1. Dr Louise Reid, Consultant Clinical Neuropsychologist
The Effect of Amantadine on Level of Consciousness following Severe Brain Injury: A Case Study
Dr Louise Reid, Consultant Clinical Neuropsychologist

2. Definitions
Mr X
Methodology
Results
Conclusions

3. “Consciousness is an ambiguous term, encompassing both wakefulness and awareness. ‘Wakefulness’ is a state in which the eyes are open and there is a degree of motor arousal; it contrasts with sleep – a state of eye closure and motor quiescence.
‘Awareness’ is the ability to have, and the having of, experience of any kind. There is no simple, single clinical sign or laboratory test of awareness. Its presence must be deduced from a range of behaviours which indicate that an individual can perceive self and surroundings, frame intentions and interact with others” (RCP, 2013).

4. A prolonged disorder of consciousness (PDoC) refers to a state where a patient has wakefulness but absent or reduced awareness for more than 4 weeks. The term encompasses both the ‘vegetative state’ (no awareness) and the ‘minimally conscious state’ (reduced awareness).
Patients can transition from one to the other and on to normal consciousness, or may remain in one state for a prolonged period of time.

5. The vegetative state (VS) is wakefulness without awareness
The vegetative state (VS) is wakefulness without awareness. Patients have a sleep-wake cycle and may respond to stimulation with reflex and spontaneous behaviours, such as grasping and grimacing. However, there is no environmental awareness or purposeful movement.
The minimally conscious state (MCS) is wakefulness with minimal awareness. There is a broad spectrum of responsiveness within this umbrella term, ranging from patients who make a few non-reflex movements, to those who smile, cry or laugh in response to emotional stimuli, verbalise, or use objects (e.g. a hairbrush) in a consistent, meaningful manner. (RCP, 2013)

6. Treatment options
The Scottish Intercollegiate Guidelines Network (SIGN) suggests that Amantadine may be considered as a means of facilitating recovery of consciousness in patients following severe brain injury (SIGN 130; 2013).
SIGN 130 concluded that a dosage of mg of Amantadine can be used safely in patients following severe traumatic brain injury and may facilitate faster recovery of behaviours consistent with improved conscious level.
Amantadine is a dopamine agonist with antiparkinsonian effects.
The mechanism of action is unclear, although amantadine appears to act as an N-methyl-D-aspartate antagonist and indirect dopamine agonist.

7. Mr X

8. Mr X 50s Severe brain injury following an assault in 2014.
Traumatic subdural haemorrhage and cerebral oedema and he underwent hemicraniectomy.
Repatriated to Scotland
Tracheostomy removed
Cranioplasty in 2015 after which he was admitted to the rehabilitation unit.

9. Background
Past medical history of asthma, hepatitis C and IV drug misuse.
Undiagnosed bipolar affective disorder
Lived alone and had no steady employment.
Supportive partner, mother and siblings. Father deceased.
Studied Social Sciences at University for one year.
Described as being “reclusive” at times, particularly in the winter months when he would socially isolate himself.

10. Presentation Minimally conscious state (MCS). Aphasic
Severe weakness in all limbs and fixed flexion contractures at both knees and ankles.
Eyelid margin disease with associated ocular surface inflammation and left filamentary keratitis.
PEG fed
Full assistance of two; hoist
Incontinent
Fatigue
MCS was classified according to Royal College of Physicians (2013) definition.

11. Multidisciplinary approach
Assessment
Multidisciplinary approach
WHIM: 4 week (SLT, Psychology, OT)
Functional assessment: Physiotherapy, Occupational Therapy, Nursing team

12. Assessment findings Visual:
able to track and focus on stimuli in his environment
Auditory:
aware of noises on both left and right sides.
Able to inconsistently follow auditory commands to produce motor movements or indicate a yes response by using a ‘thumbs up’ or moving his feet, both left and right.
Tactile:
able to indicate some awareness of hot and cold when in the shower room, and indicated a comfortable temperature by thumbs up response.

13. Assessment findings Motor Function: No head control
Unable to sit unsupported
movement with both left and right legs during self-care tasks. When prompted he was able to raise his leg following a second delay, but requires support to maintain elevation.
demonstrated movement in both right and left arms, albeit inconsistent

14. Assessment findings Communication
demonstrated ability to functionally communicate throughout assessment with a yes/no response using either a buzzer (with his foot) or a thumbs up. (Inconsistent).
Wakefulness:
Noted to deteriorate over the course of the day.

15. Aim To investigate whether Amantadine improves level of consciousness.
Considered important as clinician’s noted that GS was unable to maintain consciousness during sessions with worsening over the course of the day. Rationale to improve consciousness and improve engagement in rehabilitation.

16. Methodology

17. Procedure One assessor
Four sessions per day to assess consciousness using the 5 point scale.
Data was presented fortnightly at the multidisciplinary team meeting where dosage/timing changes were made.

18. Assessment
A selection of commands drawn from the RCP guidelines and WHIM.
For example:
One stage verbal commands e.g. open your eyes.
Eye pointing - named object selection (repeated over 3 trials)
Two stage commands e.g. close your eyes and stick out your tongue

19. Measure
Level of wakefulness was assessed using a 5 point scale derived from The Sensory Modality Assessment and Rehabilitation Technique (SMART).
unable to rouse; remained asleep during duration of session.
minimal arousal; 5 or more prompts to maintain wakefulness (eyes open or closed)
medium arousal; 2-4 prompts to maintain wakefulness (eyes open or closed).
minimal prompts; required one prompt to maintain wakefulness (e.g. “hello”.
remained awake throughout.

20. Design A baseline was established (A: no Amantadine).
Six intervention phases followed consisting of:
B1 (50mg Amantadine 1000hrs)
B2 (50mg at 2200hrs)
B3 (100mg at 2200hrs)
B4 (150mg at 2200hrs)
B5 (200mg at 2200hrs)
B6 (200mg at 1800hrs).

21. Results

22. Mean session scores by phase
Mean session scores by phase At baseline, consciousness level reduced over the course of the day. There was a significant difference between wakefulness at session 1 and session 4 (p=0.012)

23. Effect of Amantadine on mean session scores – P values for post hoc comparison of means (baseline vs phase)
Significant p<0.05
Amantadine significantly improved consciousness level at all sessions for phase B4, B5 and B6.
Phase A B1 B2 B3 B4 B5 B6
Session 1
0.067
0.014*
0.164
0.003*
0.000*
0.022*
Session 2
0.002*
0.092
0.001*
Session 3
0.004*
0.027*
Session 4
0.224

24. At phase B6, there was no significant difference between scores across sessions, indicating stability in consciousness throughout the day (p=0.21).

25. Conclusion

26. Amantadine, administered at the optimum time, was effective in improving level of consciousness following severe brain injury, allowing for active participation in rehabilitation and activities of daily living.

27. Challenges
Medical instability: recurrent respiratory tract infections.
Eye infection: under review of Ophthalmologist

28. Benefits Ability to participate in rehabilitation.
Mr X progressed to a level whereby he was able to reliably communicate his agreement e.g. thumbs up.
He was able to lift his legs to assist with dressing and personal care (bridge).
Assist with upper limb dressing
Able to select clothing via eye gaze.
Could sit unsupported for short periods of time.
Greater tolerance of seating
Mr X was able to interact with staff and visitors.
Able to access activities important to him e.g. could use a tablet to select music and look at photos.
Lift head and observe what is going on.

29. Dr Louise Reid Consultant Clinical Neuropsychologist L: +44 (0)1698 384055M:
E:  
Murdostoun Brain Injury Rehabilitation & Neurological Care Centre, Newmains, Wishaw, Lanarkshire, ML2 9BY