Review
Medication in the treatment of the behavioural sequelae of traumatic brain injury Gordon Bates MB ChB MMedSc MRCPsych, Consultant Child and Adolescent Neuropsychiatrist, Birmingham Children’s Hospital, Parkview Clinic, Birmingham, UK. Correspondence to author at Birmingham Children’s Hospital, Parkview Clinic, 60 Queensbridge Road, Moseley, Birmingham B13 8QE, UK. E-mail:
[email protected]
A significant proportion of children who sustain traumatic brain injury will go on to experience disturbance in their academic, emotional, and social functioning. There is a role for medication in the treatment of these late onset changes. This review will focus on the recognition and pharmacological treatment of the most common and most problematic presentations that may follow head injury, and supports the use of stimulant medication for secondary attention-deficit–hyperactivity disorder despite the small evidence base for use in children.
Head injury is common in young people and advances in supportive care mean that more children are surviving serious brain injury than previously. However, once out of intensive care these children and their families may encounter an entirely new set of problems as the long-term results of traumatic brain injury (TBI) become manifest in alterations of cognitive functioning, emotions, and behaviour. Less common causes of brain injury include infections, cerebrovascular accidents, brain surgery, and radiotherapy. This article provides an overview of the medications that can be useful in the treatment of these aspects of TBI. Due to the shortage of high quality studies in this area, findings from trials on adult TBI or learning disability* and from my own clinical experience have been included. Interested readers will find a more exhaustive account in Gaultieri’s book.1 Medication can be a powerful ally when used judiciously and child neurologists and psychiatrists need to develop skills in psychotropic drug use and in recognition and management of the organic causes of behavioural disturbance respectively. Background At the last national annual review of causes of hospital admissions, head injury accounted for 34 302 admissions to UK hospitals for those under the age of 15 years.2 The principal causes of TBI vary with age. In the early years, falls and non-accidental injury predominate; in later years, road traffic accidents as pedestrians and vehicle passengers are the leading cause of hospital admission. The most common types of TBI result in ‘closed’ head injury where the pathological effects are mediated by rapid deceleration. To some extent the pattern of later difficulties can be predicted by knowledge of the pathological process involved. The rapid deceleration causes damage by several mechanisms: *North American usage: mental retardation.
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direct physical trauma to the surface of the brain (coup and contracoup), shearing forces (when there is a rotational component) which affect more medial structures, and the delayed phenomenon of diffuse axonal degeneration. The superficial frontal areas of the brain are at most risk from coup and the frontotemporal structures are highly vulnerable to shearing forces. Diffuse axonal degeneration3 describes the widespread neuronal death that can occur several months after the initial insult. It follows that the psychological processes mediated by the frontal and temporal lobes are at particular risk in TBI. This is observed clinically in high rates of impulsiveness, emotional lability, impaired social judgement, and memory problems. Contrary to popular wisdom, TBI in younger children tends to have global and profound effects4 whereas in older children the effects can be more focal. The severity of the head injury shows a correlation with the likelihood of later emotional and behavioural disorder. Personality change and psychiatric disorder were found in 59% of children with head injury admitted with a Glasgow coma score of 8 or less (top score 15=normal).5 Other indicators of severity such as the duration of posttraumatic amnesia, and the period from injury to the return of continuous day-to-day memory also predict poorer outcome.6 Gerring et al. demonstrated that a premorbid diagnosis of attention-deficit–hyperactivity disorder (ADHD) was present in 20% of a group of 89 children with severe TBI and this linked to poorer prognosis.7 Assessment There are several good papers that address the assessment of children with TBI.8 This is an area where a multidisciplinary team can come into its own. Information is required from clinical interview of the child and parent, and correspondence with the school or a school visit. This should be supplemented by baseline neuropsychological evaluation and occupational therapy assessment of functioning in the home environment. Detailed neuropsychological testing may be required to pick up subtle changes in memory or cognitive deficits that may cause secondary behavioural problems due to frustration. Good communication with the school is critical. The evaluation of family functioning is equally important as TBI affects the whole family, with issues of overprotection, rejection, bereavement, change of role, and loss of income if one of the parents becomes a full-time carer. Range of disorders Neuropsychiatric assessment focuses on emotional disturbance and problem behaviours. This is an area where clearcut diagnoses are less common and clinical decision-making has to be led by the identification of behavioural clusters rather than finding that patients fulfil full internationally agreed diagnostic criteria. In the research setting, the most common diagnoses found are secondary ADHD and organic personality disorders.9 These labels are helpful only up to a point. Depressive and anxiety disorders are the next most common conditions and are rather more useful for planning treatment. Apathy, sleep problems, and impaired memory and concentration are also common. SECONDARY ADHD
The term ‘Secondary ADHD’ was introduced by Gerring et al.7 and remains controversial. Attentional problems and disinhibited behaviour are common sequelae of TBI and, in
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most, are observed to improve with time. Given that the aetiology and course differs to primary ADHD, how appropriate is it to apply the same diagnostic label? In those with head injury the pathophysiology is likely to be very different to primary ADHD and the hyperkinetic component is usually less severe.6 Nevertheless, the concept has practical utility for treatment planning and has been taken up by several authors. Max et al.9 found secondary ADHD in 5 out of 13 consecutive children admitted with severe TBI. After excluding children with premorbid ADHD, Gerring et al. diagnosed the condition in 15 out of 80 (19%) children with moderate and severe TBI.7 The perceived similarities between primary and secondary ADHD led clinicians to use stimulants after head injury with some anecdotal success. Lipper and Tuchman10 first described the successful use of stimulants in a young man with TBI in 1977. Unfortunately, the evidence base for this approach has not developed greatly since then. Jin and Schachar’s recent systematic review11 found only three studies which examined the safety and efficacy of methylphenidate in children with symptomatic brain injury. Of these, two were randomized double-blind placebo controlled trials.12,13 By the inclusion of seven adolescents from two adult studies, the total sample size amounted to 41 patients, all with severe TBI as previously defined. The average dose of methylphenidate administered was around 0.3mg/kg, a standard dose regimen. The two major paediatric studies yielded apparently contradictory results. One study demonstrated improvements across all measures of attention and concentration.13 The other showed no significant difference between methylphenidate and placebo across a number of behavioural and cognitive measures.12 The contrasting findings may be explained by two important differences. The successful treatment group were treated earlier following their injury and for a longer period. Jin and Schachar concluded that the evidence was ‘modest’ and that further research was required. They found that methylphenidate was more effective for behavioural problems, such as impulsiveness and hyperactivity, than for cognitive difficulties, such as concentration impairment or mental fatigue, and was probably more effective if used within months of the trauma, although the response rate was not as high or predictable as for primary ADHD or for adult TBI. It was safe to use in this group with no major adverse events. The standard rating scales for ADHD can also be used to monitor progress in secondary ADHD.14,15 Concerns about the possibility of increased risk of seizures in patients with brain injury who are taking methylphenidate have not been substantiated. In fact, the only study addressing this issue showed a reduction in seizure frequency in brain-injured adults with seizure disorders who were taking methylphenidate.16 In practice, many clinicians are familiar with stimulant use. At correct doses they have rapid and easily observable effects on impulsive behaviour, restlessness, and concentration. Their side effects are well described (appetite and weight loss) and short-lived. This makes them excellent for use in therapeutic trials. Provided the clinician is aware of the possibility of short-term placebo response and is prepared to discontinue early if there is no clinical response or intrusive side effects, the evidence supports early stimulant use for secondary ADHD in TBI.
INTERMITTENT EXPLOSIVE DISORDER
Intermittent explosive disorder (IED) is a useful term to describe severe episodic outbursts of physical and verbal rage which are usually out of character and disproportionate to the provocation. It has the advantages of clarity of communication and freedom from any association with aetiology, unlike episodic dyscontrol syndrome.17 This disorder is associated with a number of behavioural phenotypes, autism, and focal epilepsy syndromes as well as TBI. These temper outbursts are a common long-term outcome of TBI and occur both in association with secondary ADHD and in isolation. In the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)18 classification, IED after head injury is usually picked up by the categories of organic personality disorder (OPD)-Labile type and OPD-Aggressive type. In the study by Max et al.5 of 37 children aged between 5 and 14 years with previous severe brain injury, 59% had an OPD. The majority of these OPDs were the two subtypes discussed above. IED is among the hardest behaviours to manage and causes high levels of stress in carers.19 There are no studies that look directly at treatment of IED in children with head injury. The observation that stimulants are useful for aggression regardless of the ADHD diagnosis applies in conduct disorder20 and appears to apply to adults with head injury.21 The previous reasons for use of stimulants, cited for secondary ADHD also apply in this clinical scenario. Other medications that may be helpful for IED include carbamazepine,22 risperidone,23 and lithium,24 although the studies cited involve adults, children with learning disability, and in-patients respectively. ABULIA / APATHY
Abulia is the term given to the loss of drive and motivation seen in a variety of neuropsychiatric conditions. It is one of the most devastating sequelae of TBI. The essential features are a lack of overt behaviour, a lack of emotional reaction to circumstances, and an apparent lack of concern or thought about these issues. It can present like a depressive disorder but accurate history taking can usually separate the two. Abulia was found in 5 out of 37 (14%) children with severe TBI at 1 year follow-up in the study by Max et al.5 To my knowledge there are no case reports of medication use in children with abulia. Extrapolating findings from adult studies25 I have found stimulants to be helpful. Other authors suggest a role for the dopamine partial agonist, amantidine,26,27 and bromocriptine.28 SLEEP DISTURBANCE
Sleep disturbance following head injury has been well described in adults. The limited child literature is reviewed by Stores29 without mention of medication. Various forms of sleeplessness and excessive daytime drowsiness have been described. Problems with sleep initiation appear most common. Farmer et al.30 suggest that for milder childhood head injury this may be a non-specific effect of the emotional trauma and that the symptom is short-lived. For chronic problems of sleep onset that do not respond to behavioural management, melatonin has been useful for some patients and not just those with delayed sleep phase syndrome.31 Disordered melatonin secretion has been demonstrated in some, but not all, adults with head injury. 32 While posttraumatic narcolepsy is rare, daytime sleepiness
is common, and in adults this is more problematic than sleep initiation in the longer term. Lesions to the posterior hypothalamus, third ventricle, and posterior fossa are most commonly implicated in adults. Stimulants can have a role here too. The sustained release preparations have practical advantages and both the older stimulants methylphenidate and dexamphetamine33 and modafanil34 are used in adult practice. SEXUAL DISORDERS
Reduced sexual drive after head injury is far more common than hypersexuality but does not provide such a problem for carers or society. Gualtieri35 makes the important distinction between the combination of sexual preoccupation and social disinhibition, which occurs without interest in the sexual act itself, and the problems of increased sexual drive. Most teenage males that I have seen encounter problems as a result of their impaired social awareness as much as their disinhibition. They are less aware of where and where not to touch and of the importance of a female’s age in what constitutes acceptable sexual behaviour. Detailed history taking is, therefore, essential before considering any antilibidinal treatment. Cyproterone acetate, an antiandrogen, is the most widely used drug in these cases. It has been shown to reduce masturbation, indecent exposure, and sexual offences in men with learning disability.36 In the UK, the 1983 Mental Health Act requires the involvement of a second opinion doctor appointed by the Mental Health Commission before initiating treatment. Medroprogesterone acetate, another antiandrogen, and goserlin, a luteinizing hormone-releasing factor analogue are also used in the USA. The difficulties and hazards of drug treatment should be weighed up against the custodial sentence for the patient and the possible harm to others that may follow by not treating. FEEDING DISORDERS
Specific hypothalamic injury and temporal lesions may result in driven excessive eating behaviour (bulimia). The resulting weight gain causes additional morbidity and even mortality.37 Dietary restriction and practical approaches like the use of refrigerator locks are the most obvious interventions but not always possible. There is only a case report literature to guide the clinician in this challenging area. The complex physiology of appetite control is demonstrated by the number of approaches that have been reported as successful. Organic bulimia may respond to the opiate antagonist naltrexone,38 carbamazepine,39 the somatostatin agonist ocreotide,40 and sibutramine, a serotinergic and noradrenergic reuptake inhibitor.41 The effectiveness of topiramate42 and high-dose fluoxetine43 in other conditions of overeating, combined with their familiarity and usefulness in epilepsy and depression, has meant that they are also utilized. Loss of appetite can also follow head injury. It may be the result of a primary problem with smell or taste. It can also occur when there are swallowing difficulties, as the child learns to associate food with choking. Another group of children develop feeding problems as they learn to use mealtimes to demonstrate their control, however limited, over themselves and their destiny. Ensuring the child develops autonomy more adaptively is the most helpful intervention. Steroids usually given as part of hormone replacement therapy may also help to stimulate appetite.
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OTHER PSYCHIATRIC DISORDERS
Depression, mania, anxiety, posttraumatic stress disorder, obsessive compulsive disorder, and psychosis can all follow TBI. There can be both organic and psychosocial causes to take into account. With the exception of depression, which can be confused with abulia, the presentation is little different to that in the child without brain injury. It is important to look out for these potential complications and quite reasonable to refer to a non-specialist child psychiatrist who should consider psychological interventions as well as pharmacological ones. Unfortunately, there is some evidence of increased treatment resistance. Conclusions TBI is common and specialist services, particularly those with neuropsychiatric skills, are relatively rare. In the UK, drug treatment is underutilized in the treatment of young people with emotional and behavioural disorders following brain injury. There is a small but growing body of literature which demonstrates the effectiveness of stimulants in particular, across a variety of syndromes. Despite the complexities of assessment, stimulants are simple to use with predictable side effects and have become familiar for neurologists, developmental paediatricians, and child psychiatrists. They could even be used more often. There may also be a role for specialist prescribing in some of the more challenging behavioural syndromes described.
DOI: 10.1017/S0012162206001472 Accepted for publication 24th May 2006. Acknowledgements I would like to thank Mike Prendergast for his assistance with the initial drafts. A version of this paper was first presented at the Royal College of Psychiatrists Child and Adolescent Faculty residential meeting 2004.
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34. Broughton RJ, Fleming JA, George CF, Hill JD, Kryger MH, Moldofsky H, Montplaisir JY, Morehouse RL, Moscovitch A, Murphy WF. (1997) Randomised double-blind placebo controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurology 49: 444–451. 35. Gualtieri CT. (2002b) The static neurobehavioral syndromes. In: Brain Injury and Mental Retardation: Psychopharmacology and Neuropsychiatry. Philadelphia: Lippincott, Williams & Wilkins. 36. Clarke DJ. (1988) Antilibidinal drugs and mental retardation: a review. Med Sci Law 29: 136–146. 37. Bates GDL, Sturman SG. (1995) Unilateral temporal lobe damage and the partial Kluver-Bucy syndrome Behav Neurol 8: 103–108. 38. Childs A. (1987) Naltrexone in organic bulimia; a preliminary report. Brain Inj 1: 49–55. 39. Stewart JT. (1985) Carbamazepine treatment of a patient with
Letter to the Editor ‘Respiratory chain deficiency in Aicardi–Goutie`res syndrome’ SIR–We have read with great interest the clinical observations of Barnerias et al.,1 who describe a 4-year-old female showing Aicardi-Goutières syndrome (AGS) in association with deficiency of complex I of the mitochondrial respiratory chain (MRC) in skeletal muscle, and deficiency of complexes I and IV in cultured skin fibroblasts, without large scale rearrangement or common DNA mutations in skeletal muscle. In view of these findings, the authors ask whether the observed oxidative phosphorylation deficiency is primary or secondary in AGS, and suggest a need for systematic evaluation of the MRC in skeletal muscle and skin fibroblasts in other patients with AGS. In this context, we have recently reported the cases of a 3-month-old male and an 11-month-old female with AGS.2 Both patients met all diagnostic criteria for AGS.3,4 The male showed persistently raised serum lactic acid levels and serum lactic/pyruvic acid ratio, as well as persistently raised lactic and pyruvic acid levels in cerebrospinal fluid (CSF), while other basic metabolic parameters (amino acids in blood and CSF, blood acylcarnitine profile, organic acids in urine) were normal. We therefore performed a biopsy of the lateral vastus muscle with the aim of evaluating the possible coexistence of MRC alterations. However, both histopathological studies (light and electron microscopy) and MRC complex levels in muscle homogenates were normal, so that in this case we can rule out the coexistence of MRC alterations. Thus, although this patient showed apparent biochemical indicators of oxidative phosphorylation alterations in blood and CSF, these alterations were not confirmed in muscle biopsies; we did not perform assays in cultured skin
Kluver-Bucy syndrome. J Clin Psychiatry 46: 496–499. 40. Lustig RH, Rose SR, Burghen GA, Velasquez-Mieyer P, Broome DC, Smith K, Li H, Hudson MM, Heideman RL, Kun LE. (1999) Hypothalamic obesity caused by cranial insult in children: altered glucose and insulin dynamics and reversal by a somatostatin agonist. J Pediatr 135: 162–168. 41. Arrango C, Rojas MJ, Moreno D, Parellada M. (2002) Sibutramine for compulsive eating in hypothalamic deficiency. J Am Acad Child Adolesc Psychiatry 41: 1147–1148. 42. Shapira N, Goldsmith T, McElroy S. (2000) Treatment of binge-eating disorder with topiramate: a clinical case series. J Clin Psychiatry 61: 368–372. 43. Goldstein DJ, Wilson MG, Thompson VL. (1995) Long-term fluoxetine treatment of bulimia nervosa. Br J Psychiatry 166: 660–666.
fibroblasts. In any case it has been established that on some occasions observed MRC alterations may be secondary to non-mitochondrial diseases, and that intermediate results of MRC enzyme determinations should be interpreted with caution.5,6 DOI: 10.1017/S0012162206001484
Manuel Castro-Gago MD* Carmen Gómez-Lado MD Jesús Eirís-Puñal MD Servicio de Neuropediatría, Departamento de Pediatría, Hospital Clínico Universitario, Facultad de Medicina, Santiago de Compostela, Spain. *Correspondence to:
[email protected] References 1. Barnerias C, Giurgea I, Hertz-Pannier L, Bahi-Buisson N, Boddaert N,Oustin P, Rotig A, Desguerre I, Munnich A, de Lonlay P. (2006) Respiratory chain deficiency in a female with Aicardi-Goutières syndrome. Dev Med Child Neurol 48: 227–230. 2. Blanco-Barca MO, Curros Novo MC, Álvarez Moreno A, Alonso Martín A, Eirís-Puñal JM, Castro-Gago M. (2005) AicardiGoutières syndrome: report of two new cases. An Pediatr (Barc) 62: 166–170. 3. Goutières F, Aicardi J, Barth PG, Lebon P. (1998) AicardiGoutières syndrome: an update and results of interferonalpha studies. Ann Neurol 44: 900–907. 4. Lanzi G, Fazzi E, D’Arrigo S. (2002) Aicardi-Goutières syndrome: a description of 21 new cases and a comparison with the literature. Eur J Paediatr Neurol 6 (Suppl A): A9–A22. 5. Hui J, Kirby DM, Thorburn DR, Boneh A. (2006) Decreased activities of mitochondrial respiratory chain complexes in non-mitochondrial respiratory chain diseases. Dev Med Child Neurol 48: 132–136. 6. Castro-Gago M, Blanco-Barca MO, Campos-González Y, Arenas-Barbero J, Pintos-Martínez E, Eirís-Puñal J. (2006) Epidemiology of pediatric mitochondrial respiratory chain disorders in northwest Spain. Pediatr Neurol 34: 204–211.
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