Dorsal Rhizotomy in the Pediatric Patient.

SUMMARY: The majority of cases of dorsal rhizotomy surgeries in children are done to improve the spasticity associated with cerebral palsy, and more recent techniques are selective in nature and referred to as selective dorsal rhizotomy (SDR). The techniques applied to selective dorsal rhizotomy surgery has changed since it was first described and continues to undergo modifications. Approaches to surgery and monitoring vary slightly among centers. This article provides a review of the rationale, variety of surgical approaches, and intraoperative neurophysiologic monitoring methods used along with discussion of the risks, complications and outcomes in these surgeries.

Mapping and monitoring of tethered cord and cauda equina surgeries.

Surgery involving the cauda equina and tethered cord can be associated with significant functional disability including pain, motor and sensory deficits, as well as bladder, bowel, and sexual dysfunction. Neurophysiologic intraoperative monitoring and mapping during these surgeries using a variety of techniques and applications contributes to lessen the risk of permanent injury. This chapter reviews the anatomy of the pelvic floor, describes the techniques involved in monitoring and mapping this area, and describes the limitations of neurophysiology applications. Additionally, this chapter details mapping and monitoring techniques as they apply to tethered cord surgical release in both children and adults with review of outcome studies, and describes complications which can arise from tethered cord repair and injury to the cauda equina despite appropriate neurophysiologic intraoperative involvement.

AAV1.NT-3 gene therapy for charcot-marie-tooth neuropathy.

Charcot-Marie-Tooth (CMT) neuropathies represent a heterogeneous group of peripheral nerve disorders affecting 1 in 2,500 persons. One variant, CMT1A, is a primary Schwann cell (SC) disorder, and represents the single most common variant. In previous studies, we showed that neurotrophin-3 (NT-3) improved the trembler(J) (Tr(J)) mouse and also showed efficacy in CMT1A patients. Long-term treatment with NT-3 was not possible related to its short half-life and lack of availability. This led to considerations of NT-3 gene therapy via adenoassociated virus (AAV) delivery to muscle, acting as secretory organ for widespread distribution of this neurotrophic agent. In the Tr(J) model of demyelinating CMT, rAAV1.NT-3 therapy resulted in measurable NT-3 secretion levels in blood sufficient to provide improvement in motor function, histopathology, and electrophysiology of peripheral nerves. Furthermore, we showed that the compound muscle action potential amplitude can be used as surrogate for functional improvement and established the therapeutic dose and a preferential muscle-specific promoter to achieve sustained NT-3 levels. These studies of intramuscular (i.m.) delivery of rAAV1.NT-3 serve as a template for future CMT1A clinical trials with a potential to extend treatment to other nerve diseases with impaired nerve regeneration.

Transcranial magnetic stimulation--may be useful as a preoperative screen of motor tract function.

UNLABELLED: Transcranial motor stimulation with noninvasive cortical surface stimulation, using a high-intensity magnetic field referred to as transcranial magnetic stimulation generally, is considered a nonpainful technique. In contrast, transcranial electric stimulation of the motor tracts typically cannot be done in unanesthesized patients. Intraoperative monitoring of motor tract function with transcranial electric stimulation is considered a standard practice in many institutions for patients during surgical procedures in which there is potential risk of motor tract impairment so that the risk of paraplegia or paraparesis can be reduced. Because transcranial electric stimulation cannot be typically done in the outpatient setting, transcranial magnetic stimulation may be able to provide a well-tolerated method for evaluation of the corticospinal motor tracts before surgery. METHODS: One hundred fifty-five patients aged 5 to 20 years were evaluated preoperatively with single-stimulation nonrepetitive transcranial magnetic stimulation for preoperative assessment. RESULTS AND CONCLUSIONS: The presence of responses to transcranial magnetic stimulation reliably predicted the presence of responses to transcranial electric stimulation intraoperatively. No complications occurred during the testing, and findings were correlated to the clinical history and used in the setup of the surgical monitoring.

Evidence-based guideline update: intraoperative spinal monitoring with somatosensory and transcranial electrical motor evoked potentials*.

OBJECTIVE: To evaluate whether spinal cord intraoperative monitoring (IOM) with somatosensory and transcranial electrical motor evoked potentials (EPs) predict adverse surgical outcomes. METHODS: A panel of experts reviewed the results of a comprehensive literature search and identified published studies relevant to the clinical question. These studies were classified according to the evidence-based methodology of the American Academy of Neurology. Objective outcomes of postoperative onset of paraparesis, paraplegia, and quadriplegia were used because no randomized or masked studies were available. RESULTS AND RECOMMENDATIONS: Four class I and eight class II studies met inclusion criteria for analysis. The four class I studies and seven of the eight class II studies reached significance in showing that paraparesis, paraplegia, and quadriplegia occurred in the IOM patients with EP changes compared with the IOM group without EP change. All studies were consistent in showing all occurrences of paraparesis, paraplegia, and quadriplegia in the IOM patients with EP changes, with no occurrences of paraparesis, paraplegia, and quadriplegia in patients without EP change. In the class I studies, 16% to 40% of the IOM patients with EP changes developed postoperative-onset paraparesis, paraplegia, or quadriplegia. IOM is established as effective to predict an increased risk of the adverse outcomes of paraparesis, paraplegia, and quadriplegia in spinal surgery (four class I and seven class II studies). Surgeons and other members of the operating team should be alerted to the increased risk of severe adverse neurologic outcomes in patients with important IOM changes (level A).

Neurophysiologic intraoperative monitoring in pediatrics.

Neurophysiologic intraoperative monitoring, using somatosensory, brainstem auditory, and visual evoked potentials, transcranial electric motor stimulation, and electromyography, is typically used during complex surgeries involving the motor and sensory cortex, brainstem, cranial nerves, spinal cord, nerve root, peripheral roots, brachial plexus, lumbar plexus, and peripheral nerves. The particular type of surgery and the neurologic structures at risk determine the type of monitoring chosen. Although many methods are the same in adult and pediatric patients, some differences in the pediatric population will be discussed here. In general, monitoring consists of two types. The first involves monitoring data which is obtained on an ongoing basis, with comparisons to data obtained at the outset of surgery (baseline). The second form of monitoring involves mapping neural structures, so that a neural structure in the field is identified accurately, to avoid injuring it, or to demonstrate its degree of neurophysiologic function or impairment. In this paper we discuss both forms of monitoring and their general applications, including unique features or modifications needed in the pediatric population.

Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D.

OBJECTIVE: The aim of this study was to attain long-lasting alpha-sarcoglycan gene expression in limb-girdle muscular dystrophy, type 2D (LGMD2D) subjects mediated by adeno-associated virus (AAV) gene transfer under control of a muscle specific promoter (tMCK). METHODS: rAAV1.tMCK.hSGCA (3.25 × 10¹¹ vector genomes) was delivered to the extensor digitorum brevis muscle of 3 subjects with documented SGCA mutations via a double-blind, randomized, placebo controlled trial. Control sides received saline. The blind was not broken until the study was completed at 6 months and all results were reported to the oversight committee. RESULTS: Persistent alpha-sarcoglycan gene expression was achieved for 6 months in 2 of 3 LGMD2D subjects. Markers for muscle fiber transduction other than alpha-sarcoglycan included expression of major histocompatibility complex I, increase in muscle fiber size, and restoration of the full sarcoglycan complex. Mononuclear inflammatory cells recruited to the site of gene transfer appeared to undergo programmed cell death, demonstrated by terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling and caspase-3 staining. A patient failing gene transfer demonstrated an early rise in neutralizing antibody titers and T-cell immunity to AAV, validated by enzyme-linked immunospot on the second day after gene injection. This was in clear distinction to other participants with satisfactory gene expression. INTERPRETATION: The findings of this gene replacement study in LGMD2D subjects have important implications not previously demonstrated in muscular dystrophy. Long-term, sustainable gene expression of alpha-sarcoglycan was observed following gene transfer mediated by AAV. The merit of a muscle-specific tMCK promoter, not previously used in a clinical trial, was evident, and the potential for reversal of disease was displayed.

Dystrophin immunity in Duchenne's muscular dystrophy.

We report on delivery of a functional dystrophin transgene to skeletal muscle in six patients with Duchenne's muscular dystrophy. Dystrophin-specific T cells were detected after treatment, providing evidence of transgene expression even when the functional protein was not visualized in skeletal muscle. Circulating dystrophin-specific T cells were unexpectedly detected in two patients before vector treatment. Revertant dystrophin fibers, which expressed functional, truncated dystrophin from the deleted endogenous gene after spontaneous in-frame splicing, contained epitopes targeted by the autoreactive T cells. The potential for T-cell immunity to self and nonself dystrophin epitopes should be considered in designing and monitoring experimental therapies for this disease. (Funded by the Muscular Dystrophy Association and others; ClinicalTrials.gov number, NCT00428935.).

Limb-girdle muscular dystrophy type 2D gene therapy restores alpha-sarcoglycan and associated proteins.

OBJECTIVE: alpha-Sarcoglycan deficiency results in a severe form of muscular dystrophy (limb-girdle muscular dystrophy type 2D [LGMD2D]) without treatment. Gene replacement represents a strategy for correcting the underlying defect. Questions related to this approach were addressed in this clinical trial, particularly the need for immunotherapy and persistence of gene expression. METHODS: A double-blind, randomized controlled trial using rAAV1.tMCK.hSGCA injected into the extensor digitorum brevis muscle was conducted. Control sides received saline. A 3-day course of methylprednisolone accompanied gene transfer without further immune suppression. RESULTS: No adverse events were encountered. SGCA gene expression increased 4-5-fold over control sides when examined at 6 weeks (2 subjects) and 3 months (1 subject). The full sarcoglycan complex was restored in all subjects, and muscle fiber size was increased in the 3-month subject. Adeno-associated virus serotype 1 (AAV1)-neutralizing antibodies were seen as early as 2 weeks. Neither CD4+ nor CD8+ cells were increased over contralateral sides. Scattered foci of inflammation could be found, but showed features of programmed cell death. Enzyme-linked immunospot (ELISpot) showed no interferon-gamma response to alpha-SG or AAV1 capsid peptide pools, with the exception of a minimal capsid response in 1 subject. Restimulation to detect low-frequency capsid-specific T cells by ELISpot assays was negative. Results of the first 3 subjects successfully achieved study aims, precluding the need for additional enrollment. INTERPRETATION: The finding of this gene replacement study in LGMD2D has important implications for muscular dystrophy. Sustained gene expression was seen, but studies over longer time periods without immunotherapy will be required for design of vascular delivery gene therapy trials.

Intraoperative neurophysiologic monitoring in 80 patients with Chiari I malformation: role of duraplasty.

Neurophysiologic intraoperative monitoring of the brainstem auditory evoked potentials (BAEPs) is a widely used method to assess the functional integrity of the central auditory system during surgery involving the brainstem or the cranial nerves. The purpose of this study is to describe our experience with neurophysiologic intraoperative monitoring of BAEPs during posterior fossa decompression (PFD) surgery for the management of Chiari I malformation. Although suboccipital craniectomy is the standard surgical technique applied in all cases undergoing PFD, the role of dural patch grafting (duraplasty) remains controversial. In most cases, the PFD was supplemented by duraplasty only when the Chiari I malformation was complicated by the presence of syringomyelia. Our study reviewed the intraoperative BAEP changes during the different surgical stages of Chiari repair and correlated these with clinical and radiological findings present. Our data revealed that for both groups of patients, with or without associated syringomyelia, the predominant improvement in central conduction in most cases occurred during the period of bony decompression without significant additional improvement after the duraplasty procedure.