Pain control with laser-produced dorsal root entry zone lesions

Pain relief was evaluated in 40 patients with various types of deafferentation pain that were treated with dorsal root entry zone (DREZ) lesions produced with microsurgical lasers. Good long-term pain relief was evident in some paraplegics and in all patients with brachial plexus avulsion. Several other small subgroups of patients benefited from laser DREZ lesions as well. Pain associated with arachnoiditis and peripheral nerve injury or neuropathy did not respond to laser DREZ lesioning. Based upon the smaller lesion dimensions produced with the lasers, it is proposed that interruption of impulses in the tract of Lissauer may be a mechanism of pain control in patients that responded to laser DREZ lesions.     

Successful treatment of phantom pain with dorsal root entry zone coagulation

We studied 22 patients with amputation due to trauma, gangrene, or cancer. All developed postamputation pain, underwent a dorsal root entry zone (DREZ) procedure, and were followed from 6 months to 4 years after surgery. Overall, only 8 (36%) of these 22 patients had pain relief. However, good results were obtained in 6 (67%) of 9 patients with phantom pain alone, and in 5 (83%) of 6 patients with traumatic amputations associated with root avulsion. Poor results were obtained in patients with both phantom and stump pain, or stump pain alone. The DREZ procedure has a well-defined, but limited role in the treatment of postamputation pain.     

Dorsal root entry zone lesions in the treatment of pain following brachial plexus avulsion, spinal cord injury and herpes zoster

This paper details the long-term results in patients treated with dorsal root entry zone (DREZ) lesions for the treatment of pain following brachial plexus avulsion, spinal cord injury, and herpes zoster. With our current operative technique, 82% of patients with brachial plexus avulsion injuries were afforded long-term pain relief. Patients with pain confined to dermatomes just below the level of spinal injury also did well with DREZ lesions, although the results were less good in patients with diffuse pain or with sacral pain. The postoperative results in patients with postherpetic pain were disappointing.     

The Hopkins experience with lesions of the dorsal horn (Nashold's operation) for pain from avulsion of the brachial plexus

Lesions of the dorsal horn (DREZ operation) have been reported to be useful in reducing pain secondary to avulsion of the brachial plexus. Ten patients had the DREZ operation for this condition at The Johns Hopkins Hospital by one of us (JNC) between 1981 and 1985. Radiofrequency heat lesions were made. The patients were interviewed 7-52 months after the operation by one of two individuals not involved in the procedure to assess pain relief and postoperative complications. The mean pain relief was 85%, and there were no significant complications. It is concluded that the DREZ operation is the treatment of choice for treatment of severe pain that results from avulsion of the brachial plexus.     

Experimental anatomical considerations of the dorsal root entry zone lesions for pain relief

Dorsal root entry zone (DREZ) lesions were made in the cervical dorsal horn in cat and monkey. Terminal degeneration was observed in the lateral cervical nucleus in cat and contralateral VPL in monkey by Fink-Heimer stain. WGA-HRP was injected in the cervical dorsal horn of cat and retrograde labelled cells were observed mainly in the raphe nucleus, parabrachial nucleus, locus coeruleus, K?lliker-Fuse nucleus, Eddinger-Westphal nucleus, and hypothalamic area, indicating that these descending fiber systems are involved by the DREZ lesion. The functional role of these fibers in regard to deafferentation pain relief seems now to be open to discussion.     

Dorsal root entry zone coagulation for intractable sciatica

Chronic back and leg pain which is unresponsive to medical and/or surgical treatment is a common and difficult neurosurgical problem. Twelve patients with this condition underwent dorsal root entry zone coagulation of that region of the conus medullaris which correlated with the pain. Only 2 patients had a favorable result. The implications of this finding are discussed.     

Live imaging of dorsal root axons after rhizotomy

The primary sensory axons injured by spinal root injuries fail to regenerate into the spinal cord, leading to chronic pain and permanent sensory loss. Regeneration of dorsal root (DR) axons into spinal cord is prevented at the dorsal root entry zone (DREZ), the interface between the CNS and PNS. Our understanding of the molecular and cellular events that prevent regeneration at DREZ is incomplete, in part because complex changes associated with nerve injury have been deduced from postmortem analyses. Dynamic cellular processes, such as axon regeneration, are best studied with techniques that capture real-time events with multiple observations of each living animal. Our ability to monitor neurons serially in vivo has increased dramatically owing to revolutionary innovations in optics and mouse transgenics. Several lines of thy1-GFP transgenic mice, in which subsets of neurons are genetically labeled in distinct fluorescent colors, permit individual neurons to be imaged in vivo(1). These mice have been used extensively for in vivo imaging of muscle(2-4) and brain(5-7), and have provided novel insights into physiological mechanisms that static analyses could not have resolved. Imaging studies of neurons in living spinal cord have only recently begun. Lichtman and his colleagues first demonstrated their feasibility by tracking injured dorsal column (DC) axons with wide-field microscopy(8,9). Multi-photon in vivo imaging of deeply positioned DC axons, microglia and blood vessels has also been accomplished(10). Over the last few years, we have pioneered in applying in vivo imaging to monitor regeneration of DR axons using wide-field microscopy and H line of thy1-YFP mice. These studies have led us to a novel hypothesis about why DR axons are prevented from regenerating within the spinal cord(11). In H line of thy1-YFP mice, distinct YFP+ axons are superficially positioned, which allows several axons to be monitored simultaneously. We have learned that DR axons arriving at DREZ are better imaged in lumbar than in cervical spinal cord. In the present report we describe several strategies that we have found useful to assure successful long-term and repeated imaging of regenerating DR axons. These include methods that eliminate repeated intubation and respiratory interruption, minimize surgery-associated stress and scar formation, and acquire stable images at high resolution without phototoxicity.     

Repairing the ventral root is sufficient for simultaneous motor and sensory recovery in multiple complete cervical root transection injuries

Aim

In multiple cervical root transection injuries, motor and sensory recovery has been demonstrated after repairing both dorsal and ventral roots with autologous grafts applied to the dorsal and ventral aspects, respectively. However, in clinical situations, autologous grafts may not be sufficient to repair both roots in this situation. In this study, the authors evaluated whether repairing ventral root alone is sufficient for simultaneous sensory and motor function recovery.

Main methods

In the transected group, the left 6th–8th cervical roots were pulled and transected at the spinal cord junction. In the repair group, the transected root was anastomosed to a single autologous nerve graft, which was inserted into the ventral horn through a pial incision. Acidic fibroblast growth factor mixed with fibrin glue was applied to the surgical area. Motor function, sensory function, cortical somatosensory evoked potentials (SSEPs), axon tracing, and CGRP⁺ fibers were evaluated.

Key findings

The repaired rats exhibited simultaneous sensory and motor function recovery. At the 16th weeks, SSEPs reappeared in all animals of the repair group, but not in the transected group. Retrograde axon tracing demonstrated an increased number of sensory neurons in the dorsal root ganglia and regenerating nerve fibers in the dorsal horn. CGRP⁺ fibers were significantly increased in the repair group and restricted to laminae I and II.

Significance

This is the first report that in multiple root avulsions with insufficient grafts, repairing ventral roots alone leads to both sensory recovery and motor recovery. This finding may help patients with multiple cervical root avulsions.     

Anatomic examination of human dorsal root entry zone lesions

The anatomic delineation of radiofrequency dorsal root entry zone lesions using the Nashold thermocouple electrode is presented. The sharply delineated lesions involve a major portion of the dorsal horn of the spinal cord including Rexed's lamina V and part of VI. The extent of these lesions is appropriate, based on the currently understood mechanisms of spinal generators of chronic deafferentation pain.     

Transplantation of olfactory ensheathing cells fails to promote significant axonal regeneration from dorsal roots into the rat cervical cord

The olfactory ensheathing cell (OEC) is a class of glial cell that has been reported to support regeneration in the central nervous system after various types of lesions, including rhizotomy of spinal dorsal roots at thoracic, lumbar and sacral levels. We have therefore carried out a detailed anatomical analysis to assess the efficacy of dorsal horn OEC transplants at promoting regeneration of primary afferents across the dorsal root entry zone (DREZ) at the cervical level in the adult rat. OECs were cultured from adult rat olfactory bulb and immunopurified (90% purity). Regeneration by large diameter afferents and by both peptidergic and non-peptidergic small diameter afferents was assessed using respectively cholera toxin B (CTB) labelling and immunocytochemistry for calcitonin gene-related peptide (CGRP) and the purinoceptor P2X3. Following an extensive (C3-T3) rhizotomy, CGRP and P2X3 immunoreactive axons regenerated across the rhizotomy site as far as the DREZ but there was no evidence of regeneration across the DREZ, except through sites where the OEC transplant was directly grafted into the DREZ. No evidence of regeneration into the dorsal horn by CTB-labelled axons was obtained. In addition, there was little sign of sprouting by intact axons in the vicinity of OEC transplant sites. In contrast to these results in vivo, cocultures of OECs and adult dorsal root ganglion cells showed that OECs stimulate extensive neurite outgrowth. The failure of the OECs to promote regeneration in vivo following cervical rhizotomy is therefore most likely due to factors in the environment of the graft site and/or the method of transplantation.     

Validity of median nerve somatosensory evoked potentials in the diagnosis of supraclavicular brachial plexus lesions

Experience with median nerve SEPs in the diagnosis of brachial plexus lesions is analysed in 49 patients selected from a total material of 264 cases with brachial plexus problems tested by SEP techniques. Median nerve SEPs were always compared with the results of SEPs after stimulation of at least one other nerve relevant to the site of the lesion as suspected clinically and electromyographically. All patients presented with unilateral brachial plexus problems and all root lesions were verified by clinical presentation, EMG studies, myelogram or surgery. There were 19 brachial plexus injuries, 13 cases with cervical spondylopathic rediculopaties without myelopathy and 7 patients presented brachial plexopathy with systemic cancer. It was found that median nerve SEPs were always normal in injuries of upper trunk and root avulsions confined to one or two root levels. Median nerve SEPs were abnormal in multiple trunk lesions and multiple root avulsions. In patients with spondylopathic radiculopathies median nerve SEPs were normal apart from one case where involvement of multiple roots was present. Median nerve SEPs were useful in assessing patients presenting brachial plexus problems in the presence of systematic cancer apart from cases where lower trunk involvement was present.In general, median nerve SEPs are useful if they are combined with SEP testing of other nerves anatomically more closely related to the problem as outlined clinically and electromyographically.     

The receptor guanylyl cyclase Npr2 is essential for sensory axon bifurcation within the spinal cord

Sensory axonal projections into the spinal cord display a highly stereotyped pattern of T- or Y-shaped axon bifurcation at the dorsal root entry zone (DREZ). Here, we provide evidence that embryonic mice with an inactive receptor guanylyl cyclase Npr2 or deficient for cyclic guanosine monophosphate-dependent protein kinase I (cGKI) lack the bifurcation of sensory axons at the DREZ, i.e., the ingrowing axon either turns rostrally or caudally. This bifurcation error is maintained to mature stages. In contrast, interstitial branching of collaterals from primary stem axons remains unaffected, indicating that bifurcation and interstitial branching are processes regulated by a distinct molecular mechanism. At a functional level, the distorted axonal branching at the DREZ is accompanied by reduced synaptic input, as revealed by patch clamp recordings of neurons in the superficial layers of the spinal cord. Hence, our data demonstrate that Npr2 and cGKI are essential constituents of the signaling pathway underlying axonal bifurcation at the DREZ and neuronal connectivity in the dorsal spinal cord.     

Netrin-1 signaling for sensory axons

During development, dorsal root ganglion (DRG) neurons extend their axons toward the dorsolateral part of the spinal cord and enter the spinal cord through the dorsal root entry zone (DREZ). After entering the spinal cord, these axons project into the dorsal mantle layer after a ‘waiting period’ of a few days. We revealed that the diffusible axonal guidance molecule netrin-1 is a chemorepellent for developing DRG axons. When DRG axons orient themselves toward the DREZ, netrin-1 proteins derived from the ventral spinal cord prevent DRG axons from projecting aberrantly toward the ventral spinal cord and help them to project correctly toward the DREZ. In addition to the ventrally derived netrin-1, the dorsal spinal cord cells adjacent to the DREZ transiently express netrin-1 proteins during the waiting period. This dorsally derived netrin-1 contributes to the correct guidance of DRG axons to prevent them from invading the dorsal spinal cord. In general, there is a complete lack of sensory axonal regeneration after a spinal cord injury, because the dorsal column lesion exerts inhibitory activities toward regenerating axons. Netrin-1 is a novel candidate for a major inhibitor of sensory axonal regeneration in the spinal cord; because its expression level stays unchanged in the lesion site following injury, and adult DRG neurons respond to netrin-1-induced axon repulsion. Although further studies are required to show the involvement of netrin-1 in preventing the regeneration of sensory axons in CNS injury, the manipulation of netrin-1-induced repulsion in the CNS lesion site may be a potent approach for the treatment of human spinal injuries.     

Neurosurgical technique of the dorsal root entry zone operation

The dorsal root entry zone operation was introduced in 1976 to relieve the pain of brachial plexus avulsion. Since then it has been applied to pain treatment in paraplegia, postherpetic pain, phantom limb pain and other types of of deafferentation pain. Over 400 operations have been done at the Duke University Medical Center with overall good results in 60% of pain patients.     

Stimulating regeneration in the damaged spinal cord.

Great progress has been made in recent years in experimental strategies for spinal cord repair. In this review we describe two of these strategies, namely the use of neurotrophic factors to promote functional regeneration across the dorsal root entry zone (DREZ), and the use of synthetic fibronectin conduits to support directed axonal growth. The junction between the peripheral nervous system (PNS) and central nervous system (CNS) is marked by a specialized region, the DREZ, where sensory axons enter the spinal cord from the dorsal roots. After injury to dorsal roots, axons will regenerate as far as the DREZ but no further. However, recent studies have shown that this barrier can be overcome and function restored. In animals treated with neurotrophic factors, regenerating axons cross the DREZ and establish functional connections with dorsal horn cells. For example, intrathecal delivery of neurotrophin 3 (NT3) supports ingrowth of A fibres into the dorsal horn. This ingrowth is revealed using a transganglionic anatomical tracer (cholera toxin subunit B) and analysis at light and electron microscopic level. In addition to promoting axonal growth, spinal cord repair is likely to require strategies for supporting long-distance regeneration. Synthetic fibronectin conduits may be useful for this purpose. Experimental studies indicate that fibronectin mats implanted into the spinal cord will integrate with the host tissue and support extensive and directional axonal growth. Growth of both PNS and CNS axons is supported by the fibronectin, and axons become myelinated by Schwann cells. Ongoing studies are aimed at developing composite conduits and promoting axonal growth from the fibronectin back into the spinal cord.     

The dorsal root reflex in isolated mammalian spinal cord

1. The dorsal root reflex has been investigated in an isolated preparation of adult mammalian spinal cord. 2. Both evoked and spontaneous activity can be recorded from the cord in the dorsal spinal roots. 3. The spontaneous activity has a characteristic pattern of firing in bursts of action potentials. Spontaneous and evoked activity are optimum at temperatures between 25 and 27 degrees C; little activity can be detected above 35 degrees C. 4. The spontaneous dorsal root activity has been shown to be correlated with negative potentials in the dorsal horn of the cord, and intracellular recordings made from primary afferent fibres have shown spontaneous primary afferent depolarizations (PAD) which underlie the generation of the spontaneous dorsal root activity. 5. The evoked dorsal root reflex has been shown to spread up to 16 spinal segments both rostrally and caudally from the stimulated dorsal root, and to the contralateral side of the cord. 6. The spontaneous dorsal root activity in widely separated segments has been shown by cross-correlation analysis to be linked both ipsi- and contra-laterally. 7. The significance of such a widespread system for the generation of PAD is discussed.     

Human dorsal root ganglion neurons from embryonic donors extend axons into the host rat spinal cord along laminin-rich peripheral surroundings of the dorsal root transitional zone

Following dorsal root crush, the lesioned axons regenerate in the peripheral compartment of the dorsal root, but stop at the boundary between the peripheral and the central nervous system, the dorsal root transitional zone. We have previously shown that fibres from human fetal dorsal root ganglia grafted to adult rat hosts are able to grow into the spinal cord, but were not able to specify the route taken by the ingrowing fibres. In this study we have challenged the dorsal root transitional zone astrocyte boundary with human dorsal root ganglion transplants from 5–8-week-old embryos. By tracing immunolabelled human fibres in serial sections, we found that fibres consistently grow around the dorsal root transitional zone astrocytes in laminin-rich peripheral surroundings, and extend into the host rat spinal cord along blood vessels, either into deep or superficial laminae of the dorsal horn, or into the dorsal funiculus. Human fibres that did not have access to blood vessels grew on the spinal cord surface. These findings indicate, that in spite of a substantial growth capacity by axons from human embryonic dorsal root ganglion cells as well as their tolerance to non-permissive factors in the mature mammalian CNS, these axons are still sensitive to the repellent effects of astrocytes of the mature dorsal root transitional zone. Furthermore, this axonal ingrowth is consistently associated with laminin-expressing structures until the axons reach the host spinal cord.     

In lumbosacral plexus injuries can we identify indicators that predict spontaneous recovery or the need for surgical treatment? Results from a clinical study on 72 patients

Background

Post-traumatic lumbosacral plexus injuries seem to be rare events, spontaneously recovering in high percentage: as surgery is often challenging and results in poor outcome, many Authors have advocated conservative treatment only. Nevertheless surgery should not be ruled out: in invalidating injuries, it can restore basic function in the lower extremities. Therefore, it might be necessary to establish guidelines for the management and the indication to surgery in such cases. This study aims to identify indicators predicting spontaneous recovery or the need for surgery.

Method

The clinical and radiological data of 72 patients with a post-traumatic lumbosacral plexus injury were reviewed. A follow up equal or superior to 3 years is available in 42 cases.

Results

Lumbosacral plexus injuries mostly occurred during road accidents. The incidence of associated lesions was relevant: bone injuries were found in 85% of patients, internal lesions in 30% and vascular injuries in 8%. Lumbosacral trunk and sacral plexus palsies were the most frequent injury patterns. Root avulsions were revealed in 23% of cases and only in sacral plexus and complete lumbosacral plexus injuries: L5 and S1 were the roots more prone to avulsions. About 70% of cases recovered spontaneously, mostly in 18 months. Spontaneous recovery was the rule in lumbar plexus and lumbosacral trunk injuries (where root avulsions never occurred) or in sacral and complete lumbosacral plexus palsies due to compression injuries. The causative mechanism correlated with the injury pattern, the associated bone injury being often predictive of the severity of the nerve injury. Lumbosacral plexus injuries occurred in car crashes were generally associated with fractures causing compression on the nerves, thus resulting in injuries often amenable of spontaneous recovery. Motorcycle accidents implied high kinetic energy traumas where traction played an important role, as the high percentage of sacroiliac joint separations demonstrated (found in more than 50% of cases and always associated to root avulsions). Loss of sphincteral control and excruciating leg pain were also invariably associated with avulsions.

Conclusions

Clinical and radiological data can help to predict the occurrence of spontaneous recovery or the need for surgery in post-traumatic lumbosacral plexus injuries.     

Predictive value of computed tomographic myelography in obstetrical brachial plexus palsy

Preoperative radiologic studies to detect root avulsions of the brachial plexus caused by birth trauma are considered useful in assisting with surgical planning for reconstruction. In this study, the predictive value of computed tomographic (CT) myelography in detecting nerve root avulsions at our institution was determined. Sixty-three consecutive patients with an obstetrical brachial plexus palsy who had had both preoperative CT myelography and reconstructive surgery were selected. All CT myelograms were analyzed post hoc by a single neuroradiologist in a manner blind to the surgical findings. At each root level of the brachial plexus, the presence of a pseudomeningocele was noted along with the presence or absence of rootlets within each identified pseudomeningocele. Extraforaminal root avulsions later determined at surgery were reviewed by a single surgeon in a manner blind to the radiographic results. Surgical and radiographic findings were then compared at each corresponding root level. A total of 281 roots were examined. The sensitivity, specificity, positive predictive value, and likelihood ratio for root avulsions with pseudomeningoceles were 0.63, 0.85, 0.40, and 4.2, respectively. For pseudomeningoceles for which rootlets traversing the sac could not be identified, these values were 0.37, 0.98, 0.74, and 18.5, respectively. The presence of pseudomeningoceles with or without rootlets was not a sensitive indicator of root avulsions. Root avulsions were better predicted by identifying the absence of rootlets in a pseudomeningocele. This absence on CT myelography may be used to suggest an extraforaminal root avulsion due to its high specificity and high likelihood ratio.     

Neurochemistry of the dorsal horn

The dorsal horn region of the spinal cord, particularly the dorsal root entry zone (DREZ), represents the first central integration center for nociceptive afferent impulses. Here, the excitatory neurotransmitters/modulators, products of the primary sensory neurons, are released, the segmental interneuronal influences pertain, and the descending bulbospinal tracts terminate. A vast variety of compounds are thus involved in the processing of nociceptive information in these areas, among which are the 'classical' neurotransmitters and the more recently described neuropeptides. A continued vast interest exists concerning the chemistry of the dorsal horn/DREZ region. The current developments and understanding regarding the pharmacology of this region are presented. Particular emphasis is given to the interactions among the various compounds, the coexistence of some of these within single neuronal populations, the importance of the opiate receptor subtypes, and the actions and localizations of some of the newly discovered neuropeptides.