Anatomical damages in the spinal nerve roots and the spinal cord after brachial plexus injury: descriptive study from a cohort of consecutive patients who underwent DREZ-lesioning for pain-practical implications.

BACKGROUND: Systematic descriptions of anatomical damage after brachial plexus injury (BPI) at the intradural level have been scarcely reported in detail. However, considering these damages, not only in the spinal nerve roots but also in the spinal cord itself, is crucial in determining the appropriate surgical approach to restore upper limb function and address refractory pain. Therefore, the authors present a descriptive study focusing on intradural findings observed during microsurgical DREZ-lesioning. METHODS: This study enrolled 19 consecutive patients under the same protocol. Microsurgical observation through exposure of C4 to Th1 medullary segments allowed to describe the lesions in spinal nerve roots, meninges, and spinal cord. Electrical stimulation of the ventral roots checked the muscle responses. RESULTS: Extensive damage was observed among the 114 explored roots (six roots per patient), with only 21 (18.4%) ventral (VR) and 17 (14.9%) dorsal (DR) roots retaining all rootlets intact. Damage distribution varied, with the most frequent impairments in C6 VRs (18 patients) and the least in Th1 VRs (14 patients), while in all the 19 patients for the C6 DRs (the most frequently impaired) and in 14 patients for Th1 DRs (the less impaired). C4 roots were found damaged in 12 patients. Total or partial avulsions affected 63.3% and 69.8% of DRs and VRs, respectively, while 15.8% and 14.0% of the 114 DRs and VRs were atrophic, maintaining muscle responses to stimulation in half of those VRs. Pseudomeningoceles were present in 11 patients but absent in 46% of avulsed roots. Adhesive arachnoiditis was noted in 12 patients, and dorsal horn parenchymal alterations in 10. CONCLUSIONS: Knowledge of intradural lesions post-BPI helps in guiding surgical indications for repair and functional neurosurgery for pain control.

Sacral nerve root metastasis in a patient with lung carcinoma resembling neurinoma - a case report and literature review.

Intradural extramedullary metastases from systemic neoplasms are very rare, with an incidence ranging from 2% to 5% of all secondary spinal diseases. We present the case of a 53-year-old man diagnosed with lung adenocarcinoma with symptoms of severe back pain and tibial paresis. The magnetic resonance imaging (MRI) revealed an intradural lesion originating from the right S1 nerve root mimicking neurinoma. Total tumor removal was achieved via posterior midline approach. The histological examination was consistent with lung carcinoma metastasis. Due to the rarity of single nodular nerve root metastases, MRI images may be misinterpreted as nerve sheath tumors, such as schwannomas or neurofibromas. We performed a brief literature review outlining the mainstay of diagnosis, therapeutic approach, and the prognosis of these rare lesions.

Primary neurolymphomatosis diagnosed by spinal nerve root biopsy.

Primary neurolymphomatosis is the direct infiltration of lymphomatous neoplastic cells into nerve roots and/or peripheral nerves. A 67-year-old man had a 24-month history of progressive and severe left lower limb neuropathic pain, ipsilateral ankle dorsiflexion weakness and gait disturbance. Gadolinium-enhanced MRI showed thickening and enhancement of the cauda equina, L5, S1 and S2 nerve roots. 18Fluorodeoxyglucose positron emission tomography showed concordant hypermetabolism. L5 nerve root biopsy confirmed diffuse large B-cell lymphoma. One cycle of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy resulted in remission, but this was not sustained. Primary neurolymphomatosis is rare and diagnostically challenging, and often the diagnosis is delayed. While biopsy is the gold standard for diagnosis, neuroimaging helps to characterise lesions and to determine the feasibility of biopsy.

Application of Magnetic Resonance Diffusion Tensor Imaging in Diagnosis of Lumbosacral Nerve Root Compression

OBJECTIVE: The aim of this study was to assess the value of 3.0T magnetic resonance (MR) Diffusion tensor imaging (DTI) in the diagnosis of lumbosacral nerve root compression. METHODS: The radiology reports, and clinical records of 34 patients with nerve root compression caused by lumbar disc herniation or bulging and 21 healthy volunteers who had undergone magnetic resonance imaging (MRI) and DTI scan were retrospectively reviewed. The differences in fractional anisotropy (FA) and apparent diffusion coefficient (ADC) between compressed and non-compressed nerve roots from patients and the normal nerve roots from healthy volunteers were compared. Meanwhile, the nerve root fiber bundles were observed and analyzed. RESULTS: The average FA and ADC values of the compressed nerve roots were 0.254 ± 0.307 and 1.892 ± 0.346 10^-3mm2/s, respectively. The average FA and ADC values of the non-compressed nerve roots were 0.377 ± 0.659 and 1.353 ± 0.344 10^-3mm2/s, respectively. The FA value of compressed nerve roots was significantly lower than that of non-compressed nerve roots (P < 0.01). The ADC value of compressed nerve roots was significantly higher than that of non-compressed nerve roots. There were no significant differences between the left and right nerve roots of normal volunteers in FA and ADC values (P > 0.05). The nerve roots at different levels of L3-S1 had significantly different FA and ADC values (P < 0.01). Incomplete fiber bundles with extrusion deformation, displacement or partial defect were observed in the compressed nerve root fiber bundles. The real diagnosis of the clinical situation of the nerve can provide neuroscientists with an important computer tool to help them infer and understand the possible working mechanism from the experimental data of behavior and electrophysiology. CONCLUSION: The compressed lumbosacral nerve roots can be accurately localized through 3.0T magnetic resonance DTI, which is instructive for accurate clinical diagnosis and preoperative localization.

[Non-cerebellar ataxias: posterior column-like ataxia and cerebellar-like ataxia].

Ataxia is not only due to cerebellar lesions, but also due to non-cerebellar lesions such as those in the brain, spinal cord, dorsal root (DR), peripheral nerve. In this article, optic ataxia is excluded and 'vestibular ataxia' is briefly referred. Non-cerebellar ataxias are generically called sensory ataxia or posterior column ataxia. However, since non-cerebellar lesions, e.g. frontal lobe lesions, may develop "cerebellar-like ataxia" (Hirayama, 2010). At the same time, non-posterior column lesions, e.g. parietal lobe lesion, can show "posterior column-like ataxia". From these viewpoints, I here describe various non-cerebellar ataxia in some disorders such as tabes dorsalis and sensory neuropathies and emphasize a role of a peripheral sensory input to the cerebellum via the DR ganglia and spinocerebellar tract for sensory ataxia because there is the International Consensus (2016) that the ataxia in Miller Fisher syndrome is suggested cerebellar-like clinicophysiologically.

Spinal nerve root sleeve cysticercosis: a case report and review of the literature.

BACKGROUND: Neurocysticercosis is a parasitic infection of the central nervous system by tapeworm larvae. Spinal cysticercosis is thought to be relatively rare, and spinal nerve root sleeve cysticercosis have not been reported previously. CASE PRESENTATION: A 46-year-old Chinese Han female patient presented with low back pain and radicular pain of the right lower limb. The visual analog scale was 6. Magnetic resonance imaging showed a subarachnoid cyst at the S1 level, with a slight enhanced rim. The patient underwent surgical treatment. During surgery, we found the cyst located mainly in the subarachnoid space and partly in a sacral nerve root sleeve. Cysticercosis was also confirmed by postoperative pathological examination. Postoperative drug therapy was performed after cysticercosis was confirmed. Postoperatively, the patient was treated with oral albendazole (15 mg/kg) for 1 month. Only mild sensory impairment was left when she was discharged. After 3 years of follow-up, the visual analog scale reduced from 6 to 2, and the patient's sensory function completely recovered. Magnetic resonance imaging showed no recurrence of cysticercosis. CONCLUSION: Subarachnoid cysticercosis may extend to nerve root sleeve causing back pain and radiculopathy, which may present with similar magnetic resonance imaging manifestations to Tarlov cysts. Hence, spinal subarachnoid cysticercosis should be considered as an important differential diagnosis of arachnoid cyst and sacral Tarlov cyst. Combined treatment with surgical removal and drug therapy is effective to manage spinal subarachnoid cysticercosis.

Intraneural hemangioma of spinal nerve roots: a Case Report and literature review.

Intraneural hemangiomas are rare benign neoplasms. We report the case of a 53­year­old female with a hemangioma in a spinal nerve root. The patient presented with muscular atropy of the right arm wihout obvious predisposing factors one year ago. MRI demonstrated a heterogeneously enhanced lesion adjacent to the right C4/5 intervertebral foramen. The lesion was considered to be a schwannoma preoperatively. Histologically, the lesion was abundant with intervening malformed vascular mass lined by simple squamous epithelial cells, and CD31 was positively stained at these epithelial cells by immunohistochemistry. The patient underwent microsurgical resection and recovered without complications.

Additional benefit of ultrasonography to evaluate nerve root condition of degenerative cervical spine disease.

STUDY DESIGN: A cross-sectional explanatory study. OBJECTIVES: To clarify the nerve root condition and the association between nerve root cross-sectional area (CA) on ultrasonography (US) and other examinations such as MRI or compound muscle action potentials (CMAPs) in degenerative cervical spine diseases. SETTING: A university hospital in Japan. METHODS: Fifty-one patients diagnosed with proximal cervical spondylotic amyotrophy (CSA) (13 patients), cervical radiculopathy of C5 or C6 nerve root (CR) (26 patients), or cervical spondylotic myelopathy (CSM) (12 patients), and twenty-nine healthy volunteers were included in this study. Neurological findings, US findings and CMAPs of deltoid and biceps muscles of all participants were evaluated. In addition, CSA, CR, and CSM patients underwent MRI. RESULTS: A significant correlation was not observed between CA and CMAP amplitude or foraminal diameter on MRI (P > 0.05). In the US examination, the C6 CA of the affected side of the CR group was significantly larger than that of both the normal side and the other groups (P < 0.001). The C5 CA of the affected side of the CSA group clearly showed a bimodal distribution: enlarged and small CA groups. In the CMAP findings, CSA cases respectively showed the lower amplitude of deltoid and bicep CMAPs on both the normal and the affected side (P ≦ 0.01). CSM and healthy volunteers were nearly identical in CA and CMAPs. CONCLUSION: Utilizing US in addition to NCS and MRI can contribute towards an evaluation of the nerve root condition of degenerative cervical spine disease. SPONSORSHIP: no sponsorship.

Clinical Significance of Redundant Nerve Roots in Patients with Lumbar Stenosis Undergoing Minimally Invasive Tubular Decompression.

OBJECTIVE: Symptomatic lumbar spinal stenosis (LSS) is a common indication for surgery in the elderly. Preoperative radiographic evaluation of patients with LSS often reveals redundant nerve roots (RNRs). The clinical significance of RNRs is uncertain. RNRs have not been studied in the setting of minimally invasive surgery. This study investigates the relationship between RNRs and clinical outcomes after minimally invasive tubular decompression. METHODS: Chart review was performed for patients with degenerative LSS who underwent minimally invasive decompression. Preoperative magnetic resonance imaging parameters were assessed, and patient-reported outcomes were analyzed. RESULTS: Fifty-four patients underwent surgery performed at an average of 1.8 ± 0.8 spinal levels. Thirty-one patients (57%) had RNRs. Patients with RNRs were older (median = 72 years vs. 66 years, P = 0.050), had longer median symptom duration (32 months vs. 15 months, P < 0.01), and had more levels operated on (2.1 vs. 1.4; P < 0.01). The median follow-up after surgery was 2 months (range = 1.3-12 months). Preoperative and postoperative patient-reported outcomes were similar based on RNR presence. Patients without RNRs had larger lumbar cross-sectional areas (CSAs) (median = 121 mm2 vs. 95 mm2, P = 0.014) and the index-level CSA (52 mm2 vs. 34 mm2, P = 0.007). The CSA was not correlated with RNR morphology or location. CONCLUSIONS: Preoperative RNRs are associated with increased age, symptom duration, and lumbar stenosis severity. Patients improved after minimally invasive decompression regardless of RNR presence. RNR presence had no effect on short-term clinical outcomes. Further study is required to assess their long-term significance.

Prognostic value of contrast-enhanced MRI in Guillain-Barré syndrome in children.

BACKGROUND: The aim of this retrospective study is to explore the prognostic value of different contrast enhancement imaging patterns in childhood Guillain-Barré syndrome by comparing the clinical, laboratory, and therapeutic outcomes. METHODS: We included a total of 37 patients who were diagnosed and followed up by a pediatric neurology team at Montpellier University Hospital between 2000 and 2016. All images were reinterpreted by the first author and a senior pediatric neuroradiology staff member in two different sessions; in the case of disagreement, the expert's reading was considered. RESULTS: The study group comprised 22 (59.5%) boys and 15 (40.5%) girls. The age ranged from 1.5 year to 14.8 years. Muscle weakness was present in 33 (89.2%) patients. Cranial nerves involvement was observed in 22 (59.5%) patients, while 29 (78.4%) patients had albuminocytological dissociation. In 27 (73%) patients, contrast enhancement or thickening of the lumbosacral nerve roots was found. Simultaneous spinal nerve root and cranial nerve enhancement was noted in five (17.2%) patients, while isolated cranial nerve enhancement was identified in three (10.3%) patients. Clinical and radiological cranial nerve involvement was found in seven (18.9%) patients, while isolated clinical cranial nerves involvement occurred in 13 (35.1%) patients. No significant correlation between different magnetic resonance imaging (MRI) enhancement patterns and short-term or long-term outcomes was found in our cohort. CONCLUSION: Contrast-enhanced brain and spinal MRI is a sensitive and recommended supportive test for diagnosing acute inflammatory polyradiculopathy in children. Its predictive value for clinical, and therapeutic outcomes in the short or long term has not yet been proved.

Neuroprotection and gliosis attenuation by intravenous application of human mesenchymal stem cells (hMSC) following ventral root crush in mice.

Rupture and stretching of spinal roots are common incidents that take place in high-energy accidents. The proximal axotomy of motoneurons by crushing of ventral roots is directly related to the degeneration of half of the lesioned population within the first two weeks. Moreover, only a small percentage of surviving motoneurons can successfully achieve regeneration after such a proximal lesion, and new treatments are necessary to improve this scenario. In this sense, mesenchymal stem cells (MSC) are of great interest once they secrete a broad spectrum of bioactive molecules that are immunomodulatory and can restore the environment after a lesion. The present work aimed at studying the effects of human mesenchymal stem cells (hMSC) therapy after ventral root crush (VRC) in mice. We evaluated motoneuron survival, glial reaction, and synapse preservation at the ventral horn. For this purpose, C57BL/6 J were submitted to a crush procedure of L4 to L6 ventral roots and treated with a single intravenous injection of adipose-derived hMSC. Evaluation of the results was carried out at 7, 14, and 28 days after injury. Analysis of motoneuron survival and astrogliosis showed that hMSC treatment resulted in higher motoneuron preservation (motoneuron survival ipsi/contralateral ratio: VRC group = 53%, VRC + hMSC group = 66%; p < 0.01), combined with reduction of astrogliosis (ipsi/contralateral GFAP immunolabeling: VRC group = 470%, VRC + hMSC group = 250%; p < 0.001). The morphological classification and Sholl analysis of microglial activation revealed that hMSC treatment reduced type V and increased type II profiles, indicating an enhancement of surveying over activated microglial cells. The glial reactivity modulation directly influenced synaptic inputs in apposition to axotomized motoneurons. In the hMSC-treated group, synaptic maintenance was increased (ipsi/contralateral synaptophysin immunolabeling: VRC group = 53%, VRC + hMSC group = 64%; p < 0.05). Overall, the present data show that intravenous injection of hMSC has neuroprotective and anti-inflammatory effects, decreasing reactive astrogliosis, and microglial reaction. Also, such cell therapy results in motoneuron preservation, combined with significant maintenance of spinal cord circuits, in particular those related to the ventral horn.

Nerve Root Sedimentation Sign among Lumbar Canal Stenosis Patients Visiting the Department of Orthopaedics in a Tertiary Care Centre: A Descriptive Cross-sectional Study.

Introduction: Lumbar canal stenosis is a common cause of back pain and neurogenic claudication in the elderly population. Nerve root sedimentation sign-on Magnetic resonance imaging is a novel sign proposed for the diagnosis of lumbar canal stenosis. There is limited research so far. So, the aim of this study was to find out the prevalence of nerve root sedimentation signs in lumbar canal stenosis among patients visiting the Department of Orthopaedics in a tertiary care centre. Methods: This was a descriptive cross-sectional study conducted from 1 January 2020 to 31 July 2021 in the tertiary care centre, after receiving ethical approval from the Institutional ethical review board (Reference number: 299/(6-11)076/077). The anteroposterior diameter of the dural sac at the most stenotic level and nerve root sedimentation sign in magnetic resonance images were measured in patients with lumbar canal stenosis. Point estimate and 95% Confidence Interval were calculated. Results: Among 40 patients enrolled, 34 (85%) (84.01-85.99, 95% Confidence Interval) patients had positive nerve root sedimentation sign. Out of 34 (85%) cases with positive sedimentation signs, 32 (94.12%) had severe lumbar stenosis and the remaining 2 (5.88%) had moderate lumbar stenosis. Conclusions: The prevalence of nerve root sedimentation signs is similar to the similar studies done in similar settings. Nerve root sedimentation signs on magnetic resonance imaging can be used as an objective sign for the diagnosis of severe lumbar canal stenosis. Keywords: magnetic resonance imaging; prevalence; spinal stenosis.

Long term results of Dorsal Root Entry Zone (DREZ) lesions for the treatment of intractable pain: A systematic review of the literature on 1242 cases.

BACKGROUND: Different Dorsal root entry zone (DREZ) lesion techniques have been reported as effective treatment for intractable painful conditions, though with contradictory results. Overall, good results were reported especially in specific conditions, such as pain due to brachial plexus avulsion, spinal cord injuries and oncological pain management. However, data on long term results in different clinical conditions are still missing. OBJECTIVE: This study aims to systematically review the pertinent literature to evaluate indications, clinical outcomes, and complications of DREZ lesion (DREZotomy), in chronic pain management. METHODS: A systematic literature review was conducted according to the PRISMA statement. Papers on DREZotomy for chronic pain in cancer, brachial plexus avulsion, spinal cord injury, post herpetic neuralgia, and phantom limb pain were considered for eligibility. For each category we further identified two sub-group according to the length of follow up: medium term and long term follow up (more than 3 years) respectively. RESULTS: 46 papers, and 1242 patients, were included in the present investigation. When considering long term results DREZotomy provided favorable clinical outcomes in brachial plexus avulsion and spinal cord injury, in 60.8% and 55.8% of the cases respectively. Conversely, the success rate was 35.3% in phantom limb pain and 28.2% in post herpetic neuralgia. A poor clinical outcome was reported in over than 25% of the patients suffering from phantom limb pain, post herpetic neuralgia and spinal cord injury. The mean complications rate was 23.58%. While BPA and SCI patients presented stable improvement over time, good outcomes among PHN and PLP groups dropped by - 46.2%; and - 14.7% at long term follow up respectively. CONCLUSION: DREZotomy seems to be an effective treatment for chronic pain conditions, especially for brachial plexus avulsion, spinal cord injury and intractable cancer/post-radiation pain. According to the low level of evidence of the pertinent literature, further studies are strongly recommended, to better define potential benefits and limitations of this technique.

When Clinical Diagnosis Differs From Advanced Imaging: A Case Series of Disc Herniations Causing Radiculopathy and Review of Aberrant Nerve Root Innervation.

ABSTRACT: Radiculopathy is diagnosed using a combination of history, physical examination, and imaging. Unfortunately, well-established dermatomal and myotomal maps are an oversimplification of the convoluted nature of spinal sensory and motor innervation. When clinical presentation and imaging seemingly contradict one another, it is important to consider variant innervation patterns. This article presents three patients with objective dermatomal and/or myotomal deficits due to disc herniations whose clinical presentations are "textbook" for nerve root pathology that is adjacent to the nerve root that is actually compromised. In addition, the literature is reviewed to discuss the history of dermatomal and myotomal maps, the effectiveness of a clinician's ability to determine the precise pathologic disc and nerve root level in patients presenting with radiculopathy, and anatomical explanations as to why inconsistencies such as those seen in the patients in these cases exist.

Dorsal Root Injury-A Model for Exploring Pathophysiology and Therapeutic Strategies in Spinal Cord Injury.

Unraveling the cellular and molecular mechanisms of spinal cord injury is fundamental for our possibility to develop successful therapeutic approaches. These approaches need to address the issues of the emergence of a non-permissive environment for axonal growth in the spinal cord, in combination with a failure of injured neurons to mount an effective regeneration program. Experimental in vivo models are of critical importance for exploring the potential clinical relevance of mechanistic findings and therapeutic innovations. However, the highly complex organization of the spinal cord, comprising multiple types of neurons, which form local neural networks, as well as short and long-ranging ascending or descending pathways, complicates detailed dissection of mechanistic processes, as well as identification/verification of therapeutic targets. Inducing different types of dorsal root injury at specific proximo-distal locations provide opportunities to distinguish key components underlying spinal cord regeneration failure. Crushing or cutting the dorsal root allows detailed analysis of the regeneration program of the sensory neurons, as well as of the glial response at the dorsal root-spinal cord interface without direct trauma to the spinal cord. At the same time, a lesion at this interface creates a localized injury of the spinal cord itself, but with an initial neuronal injury affecting only the axons of dorsal root ganglion neurons, and still a glial cell response closely resembling the one seen after direct spinal cord injury. In this review, we provide examples of previous research on dorsal root injury models and how these models can help future exploration of mechanisms and potential therapies for spinal cord injury repair.

Brachial plexus tumors extending into the cervicothoracic spine: a review with operative nuances and outcomes

Background The rarity and anatomical complexity of brachial plexus tumors (BPTs) impose many challenges onto surgeons performing surgical resections, especially when these tumors invade the cervicothoracic spine. Treatment choices and surgery outcomes heavily depend on anatomical location and tumor type. Methods The authors performed an extensive review of the published literature (PubMed) focusing on “brachial plexus tumors” that identified invasion of the cervicothoracic spine. Result The search yielded 2774 articles pertaining to “brachial plexus tumors”. Articles not in the English language or involving cervicothoracic spinal invasion were excluded. Conclusions Recent research has shown that the most common method used to resect tumors of the proximal roots is the dorsal subscapular approach. Despite its association with high morbidity rate, this technique offers excellent exposure to the spinal roots and intraforaminal portion of the spinal nerve. The dorsal approach is used to resect recurrent lower trunk tumors and dumbbell-shaped neurofibromas, yet it is also the least common overall approach used in brachial plexus tumor resections. The ventral or anterior technique is commonly used to resect tumors at the cord to division level, and root to trunk level. Motor complications, transient nerve palsy, and bleeding are among the most common complications of the anterior supraclavicular approach. Further controlled studies are needed to fully determine the optimal surgical approach used to obtain the best outcomes and least complications for each type of brachial plexus tumor (AU)

High-Yield Mucosal Olfactory Ensheathing Cells Restore Loss of Function in Rat Dorsal Root Injury.

In a previous study, we reported that no axons were crossing from the severed dorsal roots to the spinal cord using the rat dorsal rhizotomy paradigm. The injury caused ipsilateral deficits of forepaw function. An attempt to restore the function by transplanting cells containing 5% olfactory ensheathing cells (OECs) cultured from the olfactory mucosa did not succeed. However, obtaining OECs from the olfactory mucosa has an advantage for clinical application. In the present study, we used the same rhizotomy paradigm, but rats with an injury received cells from a modified mucosal culture containing around 20% OECs mixed in collagen. The forelimb proprioception assessment showed that 80% of the rats receiving the transplants had functional improvement over six weeks of the study. The adhesive removal test showed that the time taken for the rats to notice the adhesive label and remove it almost returned to the normal level after receiving the transplants. Transplanted cells were identified with the expression of green fluorescent protein (ZsGreen). Some regeneration fibres immunostained for neurofilament (NF) or traced by biotinylated dextran amine (BDA) in the injury area were associated with the transplanted cells. The evidence in this study improves the prospect of clinical application using OECs from the olfactory mucosa to treat CNS injuries.

Co-targeting myelin inhibitors and CSPGs markedly enhances regeneration of GDNF-stimulated, but not conditioning-lesioned, sensory axons into the spinal cord.

A major barrier to intraspinal regeneration after dorsal root (DR) injury is the DR entry zone (DREZ), the CNS/PNS interface. DR axons stop regenerating at the DREZ, even if regenerative capacity is increased by a nerve conditioning lesion. This potent blockade has long been attributed to myelin-associated inhibitors and (CSPGs), but incomplete lesions and conflicting reports have prevented conclusive agreement. Here, we evaluated DR regeneration in mice using novel strategies to facilitate complete lesions and analyses, selective tracing of proprioceptive and mechanoreceptive axons, and the first simultaneous targeting of Nogo/Reticulon-4, MAG, OMgp, CSPGs, and GDNF. Co-eliminating myelin inhibitors and CSPGs elicited regeneration of only a few conditioning-lesioned DR axons across the DREZ. Their absence, however, markedly and synergistically enhanced regeneration of GDNF-stimulated axons, highlighting the importance of sufficiently elevating intrinsic growth capacity. We also conclude that myelin inhibitors and CSPGs are not the primary mechanism stopping axons at the DREZ.