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Emerging Therapies in
Address correspondence
to Dr Mary L. Dombovy,
Unity Health System,
Dept of Physical Medicine
and Rehabilitation,
89 Genesee St, Rochester, Neurorehabilitation
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NY 14611-3201,
mdombovy@unityhealth.org.
Mary L. Dombovy, MD, MHSA, FAAN
Relationship Disclosure:
Dr Dombovy’s institution
is compensated for her
litigation and testimony. ABSTRACT
Unlabeled Use of
Products/Investigational
Just as advancing technology has furthered our understanding of how the nervous
Use Disclosure: system recovers, technology also enables the development of novel approaches to
Dr Dombovy discusses treatment. Because nervous system disease and injury often lead to severely impaired
the unlabeled use of
pharmaceuticals and
function, patients and families are willing to try anything, so therapies are often
information on adopted with little evidence that they actually work. Evidence shows that compre-
investigational treatments. hensive rehabilitation programs produce better outcomes, but it is still not understood
Copyright * 2011, what components of these multifaceted programs are critical to their success. Func-
American Academy of
Neurology. All rights tional neuroimaging and other modalities now allow monitoring of neurophysiologic
reserved. changes that can be paired with assessments detailing clinical changes, furthering our
understanding of the factors that influence the recovery process. This article discusses
several novel and emerging therapies in neurorehabilitation as well as recent multi-
study reviews of selected treatments.
KEY POINTS
h Acetylcholinesterase Adverse reactions to these dopami- Modafinil. Modafinil is approved to
inhibitors improve nergic medications are rare at the improve wakefulness in adults with nar-
memory after traumatic doses used in clinical practice but may colepsy, obstructive sleep apnea, and
brain injury. include paranoia, anxiety, agitation, shift work disorder. It is frequently used
h Benzodiazepines and increases in heart rate and blood in clinical settings to improve arousal
antipsychotics appear to pressure, and lowering of the seizure and attention following TBI and stroke
slow recovery from threshold. with few reported significant side ef-
traumatic brain injury Piracetam. After reviewing several fects and the clinical impression that it
and stroke. studies involving more than 220 stroke is beneficial in selected patients. The
patients with aphasia, a Cochrane Re- mechanism of action is unclear. Cur-
view concluded that piracetam may be rently, few studies exist to either refute
effective as an adjunct to therapy in the or support its use.33
treatment of aphasia after stroke.32 Polypharmacy. In clinical practice,
Piracetam’s mechanism of action is not various combinations of pharmacologic
clear. It is not available in the United agents are frequently used in patients
States at the time of this writing. with TBI and stroke. This is particularly
Acetylcholinesterase inhibitors. true for those patients with severe de-
Because TBI commonly affects the basal ficits, especially impairments of arousal,
frontal lobes, cholinergic deficit is com- attention, initiation, and impulsivity. In
mon. Patients with TBI also frequently some situations, patients may be on
have impairments in memory. In clinical more than three psychoactive agents, at
trials, the effects of donepezil and riva- times including both dopaminergic and
stigmine are consistently positive, im- antidopaminergic drugs. Each practi-
proving memory, attention, and speed tioner or institution appears to have a
of processing.28,33 The Neurobehavioral unique approach. Pharmacologic treat-
Guidelines Working Group and a recent ment will be reviewed from a clinical
comprehensive review33 both recom- perspective in the article ‘‘Traumatic
mend the use of donepezil and riva- Brain Injury.’’
stigmine in patients with moderate to
severe TBI during the subacute and
chronic periods of recovery. Side effects Medications with Adverse
include nausea, diarrhea, vomiting, mus- Effects on Recovery
cle cramping, and fatigue, but these can Agitation, anxiety, insomnia, and sleep-
often be minimized by slowly escalating wake cycle disturbance are all common
the dose. Anticholinesterase inhibitors following TBI and stroke, resulting in
should not be used in patients with disruption of the rehabilitation pro-
symptomatic bradycardia or atrioven- gram as well as inappropriate behav-
tricular block. There are no reports that ior. Strong evidence from both animal
anticholinesterase inhibitors lower the and human studies demonstrates that
seizure threshold. typical +-aminobutyric acid agonists
Selective serotonin reuptake inhib- (benzodiazepines) produce residual
itors. Ample evidence exists that cognitive and behavioral effects that
depression adversely affects functional outlast their duration in the blood-
recovery following stroke and TBI and stream.35,36 There have also been long-
that treating depression improves standing concerns that the use of anti-
recovery. 34 Only limited evidence psychotics after TBI and stroke may
exists that SSRIs may improve function- reinstate deficits that had abated as well
ing following stroke or TBI indepen- as delay recovery.37,38 Although imme-
dent of their effects on depression.28 diate control of dangerous behaviors is
Case 7-1
An 18-month-old girl with cerebral palsy and a left hemiparesis presented
to the clinic. She ambulated with an ankle-foot orthosis and had
reasonable gross motor function in every muscle group in her left upper
extremity. She tended not to use the arm in any activity. Her parents were
very motivated and supportive.
She was referred to occupational therapy for constraint-induced
movement therapy and underwent periodic casting of her unimproved
right upper extremity for 3 weeks at a time with 3 weeks off. During this
time she also received intensive therapy, partly with a therapist and also
through a home program. The initial attempts were difficult, with much
crying and difficulties with cooperation, but her parents and occupational
therapist persisted over a 2-year period.
At the end of 2 years, she was using her left upper extremity
spontaneously in general activities and had individual finger control.
Comment. This case illustrates the potential impact of constraint-induced
movement therapy on upper extremity function given a long span of time
and a consistent approach.
KEY POINTS
h Reducing activation Clinical implementation of CIMT After extensive review of studies em-
of the ipsilateral is limited for several reasons. To parti- ploying either TMS or transcranial direct
hemisphere improves cipate, patients need active wrist and current stimulation (tDCS) in patients
motor function in both hand movement, including at least with stroke, Nowak and colleagues55
healthy individuals and 10 degrees of wrist and finger extension, concluded that evidence strongly sug-
those with traumatic which limits its application to patients gests that TMS and tDCS are both be-
brain injury or stroke. with mild to moderate motor impair- neficial and safe in promoting motor
h Transcranial magnetic ment. Additionally, patients with TBI recovery following stroke. Improve-
stimulation and with cognitive-behavioral impairments ment was noted following inhibition
transcranial direct and children may not be receptive to of the uninvolved hemisphere as well
current stimulation wearing a cast or other restraint on the as stimulation of the involved hemi-
produce cortical uninvolved extremity, which may re- sphere. The beneficial effects of TMS
activation changes and duce cooperation with therapies or and tDCS on cortical excitability outlast
may evolve into useful cause anxiety in caregivers and parents. the stimulus for minutes to hours and
therapy adjuncts.
Finally, CIMT repetitive practice sessions thus may be paired with poststimula-
are time intensive (which can increase tion therapy. Repeated activation over
costs), can be frustrating, and require a several days or weeks and in combina-
high degree of motivation. tion with training appears to enhance
Transcranial magnetic stimulation both the effect size and duration of
and transcranial direct current stim- improvement.
ulation. The theory behind CIMT is that Currently, TMS and tDCS are not part
in addition to forced use of the involved of the therapeutic regimen following
extremity, thus increasing input to the stroke or TBI, as many questions still
involved hemisphere, input from the exist regarding these therapies, such as
uninvolved extremity to the uninvolved the optimal frequency and intensity of
hemisphere is reduced.48 fMRI studies the stimulation, the appropriate timing
show increased activation of motor and duration of the program postinjury,
areas in both hemispheres when the and the appropriate patient selection in
affected extremity is moved soon after terms of severity and location of injury.
stroke.49,50 Concentration of activity Although studies are underway, the ef-
within the motor areas correlates with fects of pairing either TMS or tDCS with
good recovery, while persistence of standard rehabilitation approaches,
activation in the contralesional hemi- CIMT, or robot-assisted therapy are
sphere correlates with less recovery.49,51 largely unknown.
In addition, the lateralization of neural Robot-assisted therapy. After stroke
activity during unimanual activity is, in and TBI, many patients have little or
part, related to interhemispheric inhibi- no ability to use their upper extremity.
tion between motor areas exerted via Robotic devices are able to deliver high-
transcallosal connections that are dis- intensity, reproducible therapy and may
rupted following stroke.52 In theory, be useful in those with little voluntary
persisting activation of the unaffected movement as well as those with greater
hemisphere may limit activation of the ability. A review56 of 11 trials with a
involved hemisphere, thus limiting post- total of 328 patients compared robot-
injury recovery. Even in healthy sub- assisted training with either standard
jects, inhibition of the ipsilateral motor therapy or no therapy. They concluded
cortex or facilitation of the contralateral that robot-assisted training produces
motor cortex by TMS improves upper greater improvement in arm strength
extremity motor speed and motor task and motor function but not in activities
acquisition.53,54 of daily living. Considerable variation
KEY POINT
h General exercise
programs promote
Case 7-2
A 45-year-old woman had an ‘‘over the handlebars’’ bicycle accident
fitness and appear to
during a race while going downhill at about 45 miles per hour. She
enhance CNS plasticity.
sustained a C4-C5 fracture dislocation and had only minimal motor
function with considerable preserved sensation. Acutely she required a
tracheostomy and ventilation but was weaned from the ventilator at
2 months. At that time she had 3/5 strength in her legs, 4/5 proximal arm
strength, and 2/5 hand strength. Proprioception was seriously impaired
in both lower extremities.
After inpatient rehabilitation she required minimal assistance with
activities of daily living and was ambulating short distances with a walker
and minimal assistance, albeit with a very irregular gait.
She began a body weightYsupported treadmill training (BWSTT) program
for 1 hour a day 5 days a week. After 2 months her gait had noticeably
improved, and she was ambulating in the community with a cane.
Beginning 9 months postinjury her walking began to decline because
of increased pain and stiffness. MRI was negative for syrinx. She was
started on baclofen and duloxetine. Therapy was intensified. After
the addition of tizanadine and gabapentin, she resumed physical
therapy in a therapy pool with a treadmill floor. She improved partially,
but she never returned to the level she had achieved at 6 months
postinjury.
She is awaiting an intrathecal baclofen trial and is hopeful that it will
both improve her spasticity and provide additional pain control.
Comment. Reinnervation in partial spinal cord injury can lead to
devastating neuropathic pain and spasticity. BWSTT is a useful therapy
because it delivers repetitive, consistent walking. The intense repetition
appears important to the process of recovery.
KEY POINT
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