Critical Care Medicine-Neurologic Disorders>>>>>Neurotrauma
Question 3#

A 45-year-old female was riding her bicycle when she was struck by a car. She suffered a severe TBI requiring intracranial pressure (ICP) monitoring and treatment of elevated ICP with hyperosmolar therapy. Patient’s neurological status remained poor despite aggressive medical treatment, and she was eventually discharged to a skilled nursing facility following placement of a tracheostomy and gastrostomy tube. Six weeks following her initial injury, she was able to spontaneously open her eyes, track family, move all her extremities spontaneously, and reach for objects but not following commands. She had no verbal output or attempts at verbalization. Amantadine was considered by the primary team.

Which of the below comments is correct?

a. Amantadine can speed the rate of recovery
b. Amantadine can lower the seizure threshold and commonly results in seizures
c. Amantadine is the only studied pharmacologic agent in severe TBI that has shown improvement in functional outcomes
d. Amantadine can improve multiple behavioral domains, and the most commonly affected is vocalization
e. Although not fully elucidated, the mechanism by which amantadine works is through tubuloinfandibular pathway D2 receptor

Correct Answer is A

Comment:

Correct Answer: A

Approximately 10% to 15% of patients with severe TBI are discharged from acute care in a vegetative state. Amantadine is a weak antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor, which increases dopamine release and blocks dopamine reuptake. The largest study of amantadine evaluated its use in the subacute setting (approximately 1- 2 months following TBI) and involved 184 patients. All patients were in a minimally conscious state or vegetative state. Of those that received amantadine, the initial dose was 100 mg twice a day and could be increased to 200 mg twice a day. Those that received the medication had a more rapid improvement in the behavioral domains examined and of those the most affected was object recognition with the least affected being verbal output. At the end of the 4-week study, there was a 2 week washout phase all patients had continued improvement, but those in the placebo group had more rapid recovery and improvement to the same functional outcome. There were no differences in the number of adverse events with the medication as compared to placebo, and specifically there were two patients in the treatment and four patients in the placebo group with seizures. Although postulated in the trial, there is an uncertain mechanism of action for amantadine’s activation in severe TBI. Studies have demonstrated increase in PET activity in the prefrontal cortex as well as increase in striatal D2 dopamine-receptor availability.

References:

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  3. Giacino JT, Whyte J, Bagiella E, et al. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Eng J Med. 2012;366:819-826.
  4. Kraus MF, Smith GS, Butters M, et al. Effects of the dopaminergic and NMDA receptor antagonist amantadine on cognitive function, cerebral glucose metabolism and D2 receptor availability in chronic traumatic brain injury: a study using positron emission tomography (PET). Brain Inj. 2005;19:471-479.
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