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Neurofibromatosis type 1 (NF1), the most common tumor predisposition syndrome, occurs when NF1 gene variants result in loss of neurofibromin, a negative regulator of RAS activity. Plexiform neurofibromas (PN) are peripheral nerve sheath tumors that develop in patients with NF1 and are associated with substantial morbidity and for which, until recently, the only treatment was surgical resection. However, surgery carries several risks and a proportion of PN are considered inoperable. Understanding the genetic underpinnings of PN led to the investigation of targeted therapies as medical treatment options, and the MEK1/2 inhibitor selumetinib has shown promising efficacy in pediatric patients with NF1 and symptomatic, inoperable PN. In a phase I/II trial, most children (approximately 70%) achieved reduction in tumor volume accompanied by improvements in patient-reported outcomes (decreased tumor-related pain and improvements in quality of life, strength, and range of motion). Selumetinib is currently the only licensed medical therapy indicated for use in pediatric patients with symptomatic, inoperable NF1-PN, with approval based on the results of this pivotal clinical study. Several other MEK inhibitors (binimetinib, mirdametinib, trametinib) and the tyrosine kinase inhibitor cabozantinib are also being investigated as medical therapies for NF1-PN. Careful consideration of multiple aspects of both disease and treatments is vital to reduce morbidity and improve outcomes in patients with this complex and heterogeneous disease, and clinicians should be fully aware of the risks and benefits of available treatments. There is no single treatment pathway for patients with NF1-PN; surgery, watchful waiting, and/or medical treatment are options. Treatment should be individualized based on recommendations from a multidisciplinary team, considering the size and location of PN, effects on adjacent tissues, and patient and family preferences. This review outlines the treatment strategies currently available for patients with NF1-PN and the evidence supporting the use of MEK inhibitors, and discusses key considerations in clinical decision-making.

Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of AFM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for AFM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host-virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population.

The presence of Alternative lengthening of telomeres (ALT) and/or ATRX loss, as well as the role of other telomere abnormalities, have not been formally studied across the spectrum of NF1-associated solid tumors. Utilizing a telomere-specific FISH assay, we classified tumors as either ALT-positive or having long (without ALT), short, or normal telomere lengths. A total of 426 tumors from 256 NF1 patients were evaluated, as well as 99 MPNST tumor samples that were sporadic or of unknown NF1 status. In the NF1-glioma dataset, ALT was present in the majority of high-grade gliomas: 14 (of 23; 60%) in contrast to only 9 (of 47; 19%) low-grade gliomas (p = 0.0009). In the subset of ALT-negative glioma cases, telomere lengths were estimated and we observed 17 (57%) cases with normal, 12 (40%) cases with abnormally long, and only 1 (3%) case with short telomeres. In the NF1-associated malignant nerve sheath tumor (NF1-MPNST) set (n = 75), ALT was present in 9 (12%). In the subset of ALT-negative NF1-MPNST cases, telomeres were short in 9 (38%), normal in 14 (58%) and long in 1 (3%). In the glioma set, overall survival was significantly decreased for patients with ALT-positive tumors (p

Organized and hosted by the Children's Tumor Foundation (CTF), the Neurofibromatosis (NF) conference is the premier annual gathering for clinicians and researchers interested in neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). The 2016 edition constituted a blend of clinical and basic aspects of NF research that helped in clarifying different advances in the field. The incorporation of next generation sequencing is changing the way genetic diagnostics is performed for NF and related disorders, providing solutions to problems like genetic heterogeneity, overlapping clinical manifestations, or the presence of mosaicism. The transformation from plexiform neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) is being clarified, along with new management and treatments for benign and premalignant tumors. Promising new cellular and in vivo models for understanding the musculoskeletal abnormalities in NF1, the development of NF2 or SWN associated schwannomas, and clarifying the cells that give rise to NF1-associated optic pathway glioma were presented. The interaction of neurofibromin and SPRED1 was described comprehensively, providing functional insight that will help in the interpretation of pathogenicity of certain missense variants identified in NF1 and Legius syndrome patients. Novel promising imaging techniques are being developed, as well as new integrative and holistic management models for patients that take into account psychological, social, and biological factors. Importantly, new therapeutic approaches for schwannomas, meningiomas, ependymomas, PNF, and MPNST are being pursued. This report highlights the major advances that were presented at the 2016 CTF NF conference.

Traumatic peripheral nerve injuries (PNI), present with symptoms ranging from pain to loss of motor and sensory function. Difficulties in intraoperative visual assessment of nerve functional status necessitate intraoperative nerve conduction studies (INCSs) by neurosurgeons and neurologists to determine the presence of functioning axons in the zone of a PNI. This process, also referred to as nerve "inching", uses a set of stimulating and recording electrode hooks to lift the injured nerve from the surrounding surgical field and to determine whether an electrical stimulus can travel through the zone of injury. However, confounding electrical signal artifacts can arise from the current workflow and electrode design, particularly from the mandatory lifting of the nerve, complicating the definitive assessment of nerve function and neurosurgical treatment decision-making. The objective of this study is to describe the design process and verification testing of our group's newly designed stimulating and recording electrodes that do not require the lifting or displacement of the injured nerve during INCSs. Ergonomic in vivo analysis of the device within a porcine model demonstrated successful intraoperative manipulation of the device, while quantitative nerve action potential (NAP) signal analysis with an ex vivo simulated "inching" procedure on healthy non-human primate nerve tissue demonstrated excellent reproducible recorded NAP fidelity and the absence of NAP signal artifacts at all points of recording. Lastly, electrode pullout force testing determined maximum forces of 0.43 N, 1.57 N, and 3.61 N required to remove the device from 2 mm, 5 mm, and 1 cm nerve models, respectively, which are well within established thresholds for nerve safety. These results suggest that these new electrodes can safely and successfully perform accurate PNI assessment without the presence of artifacts, with the potential to improve the INCS standard of care while remaining compatible with currently used neurosurgical technology, infrastructure, and clinical workflows. [ABSTRACT FROM AUTHOR]

The neurofibromatoses (NF) are autosomal dominant genetic disorders that encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect more people worldwide than Duchenne muscular dystrophy and Huntington's disease combined. NF1 and NF2 are caused by mutations of known tumor suppressor genes (NF1 and NF2, respectively). For schwannomatosis, although mutations in SMARCB1 were identified in a subpopulation of schwannomatosis patients, additional causative gene mutations are still to be discovered. Individuals with NF1 may demonstrate manifestations in multiple organ systems, including tumors of the nervous system, learning disabilities, and physical disfigurement. NF2 ultimately can cause deafness, cranial nerve deficits, and additional severe morbidities caused by tumors of the nervous system. Unmanageable pain is a key finding in patients with schwannomatosis. Although today there is no marketed treatment for NF-related tumors, a significant number of clinical trials have become available. In addition, significant preclinical efforts have led to a more rational selection of potential drug candidates for NF trials. An important element in fueling this progress is the sharing of knowledge. For over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share novel findings, ideas, and build collaborations. The 2012 NF Conference held in New Orleans hosted over 350 NF researchers and clinicians. This article provides a synthesis of the highlights presented at the conference and as such, is a "state-of-the-field" for NF research in 2012.

The Seddon and Sunderland classifications have been used by physicians for peripheral nerve injury grading and treatment. While Seddon classification is simpler to follow and more relevant to electrophysiologists, the Sunderland grading is more often used by surgeons to decide when and how to intervene. With increasing availability of high‑resolution and high soft‑tissue contrast imaging provided by MR neurography, the surgical treatment can be guided following the above‑described grading systems. The article discusses peripheral nerve anatomy, pathophysiology of nerve injury, traditional grading systems for classifying the severity of nerve injury, and the role of MR neurography in this domain, with respective clinical and surgical correlations, as one follows the anatomic paths of various nerve injury grading systems. [ABSTRACT FROM AUTHOR]

The neurofibromatoses (NF) are autosomal dominant genetic disorders that encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect more people worldwide than Duchenne muscular dystrophy and Huntington's disease combined. NF1 and NF2 are caused by mutations of known tumor suppressor genes (NF1 and NF2, respectively). For schwannomatosis, although mutations in SMARCB1 were identified in a subpopulation of schwannomatosis patients, additional causative gene mutations are still to be discovered. Individuals with NF1 may demonstrate manifestations in multiple organ systems, including tumors of the nervous system, learning disabilities, and physical disfigurement. NF2 ultimately can cause deafness, cranial nerve deficits, and additional severe morbidities caused by tumors of the nervous system. Unmanageable pain is a key finding in patients with schwannomatosis. Although today there is no marketed treatment for NF-related tumors, a significant number of clinical trials have become available. In addition, significant preclinical efforts have led to a more rational selection of potential drug candidates for NF trials. An important element in fueling this progress is the sharing of knowledge. For over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share novel findings, ideas, and build collaborations. The 2012 NF Conference held in New Orleans hosted over 350 NF researchers and clinicians. This article provides a synthesis of the highlights presented at the conference and as such, is a “state-of-the-field” for NF research in 2012.

Injury makes sensory neurons abnormally excitable and triggers coincident alterations in relative levels of different types of voltage-gated sodium channels that they express. We report that nerve injury depress levels of SCN10A-specific mRNA in contralateral as well as ipsilateral dorsal root ganglia of rats, suggesting a possible peripheral mechanism for the contralateral ‘mirror-image’ hyperalgesia described in nerve-injured humans and experimental animals

Aim: To test the incremental value of 3T magnetic resonance neurography (MRN) in a series of unilateral radiculopathy patients with non-contributory magnetic resonance imaging (MRI)., Methods: Ten subjects (3 men, 7 women; mean age 54 year and range 22-74 year) with unilateral lumbar radiculopathy and with previous non-contributory lumbar spine MRI underwent lumbosacral (LS) plexus MRN over a period of one year. Lumbar spine MRI performed as part of the MRN LS protocol as well as bilateral L4-S1 nerves, sciatic, femoral and lateral femoral cutaneous nerves were evaluated in each subject for neuropathy findings on both anatomic (nerve signal, course and caliber alterations) and diffusion tensor imaging (DTI) tensor maps (nerve signal and caliber alterations). Minimum fractional anisotropy (FA) and mean apparent diffusion coeffcient (ADC) of L4-S2 nerve roots, sciatic and femoral nerves were recorded., Results: All anatomic studies and 80% of DTI imaging received a good-excellent imaging quality grading. In a blinded evaluation, all 10 examinations demonstrated neural and/or neuromuscular abnormality corresponding to the site of radiculopathy. A number of contributory neuropathy findings including double crush syndrome were observed. On DTI tensor maps, nerve signal and caliber alterations were more conspicuous. Although individual differences were observed among neuropathic appearing nerve (lower FA and increased ADC) as compared to its contralateral counterpart, there were no significant mean differences on statistical comparison of LS plexus nerves, femoral and sciatic nerves (P > 0.05)., Conclusion: MRN of LS plexus is useful modality for the evaluation of patients with non-contributory MRI of lumbar spine as it can incrementally delineate the etiology and provide direct objective and non-invasive evidence of neuromuscular pathology.

Background: Thoracic outlet syndrome (TOS) is one of the most controversial clinical entities in medicine. Despite many reports of operative and non-operative interventions, rigorous scientific investigation of this syndrome leading to evidence based management is lacking., Objectives: To evaluate the beneficial and adverse effects of the available operative and non-operative interventions for the treatment of thoracic outlet syndrome., Search Strategy: We searched the Cochrane Neuromuscular Disease Group Trials Specialized Register (July 2009), The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2009), MEDLINE (January 1966 to June 2009), EMBASE (January 1980 to June 2009), CINAHL (January 1981 to June 2009 ), AMED (January 1985 to June 2009 ) and reference lists of articles., Selection Criteria: We selected randomized or quasi-randomized studies in any language of participants with the diagnosis of any type of thoracic outlet syndrome (neurogenic, vascular, and 'disputed'). The primary outcome measure was change in pain rating on a validated visual analog or similar scale at least six months after the intervention. The secondary outcomes were change in muscle strength and adverse effects of the interventions., Data Collection and Analysis: Four authors independently selected the trials to be included and extracted data. The one included study was rated for risk of bias according to the methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions., Main Results: This review was complicated by a lack of generally accepted criteria for the diagnosis of TOS and had to rely exclusively on the diagnosis of TOS by the investigators in the reviewed studies. There were no studies comparing natural progression with any active intervention. In one trial with a high risk of bias involving 55 participants transaxillary first rib resection decreased pain more than supraclavicular neuroplasty of the brachial plexus. There were no adverse effects in either group., Authors' Conclusions: This review was complicated by a lack of generally accepted diagnostic criteria for the diagnosis of TOS. There was very low quality evidence that transaxillary first rib resection decreased pain more than supraclavicular neuroplasty but no randomized evidence that either is better than no treatment. There is no randomized evidence to support the use of other currently used treatments. There is a need for an agreed definition for the diagnosis of TOS, especially the disputed form, agreed outcome measures and high quality randomized trials that compare the outcome of interventions with no treatment and with each other.

Background: Symmetrical peripheral neuropathy is a common complication of diabetic neuropathy. No treatments are known to be effective for progressive pain and sensory loss associated with diabetic neuropathy. Alternative effective treatment strategies have been sought., Objectives: To systematically review the evidence from randomized controlled trials concerning the role of decompressive surgery of lower limbs for symmetrical diabetic peripheral neuropathy., Search Strategy: We searched the Cochrane Neuromuscular Disease Trials Register (May 2006), CENTRAL (The Cochrane Library, Issue 2 2006), MEDLINE from (January 1966 to August 2006), EMBASE (from January 1980 to August 2006), LILACS (from January 1982 to August 2006), and CINAHL (from January 1982 to August 2006)., Selection Criteria: We included all randomized or quasi-randomized controlled human trials in which any form of decompressive surgery of the lower limbs nerves had been used to treat diabetic symmetrical distal polyneuropathy (DSDP) compared with no treatment or medical therapy. Patients with DSDP were included if they had decompression (with or without neurolysis) of at least two of the following nerves in both lower limbs, for the treatment of DSDP: the posterior tibial nerve (including calcaneal, medial and lateral plantar nerves), deep peroneal nerve at the ankle, common peroneal nerve at the knee, lateral femoral cutaneous nerve and sural nerves in the posterior calf region. The primary outcome measure was the change in pain measured by the visual analogue scale (VAS) between the baseline and a follow-up period of greater than three months., Data Collection and Analysis: We identified 142 publications from the above search strategies. The three authors of this manuscript reviewed abstracts of all papers independently. Only eight of these were considered relevant to the question at hand. The data from these 8 studies were entered onto standardized data extraction forms. We planned to use Review Manager to pool the results from appropriate studies comparing the same treatments; dichotomous outcomes to obtain pooled relative risks (RR); measured outcomes to obtain pooled weighted mean differences; and a fixed-effect analysis unless there was evidence of serious heterogeneity between studies sufficient to justify the use of random-effects analysis., Main Results: This review failed to identify a single randomized controlled trial or any other well designed prospective study controlling for the non-operated limb that showed improvements in pre defined end points after decompressive surgery., Authors' Conclusions: The results of this review suggest that the role of decompressive surgery for diabetic symmetric distal neuropathy is unproven.