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.

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.

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.).

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.

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.

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.

Gender Disparity and Potential Strategies for Improvement in Neurology and Clinical Neurophysiology.

Discrimination in the workplace when documented is illegal but is seen to still exist in some forms whether based on culture, race, or gender. Each of these disparities warrants further discussion and study because of their significant impacts on hiring decisions, career advancement, and compensation. In this article, the authors have focused their attention on gender disparity in the fields of neurology and clinical neurophysiology and shared the data currently available to them. At a time when the field of clinical neurophysiology has seen enormous growth, gender disparity in leadership and compensation remain. Despite the increasing number of women entering the fields of neurology and clinical neurophysiology, women remain underrepresented in national leadership positions. Many women physicians report experiencing gender discrimination despite increasing efforts by universities and medical centers to improve inclusivity and diversity. Equity and inclusivity are not the same and there is a disconnect between the increased numbers of women and their shared experiences in the workplace. Implicit bias undermines the ability of women to advance in their careers. For neurologists, data indicate that the latest gender pay gap is $56,000 (24%), increased from $37,000 in 2015, and is one of the largest pay gaps in any medical specialty. One third of the top 12 medical schools in the United States require that maternity leave be taken through disability coverage and/or sick benefits, and most family leave policies constrain benefits to the discretion of departmental leadership. The authors recommend strategies to improve gender disparity include institutional training to Identify and overcome biases, changes to professional organizations and national scientific meeting structure, transparency in academic hiring, promotion and compensation, and mentorship and sponsorship programs.

MDA and AAEM informational brochures: can patients read them?

The purpose of this study was to assess patient literacy and the readability of patient education brochures from the American Academy of Electrodiagnostic Medicine and Muscular Dystrophy Association. Materials with the appropriate readability and suitability are more likely to provide instruction patients will understand. The readability of the brochure was assessed with Grammatik (Fry, 1977), the literacy of the participants with the Rapid Estimate of Adult Literacy (REALM) in Medicine test, and the suitability of the brochure was tested with the Suitability Assessment of Materials measure (Doak, Doak, & Root, 1993). The average REALM score for participation in this study correlated with a reading level of 7th-8th grade. All six brochures were found to be too difficult for many patients. Readability levels in four of the brochures were at 11th- or 12th-grade levels, one at 9th grade, and one at 10th grade. Materials with readability levels for 9th grade or higher should be rewritten to be understandable by most Americans, or supplemental instruction should be given. Readability and suitability assessments should be made to determine whether educational materials are appropriate for patients.

Intraoperative monitoring: do you know where your neurophysiologist is?

OBJECTIVE: The professional practice of intraoperative monitoring has evolved over the past 30 years. This report describes the field's current state and how site of service affects practice. METHODS: A survey queried American Academy of Neurology intraoperative monitoringneurologist members about their intraoperative monitoring volume, case type, duration, numbers of simultaneous cases, and location of the monitoring physician. RESULTS: Physicians located locally typically monitored fewer cases annually and simultaneously compared with physicians who monitored from remote locations. Physicians at remote locations monitored proportionally more spine procedures, whereas physicians who monitored locally monitored more intracranial procedures and a greater variety of cases. CONCLUSIONS: The remote monitoring practice model is different from local models in annual volume, simultaneous cases, work per case, and types of cases.

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.

TrkB and TrkC agonist antibodies improve function, electrophysiologic and pathologic features in Trembler J mice.

Neurotrophic factors have been considered as potential therapeutics for peripheral neuropathies. Previously, we showed that neurotrophin-3 (NT-3) promotes nerve regeneration in Trembler(J) (Tr(J)) mice and in sural nerves from patients with Charcot-Marie-Tooth 1A (CMT1A). The relatively short plasma half-life of NT-3 and other neurotrophins, however, pose a practical difficulty in their clinical application. Therapeutic agonist antibodies (AAb) targeting the neurotrophic receptors may circumvent this obstacle due to their high specificity and long half-life. Using morphological, electrophysiological studies and functional motor testing, we assessed the efficacy of monoclonal TrkC AAb and TrkB AAb in the Tr(J) mice. Treatments of these AAbs individually or in combination over 20 weeks increased compound muscle action potential (CMAP) amplitude, which correlated with improved grip strength, as compared to the PBS control group. Improvements in CMAP amplitude were most prominent with TrkC AAb treatment. In all treatment groups, distal to the crush site of the sciatic nerves exhibited a significantly greater number of myelinated fibers (MFs) indicating improved regenerative response to injury. In the contralateral intact sciatic nerves, the number of MFs as well as the myelin thickness was also increased significantly by the AAb treatments, suggesting that the hypomyelination/amyelination state of the peripheral nerves in Tr(J) improved. Therapeutic response to AAb combination was often, albeit not always, the most prominent, indicating a non-redundant effect of TrkB and TrkC AAbs. An early functional recovery and the correlative morphological changes of enhanced regeneration were seen with TrkC AAb treatment. These results provide evidence for potential therapeutic use of monoclonal agonist antibodies for neurotrophin receptors in CMT1A and other neuropathies.

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.