Pharmacotherapy in managing pediatric acquired brain injury

Symposium on Pediatric Brain Injury Rehabilitation

25.3.2010

Olli TenovuoMD, PhD

University of Turku

Factors Affecting Neurobehavioral Outcome after TBI

(Courtesy by D.B. Arciniegas, Univ. of Colorado)

Traumatic Brain Injury

CognitiveDisturbance

BehavioralDisturbance

EmotionalDisturbance

PhysicalDisturbancePost-Injury

Factors

Pre-InjuryFactors

Impaired ArousalImpaired AttentionSlowed Processing

Working Memory ProblemsMemory Disturbance

Functional Communication Impairments

Executive DysfunctionDepression

AnxietyIrritability/Lability

RageAgitation

AggressionDisinhibition

ApathySleep Disturbance

FatigueHeadaches

PainVisual ProblemsDizziness/Vertigo

Seizures

Pharmacotherapy of acquired brain injury

• Evidence-based recommendations are lacking, especially in children

• Current concepts are based on clinical experience (≈ personal impressions), partly also on the deficient knowledge of brain injury neurochemistry

Principles of brain injury pharmacotherapy

Brain injury usually alters the tolerance for centrally acting drugs

→• increased risk for adverse effects

• increased likelihood for paradoxical reactions

• possibility for abnormal dose-responses and central interactions

Principles of brain injury pharmacotherapy

Brain injured subjects are prone to poor compliance→

• deficient motivation or self-awareness• poor ability to attach to long-term goals• memory problems, poor initiation • poor economic situation

Principles of brain injury pharmacotherapy

Assessing the treatment response is often difficult:

• daily and periodic fluctuations are pronounced due to low cognitive reserve

• subjective assessment of cognitive and especially of neuropsychiatric symptoms is unreliable and measuring eventual change is difficult

• both the subjects and the relatives may have biased conceptions of the true efficacy

Rationale of brain injury pharmacotherapy

1. Does the symptom severity require intervention?2. Do I have a biological basis for pharmacological

intervention?3. Do I have sufficient know-how to use the agent?4. Are there non-pharmacological alternatives?5. Are there contraindications for the specific agent?6. How can I follow and assess the response?7. Do the potential benefits outweigh the potential

risks?8. Is the patient/family willing and capable to carry

out the trial?

When is pharmacologic intervention indicated?

• The symptom disrupts considerably the normal life of the subject or the family and decreases markedly the quality of life

• The target symptom can be modified by pharmacologic intervention

• There are no non-pharmacologic alternatives or they have been tested without success

What is needed to accomplish a pharmacologic treatment trial?

• Sufficient familiarity with the pharmacological agent (dosing, adverse effects, contraindications, pharmacokinetics, response profile)

• Possibility to monitor the effects closely• Possibility to evaluate the treatment response reliably

(= repeatedly?)• Ability of the subject / family to carry out the trial• Will of the subject / family to carry out the trial

Practical principles

• Start with the lowest available dose• Increase the dose slowly• Monitor the response (in good or bad) closely• If you have started the trial, carry it out properly

(until therapeutic response has been achieved or adverse effects require discontinuation or maximum dose has been achieved)

• Remember to evaluate the pros and cons! (although cons may precede the pros)

…and when time goes

• If the response remains doubtful, there is probably no use to continue, or at least an interruption is indicated to evaluate the true benefit

• A true initial response may disappear with time – reassess regularly the indications to continue

• Recovery or other causes may make the treatment useless

• Beware of long-term adverse effects, which may be largely unknown

Special issues in children

• Official indications are usually lacking (= unlabeled / unapproved use)

• The lack of clinical and scientific experience increases the risk of adverse effects

• The effects of CNS-active agents on the developing brain may manifest themselves after a long delay (= short-term benefit may turn out to be a long-term loss)

• The reported trials having shown benefits have always lacked long-term follow-ups

…accordingly, when using pharmacotherapy for brain injury in children

• Use very tight indications

• Monitor the treatment very closely

• Have a low threshold to discontinue the treatment and do not leave the drug ”on” if not clearly indicated

• Use pharmacotherapy for babies and preschool children only in exceptional cases

Adapted from anatomic illustrations in Gilman and Newman 1987

Courtesy by D.B. Arciniegas / Univ. Of Colorado

Injury Factors: Neurochemistry• Neurotransmitter “storm” at time of TBI

– acute increases in glutamate1-5, dopamine6,7, norepinephrine6,7, serotonin6-9, and acetylcholine10 are reported from CSF samples in the acute post-injury period among persons with severe TBI

– these acute neurotransmitter excesses are functionally disruptive

– among those who survive their injuries, cerebral glutamate, dopamine, norepinephrine, and serotonin levels appear to normalize in the days to weeks following TBI6;11-13

Courtesy by D.B. Arciniegas / Univ. Of Colorado

(1. Wagner et al. 2005; 2. Kerr et al. 2003; 3. Yamamoto et al. 1999; 4. Alessandri et al. 1999; 5. Koura et al. 1998; 6. Markianos et al. 1996; 7. Markianos et al. 1992; 8. Porta et al. 1975; 10. Grossman et al. 1975; 11. Obrenovitch and Urenjak 1997; 12. Matsushita et al. 2000; 13. Goodman et al. 1996; )

Injury Factors: Neurochemistry

• Persistent damage in and dysfunction of areas with dense glutamate and acetylcholine inputs

• Chronic primary cortical cholinergic dysfunction– damage to cerebral cholinergic nuclei1-3

– loss of cholinergic afferents3,4

– dysfunction of cholinergically-dependent information processing circuits5-8

• Possible chronic primary or secondary dysfunction in serotonin-, dopamine-, norepinephrine-dependent neuropsychiatric functions9

Courtesy by D.B. Arciniegas / Univ. Of Colorado

(1. Dewar and Graham 1996; 2. Murdoch et al. 2002; 3. Salmond et al. 2005; 4. Murdoch et al. 1998; 5. Arciniegas et al. 1999; 6. Arciniegas et al. 2000; 7. Arciniegas et al. 2001; 8. Arciniegas et al. 2004. 9. In: Arciniegas and Silver 2006)

Treatment options – dopamine and norepinephrine

• Although the effects of dopamine and norepinephrine on cognition are complex, both may be most simply understood as facilitating cognition by increasing the signal-to-noise ratio within sensory and/or cognitive processing circuits– optimal DA and/or NE: processing of cognitively relevant targets

is facilitated

– excess DA and/or NE: information that would otherwise be cognitive “noise” (i.e., information not relevant to the task at hand) is increased, decreasing cognitive efficiency

– deficient DA and/or NE: “signal” is inadequately targeted, decreasing cognitive efficiency Courtesy by D.B. Arciniegas / Univ. Of Colorado

• Dopaminergic– Dopamine receptor

agonists– Levodopa

• Mixed dopaminergic and noradrenergic– Methylphenidate– Dextroamphetamine– Atomoxetine

Dopamine or norepinephrine augmentation

• Indirect dopaminergic effects via:– uncompetitive NMDA

receptor antagonism

• amantadine

• memantine

– ? modafinil

– ? lamotrigine

Dopaminergic agents

• Very few reports, almost all on very severely injured children

• Dopaminergic agents may be beneficial in provoking arousal from coma or facilitating recovery during the acute period

• May be considered as an option in the subacute period of the most severely injured children

Mixed dopaminergic and noradrenergic agents

• Methylphenidate is extensively studied in children, although well-conducted studies after ABI are few

• In subjects with pre-injury ADHD the drug is clearly indicated if ADHD-type symptoms persist

• There is moderate evidence that also children without pre-injury ADHD may benefit, in regard to attention, execution and fatigue

• The sole agent that can be used in brain injured children more liberally

Mixed dopaminergic and noradrenergic agents

• Dextroamphetamine is equally effective but has higher risk for addiction and misuse

• Atomoxetine is apparently well tolerated but possibly less effective than methylphenidate and more costly

Agents with indirect dopaminergic effects

• Memantine may be beneficial in ADHD but reports from brain injured subjects are lacking

• Several small reports have suggested beneficial effects of amantadine in mainly severely injured children, and it may considered an option for dopaminergic stimulation

• Modafinil may have serious dermatological side-effects in children and is not recommended

Acetylcholine and Cognition

FunctionAnatomy

(Mesulam 2000a, 200b; Selden et al. 1998; Blokland 1995; Aigner 1995; Sarter and Bruno 1997; Sarter and Turchi 2002)

• entorhinal-hippocampal formation

• sensory gating• attention• declarative

memory• executive

function• comportment,

or social intelligence

• motivation

• frontal-subcortical circuits

Courtesy by D.B. Arciniegas / Univ. Of Colorado

• reticular formation

• arousal and attention

Widespread cholinergic deficiency in subjects with TBI

Östberg A, Virta J, Rinne JO, Oikonen V, Luoto P, Någren K, Arponen E, Tenovuo O. Cholinergic Dysfunction after Traumatic Brain Injury – A PET Study. Submitted.

Cholinergic agents• No published reports after brain injury in children

• Reported to be safe and beneficial in autistic children (small study)

• Clinical experience suggests similar efficiency profile as in adults

• Improve fatigue, attention, and executive functions

• A real alternative in adolescents, possibly with caution in younger children

Other indications and agents

• The safety of serotonergic agents in children still a concern, post-injury depression requires child psychiatric evaluation

• Risperidone apparently safe for posttraumatic aggression, carbamazepine / oxcarbazepine possibly also effective (as in adults)

• Melatonin is the drug-of-choice for post-injury sleeping problems

A cautionary note

• Post-injury growth hormone deficiency is apparently more common than thought, and may be especially harmful in children

• Hypophyseal function should be screened at least in all severely injured children and also after milder injuries if the recovery is suboptimal

Future prospects

• The execution of randomized controlled trials with pharmacological agents is difficult in brain-injured subjects, and especially so in children

• We will probably have to wait for long before strong evidence for any agent can be obtained

• Age-specificity is a great challenge in children

• Availability of transmitter-specific biomarkers could be a realistic solution to guide individual treatment decisions