Central Adaptation Following Brachial Plexus Injury

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Title Central Adaptation following Brachial Plexus Injury.

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Authors Simon, Neil G Franz, Colin K Gupta, Nalin et al.

Publication Date 2016

DOI 10.1016/j.wneu.2015.09.027

Peer reviewed

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Central Adaptation following Brachial Plexus Injury Neil G. Simon1, Colin K. Franz2,3, Nalin Gupta4, Tord Alden5,6, Michel Kliot6

Key words Brachial plexus trauma (BPT) often affects young patients and may result in - Apraxia lasting functional deficits. Standard care following BPT involves monitoring for - Brachial plexus injury - Central adaptation clinical and electrophysiological evidence of muscle reinnervation, with sur- - Nerve trauma gical treatment decisions based on the presence or absence of spontaneous - Neuroplasticity recovery. Data are emerging to suggest that central and peripheral adaptation may play a role in recovery following BPT. The present review highlights Abbreviations and Acronyms BPT: Brachial plexus trauma adaptive and maladaptive mechanisms of central and peripheral nervous system CIMT: Constraint-induced movement therapy changes following BPT that may contribute to functional outcomes. Rehabili- CNS: Central nervous system tation and other treatment strategies that harness or modulate these intrinsic EMG: Electromyography adaptive mechanisms may improve functional outcomes following BPT. ES: Electrical stimulation H-reflex: Hoffman reflex MRI: Magnetic resonance imaging OBPP: Obstetric brachial plexus palsy PNI: Peripheral nerve injury RECOVERY FROM BPT functional recovery, with no residual def- fi Recovery of nerve tracts following BPT icits identi ed on serial clinician or phys- 1St. Vincent’s Clinical School, University of New South 1 2 relies on a complex cascade of peripheral iotherapist review. However up to 15% of Wales, Australia; Department of Physical Medicine and fi Rehabilitation, Northwestern University, and 3Sensory Motor nerve regenerative processes, culminating patients have persisting signi cant fi 1 Performance Program, Rehabilitation Institute of Chicago, in target muscle reinnervation.3 In de cits, and the proportion of patients 4 Illinois, USA; Departments of Neurological Surgery and instances of severe injury to the brachial with spontaneous functional recovery Pediatrics, University of California, San Francisco, California, may be overestimated.11 5 plexus or nerve roots, successful nerve USA; Division of Neurosurgery, Ann and Robert H. Lurie In patients with residual deficits, a Children’s Hospital of Chicago, and 6Department of regeneration might not be possible Neurological Surgery, Northwestern University Feinberg without surgical brachial plexus pattern of recovery may be seen, with most fi School of Medicine, Chicago, Illinois, USA. reconstruction.4,5 de cits seen in C5- to C7-innervated To whom correspondence should be addressed: Even patients in whom regenerating muscles. Forearm pronation typically 12 Michel Kliot, M.D. nerve fibers reach the target muscles, improves before forearm supination. The [E-mail: [email protected]] there are substantial barriers to a good degree of recovery of shoulder external Citation: World Neurosurg. (2016) 85:325-332. fl functional outcome. The process of axonal rotation, elbow exion, and forearm http://dx.doi.org/10.1016/j.wneu.2015.09.027 regeneration is inefficient, and sprouting supination at 3 months predicts which Journal homepage: www.WORLDNEUROSURGERY.org fibers may not reconnect with the appro- children will retain persistent functional Available online: www.sciencedirect.com fi 12 priate fascicle beyond the injured de cits. In children with residual ª 1878-8750/$ - see front matter 2016 Elsevier Inc. segment.6,7 Fibers that reach the target impairment, functional tasks can typically All rights reserved. muscle do so in substantially reduced be performed using the injured limb, but numbers, resulting in incomplete rein- with asymmetric movement relative to fl nervation and a reduced number of func- the uninvolved limb. Elbow exion and INTRODUCTION tional motor units.8 Although the shoulder abduction are the functional Brachial plexus trauma (BPT) occurs in dynamics of motor unit recruitment can movements that prove most challenging two different age groups. Obstetric recover from nerve injury if the muscle is in patients after severe OBPP, but brachial plexus palsy (OBPP) is a recog- reinnervated by the same motor nerve,9 shoulder external rotation and forearm nized complication of childbirth, with an aberrant reinnervation can affect this supination are usually the most affected 1 12,13 incidence of 0.3% of deliveries. The next process.10 movements and recover last. These peak in the incidence of BPT is in described patterns of recovery and younger (usually male) adults, and it is Maladaptive Central Processes following residual functional impairment inform often caused by motor vehicle accidents BPT rehabilitation strategies, although therapy 2 or penetrating wounds. Beyond peripheral nerve regeneration, paradigms are largely empiric and are fl BPT can result in severe and lasting central processes are involved in deter- based on splinting of ail wrists and neurologic impairments, and because the mining successful or failed functional elbows to prevent dislocation and passive affected patients are young, it has a long- recovery following BPT. range-of-motion exercises to prevent term effect on work and societal roles. contractures. As such, optimizing recovery from Developmental Apraxia. The majority of In a small subgroup of patients with brachial plexus injury is critical. patients with OBPP make an excellent residual symptoms, electromyography

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(EMG) studies of the affected limb Investigations of patients with develop- avulsion. EMG showed no voluntary units demonstrate active motor units in weak mental apraxia identified that reduction of in his left biceps and shoulder abductor muscles, suggesting at least partial rein- motor skills and muscle strength were muscles, but little active muscle denerva- nervation, but clinical function remains exaggerated when compared with neuro- tion. A postganglionic injury of the left poor.14 This unique issue has been termed physiological and physical muscle responses upper trunk was diagnosed. developmental apraxia and is considered to to peripheral nerve stimulation.15 This He was taken to surgery and after being be an example of maladaptive central finding was interpreted as being indicative anesthetized, electrodiagnostic testing motor programming early in infancy of impaired voluntary motor unit was performed. Transcutaneous stimula- following OBPP.15 The presence of EMG activation, suggesting defective motor tion of his left Erb’s region gave rise to activity in these clinically weak muscles programming development in early infancy. contraction of his left biceps, supra- has been apportioned to “luxury A separate study used transcranial spinatus, infraspinatus, and deltoid mus- innervation,” which refers to the magnetic stimulation to examine a cohort cles. Transcranial electrical stimulation phenomenon of additional muscle of patients with OBPP without evidence of (ES) of the right motor cortex also gave innervation from spinal segments beyond functional recovery.18 Motor evoked rise to motor evoked potential responses those typical for the individual muscle. potentials were recordable in all patients, in these muscles (Figure 1). As such, a typically C5- and C6- confirming the presence of an intact He underwent surgical exploration innervated muscle, such as biceps, may connection between the motor cortex of his infraclavicular brachial plexus. A have luxury innervation from C7, resulting and muscle, and suggesting that the supraclavicular brachial plexus exploration in the presence of active motor units on failure of functional recovery could be was not performed. Direct stimulation of EMG with minimal functional movement. due to abnormalities of central motor the left musculocutaneous nerve gave rise Luxury innervation begins between weeks control processes. to contraction in the biceps muscle. 16 and 25 of gestation and is usually lost Similarly, direct stimulation of the axillary after the age of 3 months.16,17 Limb Illustrative Case 1: Developmental nerve gave rise to a contraction in deltoid. immobilization in the period of sensory Apraxia Because of a lack of functional recovery in and motor brain organization, such as A 17-month-old baby boy suffered a severe elbow flexion, a side-to-side median to following OBPP, can result in incomplete left brachial plexus injury at birth resulting musculocutaneous nerve repair was per- realization of this reserve function, and in a complete upper trunk palsy on clinical formed to provide a supplementary source harnessing this reserve capacity may examination. Magnetic resonance imaging of axons to biceps with minimal iatrogenic benefit recovery.18 (MRI) showed no evidence of nerve root neurological morbidity.19 Postoperatively he

Figure 1. Developmental apraxia following obstetric brachial plexus palsy (Illustrative Case 1). Intraoperative electrophysiology (A, B) identiﬁed retained responses from biceps to brachial plexus and cortical stimulation in the absence of voluntary activity of the muscle. (C) Three months after a side-to-side anastomosis of the median to musculocutaneous nerve, functional elbow ﬂexion returned.

326 www.SCIENCEDIRECT.com WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2015.09.027 LITERATURE REVIEWS NEIL G. SIMON ET AL. RECOVERY FROM BRACHIAL PLEXUS INJURY underwent weekly transcutaneous ES of the developmental apraxia described above, recovery. Disordered motor control left brachial plexus at Erb’spointwith but central adaptation may nonetheless may be triggered by abnormal contraction of the biceps muscle. At 4 play a role in functional recovery. In gen- potentiation of sensory inputs and motor weeks, he showed trace ability to contract eral terms, peripheral nerve injury (PNI) outputs.48 Exaggerated somatosensory his left biceps muscles; by 2 months, he initiates rapid changes in cortical activity. reorganization following nerve injury may was able to contract his left biceps muscle In animal models, nerve transection re- be an important mediator of neuropathic voluntarily and feed himself. Deltoid sults in rapid silencing of corresponding pain, such as phantom limb pain function improved spontaneously. cortical sensory areas, and equally rapid following amputation.49,50 Finally, unmasking of areas corresponding to un- recovery from nerve transfer procedures Pain and Neuronal Hyperactivity injured hand nerves.42 These unmasked may rely on cortical plasticity. As an BPT in adults is frequently complicated by areas expand progressively to become example, improved control of biceps was “nerve pain,” which is another example of detailed representations of the hand, associated with a shift in biceps cortical maladaptive central nervous system (CNS) including the adoption of median- representation following intercostal to neuroplasticity. Nerve pain can manifest innervated skin territories.42 There is musculocutaneous nerve transfer to treat itself in different ways, including neuro- decreased g-aminobutyric acid staining cervical root avulsion.51 Controlling the pathic and phantom limb patterns.20 in the silenced cortical region, extent of reorganization of sensorimotor Neuropathic pain in the affected limb suggesting the mechanism of the circuits may help to focus reorganization can range from uncomfortable tingling evolving cortical plastic changes may be toward adaptive processes.8 sensations to intense burning or shooting through decreased intracortical pains down the arm. On examination, it inhibition.43 In humans, ischemic REHABILITATION OF BRACHIAL PLEXUS is characterized by hypersensitivity to median nerve block reduces inhibition at INJURIES painful stimuli (i.e., hyperalgesia) and the motor cortical level, producing painful sensations associated with increased excitability of the corticospinal Current approaches to the rehabilitation of typically nonpainful sensations (i.e., system.44 Of interest, cortical plasticity BPT emphasize the mitigation of second- allodynia). Phantom limb pain, which is may be more extensive for gross motor ary complications from nerve damage most often associated with a referred pain than for fine motor movements, which (e.g., contractures, neuropathic pain) and perceived in the place of the missing limb may contribute to the relatively poor improvement of task performance. These 52,53 of amputees, is also known to occur in recovery of fine motor control following strategies have been reviewed recently, deafferented limbs with BPT, typically severe lower brachial plexus injury.45 but there remain no proven clinical reha- when adjacent body sites are stimulated. Brain network changes are observed bilitation strategies to enhance nerve The central mechanisms underlying pain following severe BPT.46,47 Following total reinnervation. There is a growing body of after nerve injuries seem to involve brachial plexus avulsion causing a func- basic science evidence to support specific changes in ion channel expression by tionless limb, resting state functional MRI rehabilitative interventions to accelerate 54,55 dorsal root ganglia neurons,21-23 intrinsic studies identified cortical reorganization axon regeneration and CNS plasticity. excitability of dorsal root ganglia in the hemisphere ipsilateral and contra- neurons,24-30 and reorganization at the lateral to the side of injury.46 Cortical Sensory Re-Education level of the somatosensory cortex31,32 and activity changes included motor and The function of the hand depends on the subcortical structures, such as the premotor areas and brain regions precision of both motor control and sen- thalamus33 and brainstem.34,35 This form associated with motor task integration sory feedback. Pioneering work from the of maladaptive CNS neuroplasticity is (right precuneus) and spatial aspects of groups of Wynn Parry56,57 and Dellon58 related to age, because chronic pain rarely motor control (posterior parietal cortex described novel sensory re-education occurs in infants with OBPP,36 and it and superior parietal pole).46 Of interest, training protocols supported by their appears to be inversely related to the right OBPP resulted in a left-to-right shift observations of good patient outcomes extent of reinnervation.36,37 Reinnervation of language function.47 Brain when applied after PNI and repair. This also corresponds to normalization of deep reorganization was more extensive for work was inspired by the emerging tendon reflexes after nerve injury, such as dominant than nondominant limb concepts around neural plasticity during can be demonstrated by following the injuries.46 Beyond motor cortex changes, that era59 and was widely adopted by the recovery of the Hoffman reflex (H-reflex), further adaptation occurs at spinal and rehabilitation community. In practice, the electrical analogue to the subcortical levels.8 the protocols for sensory re-education monosynaptic stretch reflex.38 The can vary. They range from the simple H-reflex is highly facilitated at early stages Is There a Role for Modulating Central recognition of common objects and tex- of reinnervation, but gradually reverts Processes following BPT? tures to pairing tactile stimuli with closer to normal levels in the subsequent How these experimental findings translate completely different sensations (e.g., months after reinnervation.39-41 in the clinic is presently unclear. Cortical vision) and illusions (i.e., mirror visual plasticity can functionally compensate for feedback) with the hope of achieving Brain Remodeling following BPT the lack of specificity in target reinnerva- activation of the deprived cortical areas.32 Central processes in adults with BPT are tion by regenerating axons following Although sensory re-education rehabilita- less profound than in cases of severe PNI,8 thus optimizing functional tion for BPT has traditionally been

WORLD NEUROSURGERY 85: 325-332, JANUARY 2016 www.WORLDNEUROSURGERY.org 327 LITERATURE REVIEWS NEIL G. SIMON ET AL. RECOVERY FROM BRACHIAL PLEXUS INJURY initiated at the first clinical signs of skin There have been no randomized control segment was resected, and a 2-cm syn- reinnervation, more recently it has been trials investigating CIMT for BPT, but thetic bioabsorbable tube was interposed explored during the pre-reinnervation there are several recent case reports that between the proximal and distal ends. phase of recovery.32 Despite the long- are suggestive of a potential beneficial Nine months later, nascent voluntary units standing use of this intervention in reha- effect.73-76 were seen in the right shoulder abductor bilitation of PNI and BPT, it is not clini- muscles (supraspinatus, infraspinatus, cally established whether improvements Exercise and deltoid muscles), but none were with sensory re-education rehabilitation Patients are routinely exercised as toler- found in the right biceps muscle. A sec- are a result of somatosensory cortex reor- ated in rehabilitation after nerve injury, ond surgery was performed in which the ganization or simply a practice effect.60 but whether this actually improves nerve right musculocutaneous nerve was Two recent systematic reviews on sensory regeneration is still not known in humans. exposed using an infraclavicular approach. re-education conclude that it still Perhaps the lack of investigation is a result Direct stimulation of the right muscu- lacks high-level clinical evidence.61,62 of early preclinical rodent work showing locutaneous nerve gave rise to no Thus, a prospective multicenter, random- mixed results from exercise, including contraction of the biceps muscles, but did ized trial of sensory re-education with no beneficial effect77 or even delayed give rise to a somatosensory evoked po- measurements of hand sensibility, hand reinnervation.78,79 Subsequent work tential response over the contralateral function, and patient-reported outcomes demonstrating increased neurotrophic cortex. The decision was made to perform would be highly desirable. factor expression after exercise80-83 a side-to-side median to musculocuta- appeared to renew interest in the study neous nerve repair. Constraint-Induced Movement Therapy of exercise on nerve regeneration. More After the surgery, the patient underwent Constraint-induced movement therapy recently, treadmill running in rats with physical therapy including constrain- (CIMT) is a well-established approach to both endurance84-88 and interval86,88 induced movement therapy, limiting the managing a paretic limb after stroke63;it training regimens have been shown to use of the unaffected limb. He received has demonstrated at least short-term effi- promote axon regeneration and to specific motor retraining, focusing on cacy in BPT compared with other conven- prevent the “synaptic stripping,” which is coactivation of biceps and the wrist flexors tional rehabilitation approaches.64 CIMT known to occur on motor neuron soma to facilitate elbow flexion. Nine months has undergone many permutations in after PNI.89-92 The functional significance later, his right biceps muscle was found to practice, but it generally consists of three of this form of central adaptation from be dually innervated by both his right principle components: (1) immobilization exercise is supported by enhanced musculocutaneous and median nerves.19 of the normal limb; (2) task-oriented recovery of spinal reflexes.87,93,94 Trying to contract his right biceps training with high repetition; and (3) Although the detail of the optimal muscles produced only a grade 1e2 behavioral strategies aimed at translating exercise prescription has yet to be motor response, as did flexing his right skills from the clinical setting to the elucidated, there is some evidence that wrist. Combining both activities patient’s home environment. Interestingly, recommendations may be gender produced a grade 3e4 motor response much of the original preclinical work specific95,96 and dependent on growth (Figure 2). underpinning CIMT in for stroke rehabili- factor upregulation.97,98 Despite the delay of 18 months from the tation was actually developed in a nerve injury to the second surgery, it was likely injury monkey model that caused upper Illustrative Case 2: Recovery from BPT that the median nerve axons extended into limb deafferentation by dorsal rhizotomy. A 34-year-old, right-handed man sustained residual biceps muscle endplates, pro- When a single forelimb was deafferented, a severe right brachial plexus injury, leav- ducing the functional improvements, with the monkey would not make use of the ing him with complete motor deficits in successful regeneration of target muscle affected limb when it had a choice, despite an upper trunk distribution. MRI showed endplates typically noted within approxi- the intact motor connections65; this was no evidence of nerve root avulsion, and mately 2 years from a nerve injury.4 The termed learned non-use. Learned non-use EMG showed extensive denervation in rehabilitation strategies described were could be overcome with training to use right shoulder abductor and biceps mus- used with the intention of optimizing the deafferented limb by restricting move- cles with no voluntary units. At 9 months, functional reorganization after the ment of the intact limb for several days.66 he underwent a surgical exploration of his neurotization procedure,5 although it Given the rapid improvements that were right brachial plexus. The upper trunk was cannot be stated with certainty that they observed and the fact that the dorsal extensively scarred. ES distal and proximal affected functional recovery. rhizotomy paradigm did not permit for to the scarred portion of upper trunk gave peripheral axon regrowth, the mechanism no motor responses. Stimulation of the Electrical Stimulation for CIMT has been long attributed to CNS upper trunk proximal to the scarred The emergence of a brief ES protocol plasticity.67 While clinical evidence to portion of upper trunk gave rise to a delivered as a single-dose treatment support central adaptation as a positive somatosensory evoked potential (supramaximal stimulation for 1 hour at 20 mechanism for CIMT rehabilitation after response over the contralateral cortex Hz), developed in the laboratory of stroke has emerged,68-72 it is not clear demonstrating the presence of axons Al-Majed et al.99,100 and inspired by earlier that this same mechanism is necessarily proximal, but not distal to the scarred works,101,102 is an excellent example of involved when CIMT is applied to BPT. segment of upper trunk. The scarred “bench to bedside” science in rehabilitation

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Figure 2. Example of central drive affecting recovery from brachial plexus injury treatment (Illustrative Case 2). A patient who underwent a side-to-side anastomosis of an intact median nerve to a damaged musculocutaneous nerve recovered elbow flexion function. Electromyelography (EMG) activity was synchronously recorded from biceps (upper tracing) and flexor carpi radialis (FCR, lower tracing). (A) Biceps EMG activity was minimal when the patient attempted to flex the elbow alone. (B) Moderate interference pattern in the biceps was observed when the patient attempted to flex the wrist alone. (C) A full interference pattern was observed in the biceps when the patient flexed the wrist and elbow together. medicine. These findings have been robust models deal with regeneration distances reinnervation. Evidence is accumulating that and reproduced in several separate labora- of 2e3 cm at the most. Repeated brief ES central adaptation factors are relevant to the tories. The results of two small, random- for brachial plexus lesions provides recovery following PNI, and in some in- ized control trials on patients with severe technical challenges because to date it has stances it can contribute to suboptimal carpal tunnel syndrome103 or traumatic been applied to humans with temporary functional outcomes. Modulating CNS digital nerve transection104 demonstrated transcutaneous wires applied directly to responses to peripheral nerve trauma is a accelerated nerve regeneration and, in the the epineurium and then removed after component of current rehabilitation strate- case of the digital nerve injury, improved the treatment. To this end, Franz et al.110 gies. Further research using methods to functional outcomes. Although brief ES have developed a brief ES transvertebral modulate central adaptation after BPT and has not been applied to patients or stimulation method in mice for other peripheral nerve injuries is suggested preclinical models of BPT, it stands to transsynaptic activation of lower motor to explore this potential therapeutic reason that it might offer similar benefits. neurons that might better lend itself to approach. Although the primary effect appears to be reapplication over long durations. the augmentation of peripheral ACKNOWLEDGMENTS reinnervation, there is emerging evidence Transcranial Stimulation N.G.S. and C.K.F. contributed equally to that brief ES may also improve the Beyond repetitive nerve stimulation, brain 41 this work as first authors. recovery of spinal reflexes and work stimulation modalities have been explored 87 synergistically with treadmill running. as a means to improve recovery after PNI, Functional reinnervation after nerve injury although this approach remains experi- REFERENCES requires the re-establishment of appropri- mental. For example, lasting increases in 1. Backe B, Magnussen EB, Johansen OJ, Sellaeg G, ately matched axon-target reconnections in the excitability of target muscles are pro- Russwurm H. Obstetric brachial plexus palsy: the periphery105 that precedes the a birth injury not explained by the known duced when transcranial magnetic stimu- risk factors. 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