Allan J. Belzberg

Mechanical hyperalgesia after an L5 spinal nerve lesion in the rat is not dependent on input from injured nerve fibers.

&NA; An injury to a peripheral nerve in animals often leads to signs of neuropathic pain including hyperalgesia to heat, cold and mechanical stimuli. The role of injured and intact nerve fibers in mechanical hyperalgesia was evaluated in rats subjected to an L5 spinal nerve ligation‐and‐cut (‘modified SNL lesion’). To assess the contribution of injured afferents, an L5 dorsal rhizotomy was performed immediately before, or 7 days after the modified SNL lesion. To study the role of adjacent intact spinal nerves, an L4 dorsal rhizotomy was performed 7 days after the modified SNL lesion. The up–down method of Dixon (Dixon WJ, Annu Rev Pharmacol Toxicol 1980;20:441–462) was used to measure the paw withdrawal threshold to mechanical stimuli at three sites on the rat hindpaw corresponding to the L3, L4, and L5 dermatomes. We found that the modified SNL lesion produced a significant, lasting (>20 days) decrease of the mechanical withdrawal threshold. The severity and duration of mechanical hyperalgesia varied across testing sites. The L5 and L4 dermatome test sites developed the most severe and lasting mechanical hyperalgesia. In contrast, the L3 testing site developed significantly less severe and shorter lasting mechanical hyperalgesia. L5 dorsal rhizotomy, by itself, produced a transient decrease in mechanical withdrawal thresholds. L5 dorsal rhizotomy performed before, or 7 days after, the modified SNL lesion did not prevent or resolve the observed decrease in mechanical withdrawal thresholds. L4 dorsal rhizotomy performed 7 days after the modified SNL lesion resulted in an immediate reversal of mechanical withdrawal thresholds back to baseline values. These results suggest that, after L5 spinal nerve ligation‐and‐cut, mechanical hyperalgesia develops and persists independent of input from injured afferents. We propose that the Wallerian degeneration that develops after a nerve injury leads to interactions between the degenerating fibers of the injured spinal nerve and the intact fibers of adjacent spinal nerves. This leads to changes in the intact fibers that play a critical role for both initiation and maintenance of mechanical hyperalgesia.

MR Neurography: Past, Present, and Future

OBJECTIVE MR neurography (MRN) has increasingly been used in clinical practice for the evaluation of peripheral nerve disease. This article reviews the historic perspective of MRN, the current imaging trends of this modality, and the future directions and applications that have shown potential for improved imaging and diagnostic capabilities. CONCLUSION MRN has come a long way in the past 2 decades. Excellent depiction of 3D nerve anatomy and pathology is currently possible. Further technical developments in diffusion-based nerve and muscle imaging, whole-body MRN, and nerve-specific MR contrast agents will likely play a major role in advancing this novel field and understanding peripheral neuromuscular diseases in the years to come.

Mechanical hyperalgesia after an L5 ventral rhizotomy or an L5 ganglionectomy in the rat.

&NA; An L5 spinal nerve ligation (SNL) in the rat leads to behavioral signs of mechanical hyperalgesia. Our recent finding that an L5 dorsal root rhizotomy did not alter the mechanical hyperalgesia following an L5 SNL suggests that signals originating from the proximal stump of the injured nerve are not essential. We postulate that Wallerian degeneration of L5 nerve fibers leads to altered properties of adjacent intact nociceptive afferents. To investigate the role of degeneration in sensory versus motor fibers, five injury models were examined concurrently in a blinded fashion. An L5 ganglionectomy produced a selective lesion of sensory fibers. An L5 ventral root rhizotomy produced a selective lesion of motor fibers. The three control lesions included: (1) SNL with L5 dorsal root rhizotomy; (2) L5 dorsal root rhizotomy; and (3) exposure of the L5 roots without transection (sham). Paw withdrawal thresholds to mechanical stimuli were measured at three sites in the rat hindpaw corresponding to the L3, L4, and L5 dermatomes. Both the ganglionectomy and the ventral rhizotomy produced a significant, lasting (≥20d) decrease of mechanical withdrawal thresholds that was comparable to that produced by the SNL lesion. The L5 dorsal rhizotomy, by itself, produced a short lasting (≤6 d) decrease in thresholds, whereas the sham procedure did not produce a significant change. We propose that interactions between degenerating motor and sensory fibers of the injured nerve and intact afferent fibers of neighboring nerves play a critical role for both initiation and maintenance of mechanical hyperalgesia in neuropathic pain.

High-resolution MR neurography of diffuse peripheral nerve lesions.

SUMMARY: High-resolution MR imaging of peripheral nerves is becoming more common and practical with the increasing availability of 3T magnets. There are multiple reports of MR imaging of peripheral nerves in compression and entrapment neuropathies. However, there is a relative paucity of literature on MRN appearance of diffuse peripheral nerve lesions. We attempted to highlight the salient imaging features of myriad diffuse peripheral nerve disorders and imaging techniques for MRN. Using clinical and pathologically proved relevant examples, we present the MRN appearance of various types of diffuse peripheral nerve lesions, such as traumatic, inflammatory, infectious, hereditary, radiation-induced, neoplastic, and tumor variants.

Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors

Neurofibromatosis 1 is a hereditary syndrome characterized by the development of numerous benign neurofibromas, a small subset of which progress to malignant peripheral nerve sheath tumors (MPNSTs). To better understand the genetic basis for MPNSTs, we performed genome-wide or targeted sequencing on 50 cases. Sixteen MPNSTs but none of the neurofibromas tested were found to have somatic mutations in SUZ12, implicating it as having a central role in malignant transformation.

Anatomic MR Imaging and Functional Diffusion Tensor Imaging of Peripheral Nerve Tumors and Tumorlike Conditions

In this study 29 patients underwent anatomic and functional imaging (DWI and DTI) of peripheral nerve masses in an attempt to improve their characterization. ADC values were lower in malignant tumors, the involved nerves had lower fractional anisotropy, and DTI showed differences between benign and malignant tumors. The authors concluded that tractography and fractional anisotropy provide insight into neural integrity while low diffusivity indicates malignancy. BACKGROUND AND PURPOSE: A number of benign and malignant peripheral nerve tumor and tumorlike conditions produce similar imaging features on conventional anatomic MR imaging. Functional MR imaging using DTI can increment the diagnostic performance in differentiation of these lesions. Our aim was to evaluate the role of 3T anatomic MR imaging and DTI in the characterization of peripheral nerve tumor and tumorlike conditions. MATERIALS AND METHODS: Twenty-nine patients (13 men, 16 women; mean age, 41 ± 18 years; range, 11–83 years) with a nerve tumor or tumorlike condition (25 benign, 5 malignant) underwent 3T MR imaging by using anatomic (n = 29), functional diffusion, DWI (n = 21), and DTI (n = 24) techniques. Images were evaluated for image quality (3-point scale), ADC of the lesion, tractography, and fractional anisotropy of nerves with interobserver reliability in ADC and FA measurements. RESULTS: No significant differences were observed in age (benign, 40 ± 18 versus malignant, 45 ± 19 years) and sex (benign, male/female = 12:12 versus malignant, male/female = 3:2) (P > .05). All anatomic (29/29, 100%) MR imaging studies received “good” quality; 20/21 (95%) DWI and 21/24 (79%) DTI studies received “good” quality. ADC of benign lesions (1.848 ± 0.40 × 10−3 mm2/s) differed from that of malignant lesions (0.900 ± 0.25 × 10−3 mm2/s, P < .001) with excellent interobserver reliability (ICC = 0.988 [95% CI, 0.976–0.994]). There were no FA or ADC differences between men and women (P > .05). FA of involved nerves was lower than that in contralateral healthy nerves (P < .001) with excellent interobserver reliability (ICC = 0.970 [95% CI, 0.946–0.991]). ADC on DTI and DWI was not statistically different (P > .05), with excellent intermethod reliability (ICC = 0.943 [95% CI, 0.836–0.980]). Tractography differences were observed in benign and malignant lesions. CONCLUSIONS: 3T MR imaging and DTI are valuable methods for anatomic and functional evaluation of peripheral nerve lesions with excellent interobserver reliability. While tractography and low FA provide insight into neural integrity, low diffusivity values indicate malignancy in neural masses.

Consensus Recommendations to Accelerate Clinical Trials for Neurofibromatosis Type 2

Purpose: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder associated primarily with bilateral schwannomas seen on the superior vestibular branches of the eighth cranial nerves. Significant morbidity can result from surgical treatment of these tumors. Meningiomas, ependymomas, and other benign central nervous system tumors are also common in NF2. The lack of effective treatments for NF2 marks an unmet medical need. Experimental Design: Here, we provide recommendations from a workshop, cochaired by Drs. D. Gareth Evans and Marco Giovannini, of 36 international researchers, physicians, representatives of the biotechnology industry, and patient advocates on how to accelerate progress toward NF2 clinical trials. Results: Workshop participants reached a consensus that, based on current knowledge, the time is right to plan and implement NF2 clinical trials. Obstacles impeding NF2 clinical trials and how to address them were discussed, as well as the candidate therapeutic pipeline for NF2. Conclusions: Both phase 0 and phase II NF2 trials are near-term options for NF2 clinical trials. The number of NF2 patients in the population remains limited, and successful recruitment will require ongoing collaboration efforts between NF2 clinics. (Clin Cancer Res 2009;15(16):5032–9)

3-T High-Resolution MR Neurography of Sciatic Neuropathy

OBJECTIVE The sciatic nerve may normally exhibit mild T2 hyperintensity in MR neurography (MRN) images, rendering assessment of sciatic neuropathy difficult. The purpose of this case-control study was to evaluate whether a quantitative and qualitative analysis of the sciatic nerves and regional skeletal muscles increases the accuracy of MRN in detecting sciatic neuropathy. MATERIALS AND METHODS We retrospectively reviewed the MRN studies of the pelvis and thighs of 34 subjects (12 men and 22 women; mean [± SD] age, 50 ± 15 years), of which 17 had a final diagnosis of sciatic neuropathy according to electrodiagnostic or surgical confirmation, and 17 had no evidence of sciatic neuropathy and served as control subjects. On each side, the sciatic nerves were evaluated for signal intensity (SI), size, course, and fascicular shape, whereas the regional skeletal muscles were evaluated for edema, fatty replacement, and atrophy. In addition, the nerve-to-vessel SI ratio was registered for each side at the same time and 8 months later. RESULTS The sciatic nerves of the abnormal sides exhibited higher nerve-to-vessel SI ratios and higher incidences of T2 hyperintensity, enlargement, and abnormal fascicular shape compared to the nerves of the normal sides. The regional muscles of the abnormal sides demonstrated a higher grade of fatty infiltration and higher frequencies of edema and atrophy. A cutoff value of nerve-to-vessel SI ratio of 0.89 exhibited high sensitivity and specificity in predicting sciatic neuropathy. Calculation of the nerve-to-vessel SI ratio demonstrated excellent inter- and intraobserver reliability. CONCLUSION Both qualitative and quantitative criteria should be used to suggest the MRN diagnosis of sciatic neuropathy.

Incidence and prognostic factors of c5 palsy: a clinical study of 1001 cases and review of the literature.

BACKGROUND C5 palsy is a known cause of postoperative deltoid weakness. Prognostic variables affecting the incidence of the palsy have been poorly understood. OBJECTIVE To determine the incidence and perioperative characteristics/predictors of C5 palsy after anterior vs posterior operations. METHODS All patients undergoing C4-5 operations for degenerative conditions were retrospectively reviewed over 21 years. Anterior operations included an anterior cervical discectomy and fusion (ACDF) or a corpectomy, whereas posterior operations included laminectomy and fusion (± foraminotomies). RESULTS Of the total 1001 operations, in 49.0% anterior and 51.0% posterior cases, there was an overall C5 palsy incidence of 5.2% (52 cases): 1.6% and 8.6%, respectively (P < .001). Of the 99 corpectomies, the palsy incidence of 4.0% was not only higher than ACDFs (1.0%), but also followed an upward trend with increasing corpectomy levels (P = .009). Of the 69 posterior and 83 anterior C4-5 foraminotomies, the incidence of C5 palsy was statistically higher in the posterior (14.5%) vs anterior (2.4%) cohort (P = .01). Multiple logistical regression identified older age as the strongest predictor of C5 palsy in the anterior (P = .02) and C4-5 foraminotomy in the posterior (P = .06) cohort. This condition improved within 3 to 6 months in 75% of patients in the anterior and 88.6% in the posterior cohort after a mean follow-up of 14.4 and 27.6 months, respectively. CONCLUSION In one of the largest cohorts on C5 palsy, we found in anterior operations an increasing number of corpectomy levels had a higher incidence of C5 palsy; however, older age was the strongest predictor of C5 palsy. In posterior operations, C4-5 foraminotomy carried the strongest correlation.

The tibial neuroma transposition (TNT) model of neuroma pain and hyperalgesia

&NA; Peripheral nerve injury may lead to the formation of a painful neuroma. In patients, palpating the tissue overlying a neuroma evokes paraesthesias/dysaesthesias in the distribution of the injured nerve. Previous animal models of neuropathic pain have focused on the mechanical hyperalgesia and allodynia that develops at a location distant from the site of injury and not on the pain from direct stimulation of the neuroma. We describe a new animal model of neuroma pain in which the neuroma was located in a position that is accessible to mechanical testing and outside of the innervation territory of the injured nerve. This allowed testing of pain in response to mechanical stimulation of the neuroma (which we call neuroma tenderness) independent of pain due to mechanical hyperalgesia. In the tibial neuroma transposition (TNT) model, the posterior tibial nerve was ligated and transected in the foot just proximal to the plantar bifurcation. Using a subcutaneous tunnel, the end of the ligated nerve was positioned just superior to the lateral malleolus. Mechanical stimulation of the neuroma produced a profound withdrawal behavior that could be distinguished from the hyperalgesia that developed on the hind paw. The neuroma tenderness (but not the hyperalgesia) was reversed by local lidocaine injection and by proximal transection of the tibial nerve. Afferents originating from the neuroma exhibited spontaneous activity and responses to mechanical stimulation of the neuroma. The TNT model provides a useful tool to investigate the differential mechanisms underlying the neuroma tenderness and mechanical hyperalgesia associated with neuropathic pain.