Core outcomes in nerve surgery: development of a core outcome set for ulnar neuropathy at the elbow.

OBJECTIVE: Ulnar neuropathy at the elbow (UNE) is common, affecting 1%-6% of the population. Despite this, there remains a lack of consensus regarding optimal treatment. This is primarily due to the difficulty one encounters when trying to assess the literature. Outcomes are inconsistently reported, which makes comparing studies or developing meta-analyses difficult or even impossible. Thus, there is a need for a core outcome set (COS) for UNE (COS-UNE) to help address this problem. The objective of this study was to utilize a modified Delphi method to develop COS-UNE. METHODS: A 5-stage approach was utilized to develop COS-UNE: stage 1, consortium development; 2, literature review to identify potential outcome measures; 3, Delphi survey to develop consensus on outcomes for inclusion; 4, Delphi survey to develop definitions; and 5, consensus meeting to finalize the COS and definitions. The study followed the Core Outcome Set-STAndards for Development (COS-STAD) recommendations. RESULTS: The Core Outcomes in Nerve Surgery (COINS) Consortium comprised 21 participants, all neurological surgeons representing 11 countries. The final COS-UNE consisted of 22 data points/outcomes covering the domains of demographic characteristics, diagnostics, patient-reported outcomes, motor/sensory outcomes, and complications. Appropriate instruments, methods of testing, and definitions were set. The consensus minimum duration of follow-up was 6 months, with the consensus optimal timepoints for assessment identified as preoperatively and 3, 6, and 12 months postoperatively. CONCLUSIONS: The authors identified consensus data points/outcomes and also provided definitions and specific scales to be utilized to help ensure that clinicians are consistent in their reporting across studies on UNE. This COS should serve as a minimum set of data to be collected in all future neurosurgical studies on UNE. The authors hope that clinicians evaluating ulnar neuropathy will incorporate this COS into routine practice and that future studies will consider this COS in the design phase.

Lateral Displacement of the Phrenic Nerve in C5 Tumors.

BACKGROUND AND OBJECTIVES: Nerve sheath tumors of the brachial plexus frequently distort the local anatomy, increasing the difficulty of safe exposure and resection. However, lateral displacement of the phrenic nerve has not been previously described. The purpose of this study was thus to illustrate the abnormal lateral displacement of the phrenic nerve in 2 cases of patients undergoing brachial plexus tumor resection and provide a possible mechanism for this observation. METHODS: Two patients underwent surgical resection of clinically progressing C5 schwannomas. During exposure, the phrenic nerve was found to be significantly more superficial and lateral than typical. This structural relationship persisted even after complete resection of the lesion. Both patients did well postoperatively. RESULTS: The phrenic nerve traverses along the anterolateral aspect of the anterior scalene. However, in these 2 cases of C5 nerve sheath tumors, the phrenic was found to be significantly more lateral and superficial than usual, draping across the medial aspect of the tumor. We believe that the C5-phrenic communicating branch may act as a functional tether that mobilizes the phrenic nerve laterally as the tumor grows. The mass effect on the anterior scalene by the underlying C5 tumor may further contribute to the anterolateral and superficial displacement of the nerve. CONCLUSION: The phrenic nerve may be seen markedly more laterally and superficially displaced in cases of C5 nerve sheath tumors. It is important for surgeons who operate on lesions of the brachial plexus to be aware of this phenomenon.

Endoscopic third ventriculostomy for VP shunt malfunction during the third trimester of pregnancy: illustrative case.

BACKGROUND: Endoscopic third ventriculostomy (ETV) is a successful procedure for treating noncommunicating hydrocephalus as an alternative to initial ventriculoperitoneal (VP) shunt placement and as a salvage procedure when a VP shunt fails. Physiological changes of pregnancy can lead to VP shunt failure and complicate the management of shunt malfunction, particularly in the third trimester. OBSERVATIONS: The authors present a case in which an ETV was successfully used in the third trimester (31 weeks of gestation) of pregnancy for acute hydrocephalus due to VP shunt malfunction, and the patient went on to deliver a healthy baby at term; the patient remained well in the long-term follow-up. An English-language PubMed literature review revealed four cases of VP shunt failure successfully treated with an ETV in the first or second trimester but no such reports in the third trimester of pregnancy. LESSONS: ETV appears to be a safe and effective alternative to VP shunt replacement in the late prenatal period of pregnancy.

Understanding the Pathognomonic Tumefactive Appearance of Neurolymphomatosis: A Unifying Theory of Neurolymphoma.

BACKGROUND: The diagnosis of peripheral neurolymphomatosis (NL) is difficult and often delayed, because patients can have isolated, nonspecific nerve symptoms. Magnetic resonance imaging will usually show nonspecific findings of enlarged, contrast-enhancing nerves. We aimed to elucidate the mechanism behind an imaging finding we believe is pathognomonic of NL and likely of other hematologic diseases with peripheral nerve involvement. METHODS: We reviewed the imaging studies of a previously reported cohort of patients, in addition to those from more recent patients, all with tumefactive NL, in which enlarged nerve bundles were surrounded by tumor. We reviewed the demographic data, clinical data (e.g., primary or secondary disease, biopsy-proven diagnosis), and imaging findings (e.g., tumefactive appearance, primary involved nerve, location of epicenter of tumefactive appearance, vascular involvement). RESULTS: All cases showed a maximum tumefactive appearance at branch or junction points, with a gradual decrease of this appearance moving proximally and distally from the epicenter in a "crescendo-decrescendo" pattern. We have described this as a phasic mechanism with 3 phases: malignant cells fill the intraneural space; extrude at a weak spot of the nerve, which often occurs at a branch or junction point; and then expand and fill the subparaneurial space, creating the grossly tumefactive appearance with proximal and distal spread. CONCLUSIONS: We have presented a novel, unifying theory explaining the pathognomonic tumefactive appearance of NL. Our theory offers the first rational explanation for the radiological appearance of NL with peripheral nerve involvement. We believe that with earlier recognition of NL on imaging studies, patients will be able to receive an earlier diagnosis and undergo earlier treatment.

DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis.

BACKGROUNDDICER1 is the only miRNA biogenesis component associated with an inherited tumor syndrome, featuring multinodular goiter (MNG) and rare pediatric-onset lesions. Other susceptibility genes for familial forms of MNG likely exist.METHODSWhole-exome sequencing of a kindred with early-onset MNG and schwannomatosis was followed by investigation of germline pathogenic variants that fully segregated with the disease. Genome-wide analyses were performed on 13 tissue samples from familial and nonfamilial DGCR8-E518K-positive tumors, including MNG, schwannomas, papillary thyroid cancers (PTCs), and Wilms tumors. miRNA profiles of 4 tissue types were compared, and sequencing of miRNA, pre-miRNA, and mRNA was performed in a subset of 9 schwannomas, 4 of which harbor DGCR8-E518K.RESULTSWe identified c.1552G>A;p.E518K in DGCR8, a microprocessor component located in 22q, in the kindred. The variant identified is a somatic hotspot in Wilms tumors and has been identified in 2 PTCs. Copy number loss of chromosome 22q, leading to loss of heterozygosity at the DGCR8 locus, was found in all 13 samples harboring c.1552G>A;p.E518K. miRNA profiling of PTCs, MNG, schwannomas, and Wilms tumors revealed a common profile among E518K hemizygous tumors. In vitro cleavage demonstrated improper processing of pre-miRNA by DGCR8-E518K. MicroRNA and RNA profiling show that this variant disrupts precursor microRNA production, impacting populations of canonical microRNAs and mirtrons.CONCLUSIONWe identified DGCR8 as the cause of an unreported autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter with schwannomatosis.FUNDINGCanadian Institutes of Health Research, Compute Canada, Alex's Lemonade Stand Foundation, the Mia Neri Foundation for Childhood Cancer, Cassa di Sovvenzioni e Risparmio fra il Personale della Banca d'Italia, and the KinderKrebsInitiative Buchholz/Holm-Seppensen.

Recognition of peroneal intraneural ganglia in an historical cohort with "negative" MRIs.

BACKGROUND: The objective of this study was to review an historical cohort of patients with peroneal neuropathy and magnetic resonance imaging (MRI) read as negative for mass or cyst to determine if occult peroneal intraneural ganglion cysts can be identified on subsequent imaging review and to use this as an estimation of how under-recognized this pathologic entity is. METHOD: The patient cohort utilized in this study was a previously published control cohort of 11 patients with peroneal neuropathy and MRI read as negative for mass or cyst. Clinical history, neurologic examination, and MRI studies of the knee were reviewed for each of the included patients. The primary outcome of interest was the presence of peroneal intraneural ganglion cyst on MRI. RESULTS: Overall, 7 of 11 (64%) patients in this historical "normal" cohort had evidence of a peroneal intraneural ganglion cyst on subsequent review of imaging. Deep peroneal-predominant weakness, knee pain, and tibialis anterior-predominant denervation/atrophy were seen more commonly in patients in whom an intraneural cyst was identified. CONCLUSIONS: This retrospective cohort study provides evidence that peroneal intraneural ganglion cysts are an historically under-recognized cause of peroneal neuropathy, with 64% of this historical "negative" cohort having evidence of a cyst on subsequent imaging review. Larger studies are needed to determine the treatment ramifications of identifying small cysts and to determine the clinical features suggestive of an intraneural ganglion cyst.

The nearly invisible intraneural cyst: a new and emerging part of the spectrum.

OBJECTIVE The authors have observed that a subset of patients referred for evaluation of peroneal neuropathy with "negative" findings on MRI of the knee have subtle evidence of a peroneal intraneural ganglion cyst on subsequent closer inspection. The objective of this study was to introduce the nearly invisible peroneal intraneural ganglion cyst and provide illustrative cases. The authors further wanted to identify clues to the presence of a nearly invisible cyst. METHODS Illustrative cases demonstrating nearly invisible peroneal intraneural ganglion cysts were retrospectively reviewed and are presented. Case history and physical examination, imaging, and intraoperative findings were reviewed for each case. The outcomes of interest were the size and configuration of peroneal intraneural ganglion cysts over time, relative to various interventions that were performed, and in relation to physical examination and electrodiagnostic findings. RESULTS The authors present a series of cases that highlight the dynamic nature of peroneal intraneural ganglion cysts and introduce the nearly invisible cyst as a new and emerging part of the spectrum. The cases demonstrate changes in size and morphology over time of both the intraneural and extraneural compartments of these cysts. Despite "negative" MR imaging findings, nearly invisible cysts can be identified in a subset of patients. CONCLUSIONS The authors demonstrate here that peroneal intraneural ganglion cysts ride a roller coaster of change in both size and morphology over time, and they describe the nearly invisible cyst as one end of the spectrum. They identified clues to the presence of a nearly invisible cyst, including deep peroneal predominant symptoms, fluctuating symptoms, denervation changes in the tibialis anterior muscle, and abnormalities of the superior tibiofibular joint, and they correlate the subtle imaging findings to the internal fascicular topography of the common peroneal nerve. The description of the nearly invisible cyst may allow for increased recognition of this pathological entity that occurs with a spectrum of findings.

Tumefactive appearance of peripheral nerve involvement in hematologic malignancies: a new imaging association.

OBJECTIVE: In neurolymphomatosis (NL), the affected nerves are typically described to be enlarged and hyperintense on T2W MR sequences and to avidly enhance on gadolinium-enhanced T1WI. This pattern is highly non-specific. We recently became aware of a "tumefactive pattern" of NL, neuroleukemiosis (NLK) and neuroplasmacytoma (NPLC), which we believe is exclusive to hematologic diseases affecting peripheral nerves. MATERIALS AND METHODS: We defined a "tumefactive" appearance as complex, fusiform, hyperintense on T2WI, circumferential tumor masses encasing the involved peripheral nerves. The nerves appear to be infiltrated by the tumor. Both structures show varying levels of homogenous enhancement. We reviewed our series of 52 cases of NL in search of this pattern; two extra outside cases of NL, three cases of NLK, and one case of NPLC were added to the series. RESULTS: We identified 20 tumefactive lesions in 18 patients (14 NL, three NLK, one NPLC). The brachial plexus (n = 7) was most commonly affected, followed by the sciatic nerve (n = 6) and lumbosacral plexus (n = 3). Four patients had involvement of other nerves. All were proven by biopsy: the diagnosis was high-grade lymphoma (n = 12), low-grade lymphoma (n = 3), acute leukemia (n = 2), and plasmacytoma (n = 1). CONCLUSIONS: We present a new imaging pattern of "tumefactive" neurolymphomatosis, neuroleukemiosis, or neuroplasmacytoma in a series of 18 cases. We believe this pattern is associated with hematologic diseases directly involving the peripheral nerves. Knowledge of this association can provide a clue to clinicians in establishing the correct diagnosis. Bearing in mind that tumefactive NL, NLK, and NPLC is a newly introduced imaging pattern, we still recommend to biopsy patients with suspicion of a malignancy.

Hilton's law revisited.

Hilton's Law, put forth 150 years ago, is well known and frequently taught in anatomy courses. We critically analyzed the complex description of associated muscular, cutaneous, and articular innervations in order to assess the general applicability of Hilton's Law. We applied rules for interpretation of the Law extrapolated upon but based on Hilton's original writings, and excluded obscure supplementary clauses not considered as part of the Law. We found the Law, as originally written and as we interpreted with some latitude, to be reliable and applicable to all cranial and peripheral nerves. Hilton's Law is a powerful springboard to understand articular anatomy and pathophysiology.

Neurological outcome following resection of benign presacral neurogenic tumors using a nerve-sparing technique.

BACKGROUND: Benign presacral nerve sheath tumors represent up to 10% of all presacral tumors. Limited data exist regarding the impact of the surgical technique on neurological outcomes following resection. OBJECTIVE: The aim of this study was to test our hypothesis that a nerve-sparing resection technique results in the improvement of preoperative neurological dysfunction and minimal postoperative neurological morbidity. DESIGN: This study is a case series of all patients with benign neurogenic presacral tumors operated on by the same 2 surgeons between 2004 and 2010 at our institution. SETTINGS: This study was performed at a tertiary care center. PATIENTS: Adult patients with benign presacral neurogenic tumors who underwent a nerve-sparing resection were included. MAIN OUTCOME MEASURES: Postoperative urogenital, anorectal, and lower-extremity neurological functions were analyzed. RESULTS: Seventeen patients were identified with a mean age of 40 years; 14 were women. Preoperatively, 13 patients had symptoms from neurological dysfunction or presumed mass effect of the tumor. The mean tumor size was 7.4 cm. The pathology was a schwannoma in 12 patients and neurofibroma in 5 patients. Mortality was nil, and 30-day morbidity was noted in 3 patients (hemorrhage, ileus, acute respiratory distress syndrome, deep vein thrombosis, and transient foot drop). Mean follow-up was 36 months. Of the 13 symptomatic patients, 7 achieved complete resolution of symptoms and 5 had improved, but persistent symptoms. None of the 4 asymptomatic patients developed postoperative neurological dysfunction. LIMITATIONS: Small sample size was a limitation of this study. CONCLUSIONS: With the use of a nerve-sparing technique, function-preserving resection can be safely completed with an overall improvement in symptoms.

Cerebrospinal fluid volume-depletion headaches in patients with traumatic brachial plexus injury.

OBJECT: Patients with brachial plexus injury (BPI) present with a combination of motor weakness/paralysis, sensory deficits, and pain. Brachial plexus injury is generally not believed to be associated with headaches. However, CSF leaks may be associated with CSF volume-depletion (low-pressure) headaches and can occur in BPI secondary to nerve root avulsion. Only a few cases of headaches associated with BPI have been reported. It is unknown if headaches in patients with BPI occur so rarely, or if they are just unrecognized by physicians and/or patients in which the focus of attention is the affected limb. The aim of this study was to determine the prevalence of CSF volume-depletion headaches in patients with BPI. METHODS: All adult patients presenting at the Mayo brachial plexus clinic with traumatic BPI were asked to complete a questionnaire addressing the presence and quality of headaches following their injury. The patients' clinical, injury, and imaging characteristics were subsequently reviewed. RESULTS: Between December 2008 and July 2010, 145 patients completed the questionnaire. Twenty-two patients reported new onset headaches occurring after their BPI. Eight of these patients experienced positional headaches, suggestive of CSF volume depletion. One of the patients with orthostatic headaches was excluded because the headaches immediately followed a lumbar puncture for a myelogram. Six of the other 7 patients with positional headaches had a clear preganglionic BPI. The available imaging studies in these 6 patients revealed evidence of CSF leaks: pseudomeningoceles (n = 5), CSF tracking into soft tissues (n = 3), CSF tracking into the intraspinal compartment (n = 3), CSF tracking into the pleural space (n = 2), and low-positioned cerebellar tonsils (n = 2). CONCLUSIONS: In this retrospective study, 15.2% of patients (22 of 145 patients) with traumatic BPI suffered from a new-onset headache. Seven of these patients (4.8%) experienced postural headaches clearly suggestive of CSF volume depletion likely secondary to a CSF leak associated with the BPI, whereas the other 15 patients (10.3%) suffered headaches that may have represented a variant of CSF depletion headaches without a postural characteristic or a headache from another cause. These data suggest that CSF volume-depletion headaches occur in a significant proportion of patients with BPI and have been underrecognized and underreported.

Short- and long-term peripheral nerve regeneration using a poly-lactic-co-glycolic-acid scaffold containing nerve growth factor and glial cell line-derived neurotrophic factor releasing microspheres.

Addition of neural growth factors to bioengineered scaffolds may improve peripheral nerve regeneration. The aim of this study is to evaluate the short- and long term effect of microsphere delivered nerve growth factor (NGF) and glial cell derived neurotrophic factor (GDNF) in the 10 mm rat sciatic nerve gap. Eighty-four rats were assigned to seven groups (n = 6) at two endpoints (6 and 16 weeks): saline, saline NGF, saline NGF-microspheres, saline GDNF, saline GDNF-microspheres, saline blank microspheres, and autologous nerve graft. Total fascicular area and total number of myelinated fibers at mid-tube increased in all conduit groups between 6 and 16 weeks. Autologous, saline NGF-microsphere and saline GDNF-microsphere groups reached maximal histomorphometric values by 6 weeks (p < 0.05). Compound muscle action potentials returned after 6 weeks for the autologous graft and continued to increase to a level of 3.6 ± 1.9 mV at endpoint. No significant differences were found between study groups as measured by ankle angle. These experiments show an initial beneficial effect of incorporation of NGF- or GDNF-microspheres in a PLGA 85/15 nerve conduit, since histomorphometric values reached their maximum by 6 weeks compared to control groups. These results do not yet extrapolate into improved electrophysiological or functional improvement.

Adipose lesions of nerve: the need for a modified classification.

OBJECT: Adipose lesions of nerve are rare and poorly understood. Their current classification, although not universally accepted, generally includes lipomatosis of nerve with or without localized macrodactyly, and intra- as well as extraneural lipoma. The authors believe that the spectrum of these lesions and their interrelationships are not currently appreciated. They propose an adaptation to the existing framework to illustrate the expanding spectrum of adipose lesions of nerve by considering lipomatosis and lipoma singly or in combination. METHODS: Fourteen representative cases are presented to demonstrate not only the intraneural and extraneural examples of lipomatosis and lipoma, but also their anatomical combinations. RESULTS: Based on the cases presented and a careful literature review, a conceptual approach to the classification of adipose lesions of nerve is generated. This approach incorporates the 2 essential lesions, lipomatosis of nerve and lipoma, in both their intra- and extraneural forms. This permits expansion to encompass combinations. CONCLUSIONS: To press the concept that adipose tumors of nerve are a broad but interrelated spectrum of lesions, the authors propose modification of the present classification system. This approach provides an orderly platform for progress, reflects understanding of these interrelated lesions, and facilitates optimal treatment by distinguishing resectable from nonresectable components.

Fibromatosis: a potential sequela of neuromuscular choristoma.

OBJECT: Neuromuscular choristoma (NMC) is a rare peripheral nerve lesion in which mature skeletal muscle fibers lie within the nerve and its fascicles. Given limited follow-up, its natural history is poorly understood. The occurrence of aggressive fibromatosis in one of the authors' patients and its occurrence in reported cases suggests an etiological relationship between the 2 lesions. This study attempts to explain the association and its frequency. METHODS: All cases of NMCs seen in consultation or treated at the Mayo Clinic were identified. Demographic and clinical data were reviewed in cases with coexistent aggressive fibromatosis. Pathology and neuroimaging studies were reexamined. In addition, an extensive literature review was performed to explore the association of NMC with aggressive fibromatosis, with special attention given to pathological and imaging characteristics and the development of aggressive fibromatosis. RESULTS: The authors identified 10 patients with a diagnosis of NMC who were treated at the Mayo Clinic between 1992 and 2010. Four of 5 with adequate follow-up had developed a definite or suspected aggressive fibromatosis. A review of the initial pathological specimens in these cases revealed no evidence of fibromatosis, but all of the lesions exhibited accompanying hypocellular collagenous tissue. On MR images, all cases showed areas of low signal intensity, which significantly differed from muscle, nerve, and NMC components. On available serial MR imaging studies, aggressive fibromatosis seemed to originate in such lower-intensity regions. In the 18 previously reported cases of NMC, 5 patients developed recurrent masses diagnosed as either definite (2 cases) or possible (3 cases) fibromatosis. Review of the published imaging studies in these cases suggests the presence of lower intensity areas similar to those observed in the 10 patients treated at the Mayo Clinic. CONCLUSIONS: This study confirms that the development of aggressive fibromatosis in patients with NMC has been underreported. A direct relationship between the NMC and the development of aggressive fibromatosis is suggested by pathological and neuroimaging evidence.

Extraneural rupture of intraneural ganglion cysts.

Rupture of simple (extraneural) cysts such as popliteal cysts (Baker's cysts) is a well-known occurrence. The purpose of this report is to introduce the similar occurrence of extraneural rupture of peroneal and tibial intraneural cysts in the knee region, describe the associated magnetic resonance imaging (MRI) findings, and identify risk factors. There was MRI evidence of rupture in 20 of 38 intraneural cases reviewed, mainly in the region of the fibular head and popliteal fossa. Ruptured intraneural cysts and simple cysts share these MRI findings: T2 hyperintense fluid within surrounding intermuscular fascial planes and enhancement with intravenous contrast consistent with inflammation. The mean maximal diameter of the ruptured intraneural cysts was statistically significantly smaller than that of the unruptured cysts. The authors believe that extraneural rupture of an intraneural cyst is due to increased intraarticular pressures transmitted within the cyst and/or elevated extrinsic pressure delivered to the cyst, such as by trauma, akin to the etiology of rupture of extraneural ganglion cysts.

An anatomically based imaging sign to detect adventitial cyst derived from the superior tibiofibular joint.

The origin for complex intraneural cysts remains controversial despite recent emerging evidence to support their articular origin. The coexistence of intraneural and adventitial cysts has been described due to the proximate neurovascular bundle, i.e., the articular (neural) branch and vessels at the joint capsule. To clarify the pathogenesis, anatomically based imaging patterns can be identified. This paper characterizes a common finding identified on MRI describing the adventitial component originating from the superior tibiofibular joint (STFJ). MRIs of patients with fibular (peroneal) (n = 24) and tibial (n = 7) intraneural ganglion cysts were reviewed. Eleven patients with fibular intraneural ganglion cysts were identified as having a coexisting adventitial component. In all cases, the adventitial cyst extended from the anterior portion of the STFJ, within the capsular vessels, and along the anterior tibial vessels. The reproducible anatomy permitted the identification of an imaging pattern: the "vascular U" sign, consisting of cystic anterior tibial vessels running through the interosseous membrane between the proximal tibia and fibula. This sign was seen on axial MR image(s) obtained at the level of the fibular neck in all cases. To generalize these findings, the rare tibial intraneural ganglion cysts (derived from the posterior aspect of the STFJ) were examined; two cases had coexisting adventitial cysts with visualization of the vascular U sign. This new imaging pattern can improve the identification of adventitial cysts at the level of the STFJ.