients with severe TBI, including off-label use of stimulant therapy in the intensive care unit (ICU).3 The clinical rationale for early initiation of stimulant therapy in the ICU is that accelerating recovery of consciousness in patients with acute severe TBI may facilitate self-expression, reduce immobility-related complications, improve access to rehabilitative care, and potentially aid prognostication.
Available evidence suggests that amantadine, methylphenidate, and modafinil are the most commonly utilized stimulant therapies in the ICU setting.4,5 Adverse drug effects of stimulant therapy in non-brain-injured people include insomnia, hallucinations, anxiety, aggression, agitation, delirium, and seizures.6 However, there are currently limited data on the side effect profile of stimulant therapies in patients with severe TBI, particularly in the ICU setting. Chief among ICU clinicians’ concerns is the possibility that these medications could increase the risk of seizures. The incidence of post-traumatic seizures varies widely in the literature, with data suggesting a new-onset seizure incidence of 8.9% within 24 hours of injury, 1.9% 1-7 days post-injury, and 1.8% > 7 days post-injury.7 However, early post-traumatic seizure rates have been reported to be as high as 25% in patients with severe TBI.8 Thus, for ICU clinicians considering initiation of stimulant therapy for patients with severe TBI, the potential increased risk of seizures is under heightened scrutiny.
In the 2012 amantadine trial, seizures were not more frequent in the amantadine group (2%) compared to the placebo group (4%), nor were epileptiform changes on electroencephalography.1 However, patients with >1 seizure in the previous month were excluded from the trial, making it difficult to ascertain the risk of seizures in this higher-risk patient population. Patients with TBI treated with dopamine agonists have not been found to have a higher risk of seizures in the retrospective or prospective literature to date, though safety outcomes were not always comprehensively reported.5,9-15 Recently, our group performed a retrospective study of stimulant use in 48 patients with acute TBI admitted to the ICU at two Level 1 trauma centers and found that adverse events requiring stimulant dose reduction or discontinuation were rare, with delirium (n=2), insomnia (n=1), anxiety (n=1) and rash (n=1) being the only documented adverse events (stimulant initiation 2-28 days post-injury).4
The risk of seizures with stimulant therapy has been more comprehensively studied in pediatric patients, particularly those diagnosed with both epilepsy and attention-deficit/hyperactivity disorder (ADHD). While cases of amantadine-induced seizures and electrographic epileptiform activity have been reported,16,17 amantadine has also been proposed as a potential adjunct anticonvulsant in select patient populations. Amantadine has been explored as a therapeutic option for refractory epilepsy in children with reported success for absence seizures at doses up to 7 mg/kg/day (200 mg/day maximum).18 A registry-based cohort study of 995 pediatric patients with ADHD and epilepsy recently found that stimulant medications, including methylphenidate, were not associated with an increased rate of seizures and trended towards a reduced rate of acute seizures following initiation.19 Furthermore, there are reports that epileptiform activity is either unchanged or reduced after initiation of methylphenidate therapy in this setting, despite the presence of refractory epilepsy or abnormal EEG.18, 20-23
Nevertheless, the United States Food and Drug Administration’s product description of methylphenidate warns that stimulants may lower the seizure threshold in patients with a prior history of seizures, with prior EEG abnormalities, and rarely, in patients without a history of seizures.24 Similar warnings in patients with epilepsy are noted with amantadine therapy.25 Clinicians thus must carefully consider the seizure risk in any patient receiving stimulant therapy, particularly patients with severe TBI for whom stimulant reduction of the seizure threshold is a possibility.
Overall, while the theoretical risks of stimulant-induced seizures in patients with severe TBI must be considered by clinicians, currently available data do not suggest a heightened risk of seizures in this patient population. However, studies conducted in the ICU setting have been underpowered to detect a statistically significant association between stimulant therapies and seizures. It therefore remains unknown whether early initiation of pharmacologic stimulant therapy for patients with acute TBI in the ICU is associated with an increased risk of seizures. In our opinion, the potential for an increased seizure risk should not preclude initiation of stimulant therapy in patients who may benefit from such treatment. Clinicians should consider other factors that may lower the seizure threshold (e.g. electrolyte disturbances, concomitant interacting medications, infection) when weighing the risks and benefits of stimulant therapy. Initiation of stimulant therapy at a low dose, with consideration of patient-specific pharmacokinetic parameters, careful uptitration, and close monitoring, may minimize risk in this patient population. Future clarification of the efficacy and adverse event rate of stimulant therapy in ICU patients with acute TBI will require large, multi-center studies that are statistically powered to account for potential confounders of the relationship between stimulants, outcomes, and adverse events.
- Giacino JT, Whyte J, Bagiella E, et al. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J Med 2012; 366: 819 – 826
- Giacino JT, Katz DI, Schiff ND, et al. Practice guideline update recommendations summary: Disorders of consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research. Neurology 2018; 91: 450 – 460
- Morrison A, Houtrow A, Zullo J, et al. Neurostimulant prescribing patters in children admitted to the intensive care unit after traumatic brain injury. J Neurotrauma 2019. DOI 10.1089/neu.2017.5585
- Barra ME, Izzy S, Sarro-Schwartz A, et al. Stimulant therapy in acute traumatic brain injury: Prescribing patterns and adverse event rates at two Level 1 trauma centers. Journal of Intensive Care Medicine. 2019; in press. PMCID pending.
- Frenette AJ, Janji S, Rees L, et al. Efficacy and safety of dopamine agonists in traumatic brain injury: a systematic review of randomized controlled trials. Journal of neurotrauma 2012; 29: 1 – 18
- Lexicomp Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2013; April 15, 2013
- Ritter AC, Wagner AK, Fabio A, et al. Incidence and risk factors of posttraumatic seizures following traumatic brain injury: a traumatic brain injury model systems. Epilepsia 2016; 57(12): 1968-1977
- Carney N, Totten AM, O’Reilly C, et al. Guidelines for the management of severe traumatic brain injury, fourth edition. Neurosurgery 2017; 80(1): 6 – 15
- Plenger PM, Dixon CE, Castillo RM, et al. Subacute methylphenidate treatment for moderate to moderately severe traumatic brain injury: a preliminary double-blind placebo-controlled study. Arch Phys Med Rehab 1996; 77(6): 536-540
- Moein H, Khalili HA, Keramatian K, et al. Effect of methylphenidate on ICU and hospital length of stay in patients with severe and moderate traumatic brain injury
- Ghalaenovi H FA, Koohpayehzadeh J, et al. The effects of amantadine on traumatic brain injury outcome: a double-blind randomized, controlled, clinical trial. Brain Injury 2018;32:1050 – 5
- Saniova B DM, Kneslova L, et al. The outcome of patients with severe head injuries treated with amantadine sulphate. J Neural Transm 2004;111:511-4
- Meythaler JM BR, Johnson A, Novack TA. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial. Journal of Head Trauma Rehabilitation 2002;17:300 – 13
- Abbasivash R, Hasanloei V, Kazempour A, et al. The effect of oral administration of amantadine on neurological outcome of patients with diffuse axonal injury in ICU. J Exp Neurosci 2019 [epub ahead of print]
- Gramish JA, Kopp BJ, Patanwala AE. Effect of amantadine on agitation in critically ill patients with traumatic brain injury. Clinical Neuropharmacology 2017; 40(5): 212-216
- Ohta K, Matsushima E, Matsuura M, et al. Amantadine-induced multiple spike waves on an electroencephalogram of a schizophrenic patient. The World Journal of Biological Psychiatry 2000; 1(1): 59 – 64
- Claudet I, Marechal C. Status epilepticus in a pediatric patient with amantadine overdose. Pediatr Neurol 2009; 40(2): 120 – 122
- Turner L, Perry MS. Outside the box: medications worth considering when traditional antiepileptic drugs have failed. Seizure – European Journal of Epilepsy 2017; 50: 173-185
- Brikell I, Chen Q, Kuja-Halkola R, et al. Medication treatment for attention-deficit/hyperactivity disorder and the risk of acute seizures in individuals with epilepsy. Epilepsia 2019; 60: 284 – 293
- Gucuyener K, Erdemoglu AK, Senol S, et al. Use of methylphenidate for attention-deficit hyperactivity disorder in patients with epilepsy or electroencephalographic abnormalities. J Child Neurol 2003; 18(2): 109 – 112
- Radziuk AL, Kieling RR, Santos K, et al. Methylphenidate improves the quality of life of children and adolescents with ADHD and difficult-to-treat epilepsies. Epilepsy and Behavior 2015; 46: 215 – 220
- Socanski D, Aurlien D, Herigstad A, et al. Attention deficit/hyperactivity disorder and interictal epileptiform discharges: it is safe to use methylphenidate? Seizure 2015; 25: 80 – 83
- Koneski JA, Casella EB, Agertt F, et al. Efficacy and safety of methylphenidate in treating ADHD symptoms in children and adolescents with uncontrolled seizures: a Brazilian sample study and literature review. Epilepsy Behav 2011; 21(3): 228 – 232
- Oral Ritalin (methylphenidate hydrochloride) Product Description [online]. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021284s020lbl.pdf. Accessed March 14, 2019
- Oral Symmetrel (amantadine hydrochloride, USP) Product Description [online]. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/016023s041,018101s016lbl.pdf. Access March 14, 2019