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Three Part Question

For [children with an acquired brain injury] does the [administration of carbamazepine] reduce [agitation and aggressive behaviour]?

Clinical Scenario

A 14-year-old boy sustains a brain injury and is admitted with a Glasgow Coma Scale score of 3/15. Imaging reveals evidence of diffuse injury. Approximately 12 months later, the patient is seen for a planned review in an outpatient clinic. Full reintegration into school has occurred and clear cognitive and physical improvements are evident. Despite this, the patient and his family explain that unprovoked episodes of agitation, aggression and emotional lability occur. These have not lessened in frequency and represent a clear departure from the patient's preinjury behaviour. Parental and school management of this concerning conduct is structured and consistent. You have heard that carbamazepine (CBZ) may be of value in managing post-injury agitation and aggression.

Search Strategy

An advanced search of AMED, CINAHL, EMBASE, MEDLINE, psychINFO and Google Scholar was completed. All databases were searched from 1980 to the present (February 2010) except AMED, which was searched from 1985 to the present.
Cochrane Library (including Cochrane Reviews, Database of Abstracts of Review of Effects (DARE) and Clinical Trials and BestBETS) were searched using the terms ‘brain injury’ and ‘aggress*’ and ‘paediat*’ or ‘child*’ in the ‘Search All Text’ fields: no relevant results were found.

Search Outcome

Search terms included: ((traumatic adj2 brain adj2 injur*) OR (brain adj2 injur*) OR (head adj2 injur*) OR (acquired adj2 brain adj2 injur*)) AND ((paediat*) OR (child*)) AND ((treat*) OR (interven*)) AND ((aggress*) OR (irrita*) OR (agitat*) OR (anger*)) AND ((antiepileptic adj2 drug*) OR (anti-epileptic adj2 drug*) OR (AED*)) OR ((Carbamazepine OR Tegretol)).

Of 24 papers retrieved, only two were relevant to the question

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Roberts et al, 1995	N=1 (aged 7 at time of accident) with mild TBI	Single case study (level 5)	Number of episodic symptoms	Length of follow-up: 6 years post-injury. Significant improvement in many episodic symptoms.	Only started on clinical trial of CBZ 4 years after injury. Does not state how improvement in episodic symptoms was measured.
Parmalee et al, 1988	3 cases	Single case study (level 5)	Case 1 N=1 (aged 14) with TBI - Aggression and psychotic features	No improvement in aggression or psychotic features. Developed “decreased motivation”. Discontinued on day 14.	Case 1 CBZ co-administered with lithium carbonate. Does not state how aggression or psychotic features were measured. Co-morbidity of hallucinations and delusions. Case 2 CBZ co-administered with lithium carbonate. Does not state how agitation and aggression were measured. Extensive history of drug and alcohol abuse. Case 3 CBZ co-administered with lithium carbonate. Patient's past history included possible diagnosis of attention deficit disorder.
			Case 2 N=1 (aged 17) with TBI - Agitation and aggression	No improvement in “general manageability” of patient. Marked deterioration in behaviour and mental status noted. Discontinued on day 13.
			Case 3 N=1 (aged 19) with TBI - Irritation and aggression	Displayed increasing disorientation and obtundation with severe regression in all spheres of rehabilitation

Comment(s)

In 2008–2009, head injury accounted for over 34 000 admissions to UK hospitals of patients under the age of 15 years (DOH). Children often exhibit increased aggressive behaviour after acquired brain injury (ABI), particularly when there was a pre-morbid history of aggression, attention problems or anxiety (Cole). These aggressive behaviours may include anger outbursts, agitation, irritability and disinhibition. These characteristics are a source of burden to the family, compromise social functioning (Perino), may impair engagement with warranted therapies and delay discharge. Adult studies have indicated antiepileptic drugs (AEDs) may be useful in the treatment of these symptoms. In particular, these studies highlight the use of CBZ in alleviating such behaviours (Perino, Azouvi).

A systematic review revealed little published evidence for the use of CBZ in the management of agitation and aggressive behaviours in a paediatric population. Only two citations were retrieved involving the administration of CBZ to paediatric patients with ABI for this purpose. These citations both involved single case studies. Roberts et al reported the efficacy of CBZ in the treatment of emotional outbursts following mild traumatic brain injury (TBI) and Parmelee and O'Shanick reported three separate cases in which CBZ was co-administered with lithium to adolescents following TBI, producing adverse effects. Results from the latter study may have been attributable to confounding variables such as co-morbidities and the co-administration of lithium carbonate. The retrieved studies made no reference to a possible effect of puberty.

The 2008 Cochrane review of the pharmacological management of agitation and aggression in individuals with ABI identified six randomised controlled trials (RCTs) (Greendyke et al,Brooke et al,Mooney and Haas and Schneider et al), none of which evaluate the use of CBZ. Four of the six RCTs investigated the role of beta-blockers. The authors found no firm evidence for the efficacy of AEDs in the management of agitation and aggression following ABI, nor did they distinguish between studies involving a paediatric or adult population. The Cochrane review excluded 67 papers, only one of which evaluated the use of CBZ in the paediatric population, using case study methodology (Parmelee and O'Shanick). The presented Roberts et al article was not included in the Cochrane review and was retrieved by the present authors. Further scrutiny of the 67 studies excluded by the Cochrane review determined that many of them did not involve a paediatric population. The Cochrane review concluded that numerous drugs have been used in the management of agitation and aggression in patients with ABI but without firm evidence of their efficacy. The authors explicitly advocate the use of CBZ in patients demonstrating agitation and aggression after ABI, as CBZ appears to be well tolerated yet without neurological side effects. This is further supported by previous investigation into the effects of CBZ in the paediatric population (Pellock). From the retrieved and reviewed studies, length of CBZ administration ranged from 6 to 12 weeks with a dosage range from 100–400 mg/day (starting dose) to a maximum of 600–1200 mg/day. While the Cochrane review recommended that if no benefit became apparent after 6 weeks the drug should be withdrawn, the retrieved studies demonstrated an administration period of 6–12 weeks.

The Cochrane review revealed that despite CBZ typically being chosen as the drug of choice when attempting to manage aggressive behaviours following ABI, there is a complete lack of well designed RCTs investigating its effectiveness. While an absence of evidence for effectiveness is not synonymous with evidence for ineffectiveness, appropriately designed trials evaluating the use of CBZ in the management of agitation and aggression are required for the paediatric population.

It is important for both research and clinical practice that an RCT on the use of CBZ for the management of aggressive behaviours following paediatric ABI is conducted; the implications may be significant if CBZ is found to be effective. Agitated behaviour is common following paediatric ABI and may significantly impede engagement with planned rehabilitation (Cole), so AED management of such behaviour could facilitate faster and enhanced recovery. Given the potential benefits of CBZ, it is recommended that (i) treatment is conducted using a planned, closely monitored n-of-1 trial approach and (ii) an RCT is carried out to establish the efficacy of CBZ in the management of agitation and aggression in paediatric patients with an ABI, and this too is supported by the 2008 Cochrane review.

Editor Comment

ABI, acquired brain injury; CBZ, carbamazepine; TBI, traumatic brain injury.

Clinical Bottom Line

Carbamazepine (CBZ) has been used in individuals with aggressive behaviours after acquired brain injury (ABI) with conflicting results. (Grade D)

Individualised n-of-1 monitored trials of CBZ for paediatric ABI with agitation and aggression over 6–12 weeks or inclusion in a therapeutic randomised controlled trial is advised. (Grade D)

References

1. Department of Health. Hospital Episode Statistics, 2008–2009. http://www.dh.gov.uk/en/publicationsandstatistics/statistics/hospitalepisodestatistics/index.htm (Accessed January 2010).
2. Cole WR, Gerring JP, Gray RM, et al. Prevalence of aggressive behaviour after severe paediatric traumatic brain injury. Brain Inj 2008;13:139–48.
3. Perino C, Rago R, Cicolini A, et al. Mood and behavioural disorders following traumatic brain injury: clinical evaluation and pharmacological management Brain Inj 2001;15:139–48.
4. Azouvi P, Jokic C, Attal N, et al. Carbamazepine in agitation and aggressive behaviour following severe closed-head injury: results of an open trial. Brain Inj 1999;13:797–804.
5. Roberts MA, Manshadi FF, Bushnell DL et al. Neurobehavioural dysfunction following mild traumatic brain injury in childhood: a case report with positive findings on positron emission tomography (PET). Brain inj 1995;9:427–36.
6. Parmelee DX, O'Shanick GJ. Carbamazepine-lithium toxicity in brain-damaged adolescents. Brain inj 1988;2:305–8.
7. Fleminger S, Greenwood RRJ, Oliver DL. Pharmacological management for agitation and aggression in people with acquired brain injury. Cochrane Database Syst Rev . 2008;3:CD003299
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12. Mooney GF, Haas LJ. Effect of methylphenidate on brain injury-related anger. Arch Phys Med Rehabil 1993;74:153–60.
13. Schneider WN, Drew-Cates J, Wong TM, Cognitive and behavioural efficacy of amantadine in acute traumatic brain injury: an initial double-blind placebo-controlled study. Brain Inj 1999;13:863–72.
14. Pellock JM. Carbamazepine side effects in children and adults. Epilepsia 1987;28:S64–70.