Martijn J. A. Malessy

Natural history of obstetric brachial plexus palsy: a systematic review

Obstetric brachial plexus palsy (OBPP) is caused by traction to the brachial plexus during labour.1,2 In the majority of cases delivery of the upper shoulder is blocked by the mother’s pubic symphysis (shoulder dystocia). If additional traction is applied to the child’s head, the angle between the neck and the shoulder is forcefully widened, overstretching the ipsilateral brachial plexus. The resulting traction injury may vary from neurapraxia or axonotmesis to neurotmesis and avulsion of rootlets from the spinal cord. Recently, the exact origin of OBPP was again a matter of debate.3 It was suggested that intrauterine maladaptation, not nerve traction, causes the plexopathy. The incidence of OBPP varies from 1.6 to 2.9 per 1000 births in prospective studies.4,5 The upper brachial plexus is most commonly affected, resulting in paresis of the shoulder and biceps muscles, as first described by Erb and Duchenne.6 Hand function is additionally impaired in approximately 15% of patients;4,7,8 isolated injury to the lower plexus (Déjèrine-Klumpke’s type) is rare.9 The extent of neural damage can only be assessed by evaluating recovery in the course of time because nerve lesions of different severity initially present with the same clinical features. Neurapraxia and axonotmesis eventually result in complete recovery. Neurotmesis and root avulsion, on the other hand, result in permanent loss of arm function, which may lead in time to the development of skeletal malformations, cosmetic deformities, behavioural problems, and socioeconomic limitations.10–14 At present, most authors advise surgical exploration of the brachial plexus if spontaneous recovery is considered insufficient at a preset age.15–17 Absence of biceps function at 3 months of age is regarded as the key indicator for surgical exploration by some authors.15,18 Others use a combined score of different movements to decide whether nerve surgery should be performed at 9 months.16 Ancillary testing, in particular electromyography, is not considered reliable enough for prognostication.19,20 Methods of repair include nerve grafting after resection of the neuroma and nerve transfer in the case of root avulsion.15,21–25 Results achieved by these surgical approaches are claimed to be superior to the outcome in conservatively treated patients with equally severe lesions.15,26–28 However, this comparison relies on historical controls;29 no randomized study has been performed.6,30 In this context, the true percentage of infants who do not recover from OBPP becomes important as these children might benefit from reconstructive surgery. Reliable data on the frequency and severity of functional deficits in the natural course of OBPP are a prerequisite for developing adequate treatment strategies. Furthermore, such data would provide parents of newborn infants with OBPP with realistic information on prognosis. The prognosis of OPBB is generally considered to be very good, with complete or almost complete spontaneous recovery in over 90% of patients.25,31–35 However, this view is based on a limited number of studies37 which are cited indiscriminately without considering the methodology used. In the present review we performed a systematic literature search38 to clarify the natural course of untreated OBPP. Ideally, a study on the natural course of OBPP should be a prospective analysis of a demographic population with sufficient followup and clear end-stage assessment. We applied four predefined criteria to assess the methodological quality of the available studies: study-design, population, duration of follow-up, and assessment of end-stage.39

Designing ideal conduits for peripheral nerve repair

Nerve tubes, guides, or conduits are a promising alternative for autologous nerve graft repair. The first biodegradable empty single lumen or hollow nerve tubes are currently available for clinical use and are being used mostly in the repair of small-diameter nerves with nerve defects of < 3 cm. These nerve tubes are made of different biomaterials using various fabrication techniques. As a result these tubes also differ in physical properties. In addition, several modifications to the common hollow nerve tube (for example, the addition of Schwann cells, growth factors, and internal frameworks) are being investigated that may increase the gap that can be bridged. This combination of chemical, physical, and biological factors has made the design of a nerve conduit into a complex process that demands close collaboration of bioengineers, neuroscientists, and peripheral nerve surgeons. In this article the authors discuss the different steps that are involved in the process of the design of an ideal nerve conduit for peripheral nerve repair.

Obstetric lesions of the brachial plexus.

The few studies on prognosis of obstetric lesions of the brachial plexus that are not hampered by selection bias or a short follow‐up suggest that functional impairment persists in 20–25% of cases, more than commonly thought. Electromyography (EMG), potentially useful for prognosis, is often considered of little value. Denervation in the first week of life has been interpreted as evidence of an antenatal lesion, but is the logical result of the short axonal length affected. EMG performed at close to the time of possible intervention (3 months) usually shows a discrepancy: motor unit potentials are seen in clinically paralyzed muscles. This can be explained in five ways: an overly pessimistic clinical examination; overestimation of EMG recruitment due to small muscle fibers; persistent fetal innervation; developmental apraxia; or misdirection, in which axons reach inappropriate muscles. Further research into the pathophysiology of obstetric lesions of the brachial plexus is needed to improve prognostication.

Differential effects of lentiviral vector-mediated overexpression of nerve growth factor and glial cell line-derived neurotrophic factor on regenerating sensory and motor axons in the transected peripheral nerve

Even after reconstructive surgery, major functional impairments remain in the majority of patients with peripheral nerve injuries. The application of novel emerging therapeutic strategies, such as lentiviral (LV) vectors, may help to stimulate peripheral nerve regeneration at a molecular level. In the experiments described here, we examined the effect of LV vector‐mediated overexpression of nerve growth factor (NGF) and glial cell line‐derived neurotrophic factor (GDNF) on regeneration of the rat peripheral nerve in a transection/repair model in vivo. We showed that LV vectors can be used to locally elevate levels of NGF and GDNF in the injured rat peripheral nerve and this has profound and differential effects on regenerating sensory and motor neurons. For sensory neurons, increased levels of NGF and GDNF do not affect the number of regenerated neurons 1 cm distal to a lesion at 4 weeks post‐lesion but do cause changes in the expression of markers for different populations of nociceptive neurons. These changes are accompanied by significant alterations in the recovery of nociceptive function. For motoneurons, overexpression of GDNF causes trapping of regenerating axons, impairing both long‐distance axonal outgrowth and reinnervation of target muscles, whereas NGF has no effect on these parameters. These observations show the feasibility of combining surgical repair of the transected nerve with the application of viral vectors. Furthermore, they show a difference between the regenerative responses of motor and sensory neurons to locally increased levels of NGF and GDNF.

Misdirection of regenerating motor axons after nerve injury and repair in the rat sciatic nerve model

Misdirection of regenerating axons is one of the factors that can explain the poor results often found after nerve injury and repair. In this study, we quantified the degree of misdirection and the effect on recovery of function after different types of nerve injury and repair in the rat sciatic nerve model; crush injury, direct coaptation, and autograft repair. Sequential tracing with retrograde labeling of the peroneal nerve before and 8 weeks after nerve injury and repair was performed to quantify the accuracy of motor axon regeneration. Digital video analysis of ankle motion was used to investigate the recovery of function. In addition, serial compound action potential recordings and nerve and muscle morphometry were performed. In our study, accuracy of motor axon regeneration was found to be limited; only 71% (+/-4.9%) of the peroneal motoneurons were correctly directed 2 months after sciatic crush injury, 42% (+/-4.2%) after direct coaptation, and 25% (+/-6.6%) after autograft repair. Recovery of ankle motion was incomplete after all types of nerve injury and repair and demonstrated a disturbed balance of ankle plantar and dorsiflexion. The number of motoneurons from which axons had regenerated was not significantly different from normal. The number of myelinated axons was significantly increased distal to the site of injury. Misdirection of regenerating motor axons is a major factor in the poor recovery of nerves that innervate different muscles. The results of this study can be used as basis for developing new nerve repair techniques that may improve the accuracy of regeneration.

Accuracy of motor axon regeneration across autograft, single-lumen, and multichannel poly(lactic-co-glycolic acid) nerve tubes.

OBJECTIVE The accuracy of motor axon regeneration becomes an important issue in the development of a nerve tube for motor nerve repair. Dispersion of regeneration across the nerve tube may lead to misdirection and polyinnervation. In this study, we present a series of methods to investigate the accuracy of regeneration, which we used to compare regeneration across autografts and single-lumen poly(lactic-co-glycolic acid) (PLGA) nerve tubes. We also present the concept of the multichannel nerve tube that may limit dispersion by separately guiding groups of regenerating axons. METHODS The simultaneous tracing of the tibial and peroneal nerves with fast blue and diamidino yellow was performed 8 weeks after the repair of a 1-cm nerve gap in the rat sciatic nerve to determine the percentage of double-projecting motoneurons. Sequential tracing of the peroneal nerve with diamidino yellow 1 week before repair and fast blue 8 weeks after repair was performed to determine the percentage of correctly directed peroneal motoneurons. RESULTS In the cases in which there was successful regeneration across single-lumen nerve tubes, more motoneurons had double projections to both the tibial and peroneal nerve branches after single-lumen nerve tube repair (21.4%) than after autograft repair (5.9%). After multichannel nerve tube repair, this percentage was slightly reduced (16.9%), although not significantly. The direction of regeneration was nonspecific after all types of repair. CONCLUSION Retrograde tracing techniques provide new insights into the process of regeneration across nerve tubes. The methods and data presented in this study can be used as a basis for the development of a nerve tube for motor nerve repair.

Obstetric Brachial Plexus Injuries

Obstetric brachial plexus lesions (OBPLs) are typically caused by traction to the brachial plexus during labor. The incidence of OBPL is about 2 per 1000 births. Most commonly, the C5 and C6 spinal nerves are affected. The prognosis is generally considered to be good, but the percentage of children who have residual deficits may be as high as 20% to 30%. Surgery should be restricted to severe cases in which spontaneous restoration of function is not likely to occur (ie, in neurotmesis or root avulsions). In this article, the authors present an overview of our current understanding of the neuropathophysiology of OBPLs. The studies of preoperative electromyographic and intraoperative nerve action potential and compound motor action potentials, and of results of nerve surgery, of which some parts have been published, are discussed.

Surgery for large vestibular schwannoma: residual tumor and outcome.

Objective: To evaluate clinical outcome with regard to the amount of residual tumor after surgery for large vestibular schwannoma. Patients: Between January 2000 and December 2005, 51 large vestibular schwannoma tumors with extrameatal diameter of 2.6 cm or greater (mean, 32 mm; median, 30 mm; range, 26-50 mm) were operated using the translabyrinthine approach. The extent of the resection was intraoperatively estimated as complete, near, and subtotal. The amount of residual tumor was measured, and the shape and localization was scored on gadolinium-enhanced magnetic resonance imaging (MRI). Correlation between intraoperative and MRI assessment was performed using the Fishers exact test. Potential growth of residual tumor was documented with frequent MRI follow-up. Postoperative facial nerve function was classified according to the House-Brackmann classification. Results: Complete resection was performed in 26% of the patients, near-total resection in 58%, and subtotal resection in 16%. Magnetic resonance imaging showed residual tumor in 46% of patients (mean, 16.7 mm; SD, ±8, range, 5-36 mm). Postoperative facial nerve function was House-Brackmann Grades I to II in 78% of the patients. The intraoperative assessment of near-total resection did not correlate with postoperative MRI (p = 0.25). Postoperative MRI showed either no residual tumor or residue that should actually have been classified as a subtotal resection. After a follow-up of 4 years (49 mo; mean, 48 mo), 94% of patients did not show changes on MRI. Conclusion: Tumor control with good facial nerve function could be obtained in most patients. Intraoperative assessment did not correlate with the amount of residual tumor on postoperative MRI. Objective documentation with postoperative MRI to measure the extent of removal is therefore mandatory.

Nerve Tubes for Peripheral Nerve Repair

The concept of the nerve tube has been a major topic of research in the field of peripheral nerve regeneration for more than 25 years. The first nerve tubes are currently available for clinical use. This article gives an overview of the experimental and clinical data on nerve tubes for peripheral nerve repair and critically analyzes the data on which the step from laboratory to clinical use is based. In addition, it briefly discusses the different modifications to the common single lumen nerve tubes that may improve the results of generation.

Gene therapy for the peripheral nervous system: a strategy to repair the injured nerve.

Peripheral nerve injury in humans often leads to incomplete functional recovery. In this review we discuss the potential for gene therapy to be used as a strategy alongside surgical repair techniques for the study of peripheral nerve regeneration in rodent models and with a view to its eventual use for the promotion of successful regeneration in the clinic. Gene therapy vectors based on herpes simplex virus, adenovirus, lentivirus and adeno-associated virus have been developed to deliver genes to the neurons of the peripheral nervous system, i.e. primary sensory neurons in the dorsal root ganglia and primary motor neurons. Adenoviral and lentiviral vectors have also been used to transduce Schwann cells and fibroblasts in the injured nerve. We present an overview of these vectors, their application so far in the peripheral nervous system, their potential as vectors for enhancing peripheral nerve repair, and the successful interventions that have been demonstrated in animal models. We also discuss some of the limitations of current vectors and how they may be overcome. While the technology for gene delivery is approaching a state of readiness for clinical translation, the current range of therapeutic genes for the repair of the traumatically injured peripheral nerve is mostly limited to neurotrophic factors delivered to neurons, Schwann cells or possibly the target organs. Finally, therefore, we consider what type of therapeutic transgene may be desirable to enhance nerve regeneration in the future.