1. Pharmacotherapy in managing pediatric acquired brain injury Symposium on Pediatric Brain Injury Rehabilitation 25.3.2010 Olli Tenovuo MD, PhD University of Turku

2. Factors Affecting Neurobehavioral Outcome after TBI (Courtesy by D.B. Arciniegas, Univ. of Colorado) Traumatic Brain Injury Cognitive Disturbance Behavioral Disturbance Emotional Disturbance Physical Disturbance Post-Injury Factors Pre-Injury Factors Impaired Arousal Impaired Attention Slowed Processing Working Memory Problems Memory Disturbance Functional Communication Impairments Executive Dysfunction Depression Anxiety Irritability/Lability Rage Agitation Aggression Disinhibition Apathy Sleep Disturbance Fatigue Headaches Pain Visual Problems Dizziness/Vertigo Seizures

3. 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

4. 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

5. 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

6. 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

7. 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?

8. 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

9. 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

10. 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)

11. …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

12. 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

13. …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

14. Adapted from anatomic illustrations in Gilman and Newman 1987 Courtesy by D.B. Arciniegas / Univ. Of Colorado

15. Injury Factors: Neurochemistry Neurotransmitter “storm” at time of TBI –acute increases in glutamate 1-5, dopamine 6,7, norepinephrine 6,7, serotonin 6-9, and acetylcholine 10 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 TBI 6;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; )

16. 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 nuclei 1-3 –loss of cholinergic afferents 3,4 –dysfunction of cholinergically-dependent information processing circuits 5-8 Possible chronic primary or secondary dysfunction in serotonin-, dopamine-, norepinephrine-dependent neuropsychiatric functions 9 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)

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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.

25. 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

26. 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

27. 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

28. 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