Thoracic Spinal Intradural Arachnoid Cyst With a Fulminant Course.

Background: Spinal arachnoid cysts are rarely occurring benign cerebrospinal fluid-containing lesions that can occur anywhere along the spinal axis but are principally seen in the thoracic spine. They occur either ventrally or dorsally and can be extradural, intradural extramedullary, or intramedullary. They may be asymptomatic or can present with insidious pain and neurologic symptoms related to spinal cord and/or nerve root compression. Case Report: A 49-year-old male developed sudden midback pain with rapid progression to gait instability, urinary retention, and paraplegia within 10 hours. His presentation for neurosurgical care was delayed because of lack of funds and unfavorable insurance policies. At presentation 3 months after the onset of symptoms, magnetic resonance imaging of his spine showed a ventrolateral intradural extramedullary cystic lesion at T5-T6 with severe cord compression. He underwent T5-T6 and T6-T7 laminectomies with a limited left sixth rib costotransversectomy for microsurgical resection of the cyst. Postoperatively, the patient reported improvement in bladder and bowel control, but his paraplegia persisted. Conclusion: Arachnoid cysts are mostly benign lesions; however, they may have disastrous outcomes if not promptly addressed with the necessary urgency when symptoms are progressive, as in our patient.

Machine intelligence for nerve conduit design and production.

Nerve guidance conduits (NGCs) have emerged from recent advances within tissue engineering as a promising alternative to autografts for peripheral nerve repair. NGCs are tubular structures with engineered biomaterials, which guide axonal regeneration from the injured proximal nerve to the distal stump. NGC design can synergistically combine multiple properties to enhance proliferation of stem and neuronal cells, improve nerve migration, attenuate inflammation and reduce scar tissue formation. The aim of most laboratories fabricating NGCs is the development of an automated process that incorporates patient-specific features and complex tissue blueprints (e.g. neurovascular conduit) that serve as the basis for more complicated muscular and skin grafts. One of the major limitations for tissue engineering is lack of guidance for generating tissue blueprints and the absence of streamlined manufacturing processes. With the rapid expansion of machine intelligence, high dimensional image analysis, and computational scaffold design, optimized tissue templates for 3D bioprinting (3DBP) are feasible. In this review, we examine the translational challenges to peripheral nerve regeneration and where machine intelligence can innovate bottlenecks in neural tissue engineering.

Transforming Growth Factor Beta 1 Regulates Fibroblast Growth Factor 7 Expression in Schwann Cells.

Background: Our previous work demonstrated that application of transforming growth factor beta 1 (TGF-ß1) and forskolin to the repair site after chronic denervation and axotomy has a mitogenic effect, reactivates Schwann cells (SCs), and supports axonal regeneration. We found decreased expression of fibroblast growth factor 7 (FGF-7), a factor involved in synaptic organization and maintenance. Using an in vitro system, we examined the molecular mechanism of TGF-ß1 and forskolin on the regulation of FGF-7 expression in SCs. Methods: SCs were prepared from the sciatic nerve and stimulated with forskolin (0.5 µM), TGF-ß1 (1 ng/mL), or TGF-ß1 + forskolin for 6 or 24 hours. SCs were also pretreated with LY2109761 (0.5 µM), a TGF-ß receptor inhibitor, prior to stimulation with TGF-ß1 + forskolin for 6 hours. Real-time TaqMan quantitative polymerase chain reaction analyses for FGF-7, myelin basic protein, and peripheral myelin protein 22 expression were performed. Cycle threshold (Ct) data were normalized to a reference gene, and fold changes relative to untreated SCs were determined using the 2-ΔΔCt method. Statistical analysis was done using t test (P<0.05). Results: TGF-ß1 alone or in combination with forskolin for 24 hours resulted in a 3.3- and 2.8-fold decrease in FGF-7 expression in SCs, respectively. No change in FGF-7 expression was found with forskolin alone. TGF-ß1 + forskolin treatment for 6 hours resulted in a 4.0-fold decrease in FGF-7 expression, while the addition of LY2109761 resulted in a 2.7-fold decrease in FGF-7 expression. Conclusion: We showed that SC expression of FGF-7 is regulated by TGF-ß1. The positive effect of TGF-ß1 and forskolin on SC reactivation and axonal regeneration may involve modulation of FGF-7 expression and activity in SCs.

A rat study of the use of end-to-side peripheral nerve repair as a "babysitting" technique to reduce the deleterious effect of chronic denervation.

OBJECTIVE: Functional recovery is disappointing after surgical repair of nerves that are injured far from their target organs and/or after delayed repair. In the former case, a nerve transfer that transects a distal nerve fascicle to innervate denervated targets is one strategy to promote nerve regeneration and functional recovery. An alternate strategy tested in this study is to perform an end-to-side neurorrhaphy to "babysit" (protect) the denervated distal nerve stump at the time of nerve repair and reduce the deleterious effect of chronic denervation on nerve regeneration. METHODS: In the hindlimbs of Sprague-Dawley rats, the common peroneal (CP) nerve was transected unilaterally and the distal CP nerve stump inserted through a perineurial window into the intact tibial (TIB) nerve, i.e., CP-TIB end-to-side neurorrhaphy. In the first experiment, TIB nerve motoneurons that had regenerated and/or sprouted axons into the CP nerve within 3 months were stimulated to elicit contractions, and thereafter, identified with retrograde dyes for counting. In the second experiment, the intact TIB nerve was transected and cross-sutured to a 3-month chronically denervated distal CP nerve stump that had either been "protected" by ingrown TIB nerves after CP-TIB neurorrhaphy or remained chronically denervated. Thereafter, the number of retrogradely labeled TIB nerve motoneurons that had regenerated their nerves within 3 months were counted and reinnervated tibialis anterior (TA) muscles weighed. RESULTS: A mean (± SE) of 231 ± 83 TIB nerve motoneurons grew into the end-to-side CP distal nerve stump with corresponding ankle flexion; 32% regenerated their axons and 24% sprouted axons from the intact TIB nerve, eliciting ankle flexor-extensor co-contraction. In the second experiment, after a 3-month period of TIB nerve regeneration, significantly more TIB motoneurons regenerated their axons into "protected" than "unprotected" CP distal nerve stumps within 3 months (mean 332 ± 43.6 vs 235 ± 39.3 motoneurons) with corresponding and significantly higher numbers of regenerated nerve fibers, resulting in significantly better recovery of reinnervated TA muscle weight. CONCLUSIONS: These experiments in rats demonstrated that delayed nerve repair is more effective when the deleterious effects of chronic denervation of the distal nerve stump are reduced by protecting the nerve stump with ingrowing nerve fibers across an end-to-side insertion of the distal nerve stump into a neighboring intact nerve. Such an end-to-side neurorrhaphy may be invaluable as a means of preventing the atrophy of distal nerve stumps and target organs after chronic denervation, which allows for effective reinnervation of the protected distal nerve stumps and target organs over distance and time.

Long-Term Denervated Rat Schwann Cells Retain Their Capacity to Proliferate and to Myelinate Axons in vitro.

Functional recovery is poor after peripheral nerve injury and delayed surgical repair or when nerves must regenerate over long distances to reinnervate distant targets. A reduced capacity of Schwann cells (SCs) in chronically denervated distal nerve stumps to support and interact with regenerating axons may account for the poor outcome. In an in vitro system, we examined the capacity of adult, long-term denervated rat SCs to proliferate and to myelinate neurites in co-cultures with fetal dorsal root ganglion (DRG) neurons. Non-neuronal cells were counted immediately after their isolation from the distal sciatic nerve stumps that were subjected to acute denervation of 7 days or chronic denervation of either 7 weeks or 17 months. Thereafter, equal numbers of the non-neural cells were co-cultured with purified dissociated DRG neurons for 5 days. The co-cultures were then treated with 3H-Thymidine for 24 h to quantitate SC proliferation with S100 immunostaining and autoradiography. After a 24-day period of co-culture, Sudan Black staining was used to visualize and count myelin segments that were elaborated around DRG neurites by the SCs. Isolated non-neural cells from 7-week chronically denervated nerve stumps increased 2.5-fold in number compared to ~2 million in 7 day acutely denervated stumps. There were only <0.2 million cells in the 17-week chronically denervated stumps. Nonetheless, these chronically denervated SCs maintained their proliferative capacity although the capacity was reduced to 30% in the 17-month chronically denervated distal nerve stumps. Moreover, the chronically denervated SCs retained their capacity to myelinate DRG neurites: there was extensive myelination of the neurites by the acutely and chronically denervated SCs after 24 days co-culture. There were no significant differences in the extent of myelination. We conclude that the low numbers of surviving SCs in chronically denervated distal nerve stumps retain their ability to respond to axonal signals to divide and to elaborate myelin. However, their low numbers consequent to their poor survival and their reduced capacity to proliferate account, at least in part, for the poor functional recovery after delayed surgical repair of injured nerve and/or the repair of injured nerves far from their target organs.

Mini-Open Thoracolumbar Corpectomy: Perioperative Outcomes and Hospital Cost Analysis Compared with Open Corpectomy.

BACKGROUND: Standard open surgical management of thoracolumbar infection, trauma, and tumor is associated with significant morbidity. We compared perioperative and immediate postoperative morbidity of open and mini-open thoracolumbar corpectomy techniques including direct hospital costs. METHODS: We retrospectively reviewed medical records of all patients who underwent open or mini-open corpectomy. Demographics (age, sex, body mass index, primary diagnosis), operative data (length of surgery, estimated blood loss, blood transfusion), surgical level, preoperative and postoperative neurologic status (using American Spinal Injury Association Impairment Scale), immediate perioperative complications (within 30 days postoperatively), overall length of stay from admission, length of stay from surgery, and total direct hospital costs were tabulated and analyzed. RESULTS: The study included 43 patients, 20 (46.51%) undergoing open corpectomy and 23 (53.48%) undergoing mini-open corpectomy. Clinical and statistically significant findings in favor of mini-open corpectomy included lower estimated blood loss (1305 mL vs. 560 mL, P = 0.0072), less blood transfusion (241 mL vs. 667 mL, P = 0.029), shorter overall length of stay (7.2 days vs. 12.2 days, P = 0.047), and shorter surgery time (376 minutes vs. 295 minutes, P = 0.035) as well as lower total direct hospital cost ($34,373 vs. $45,376, P = 0.044). There was no statistically significant difference in postoperative complications between the 2 groups (medical complications 5% vs. 4.3%, P = 0.891; surgical complications 5% vs. 8.69%, P = 0.534). CONCLUSIONS: Mini-open TL corpectomy is a safe, cost-effective, clinically effective, and less morbid alternative to standard open thoracotomy surgical techniques.

First Case of Autonomic Dysreflexia Following Elective Lower Thoracic Spinal Cord Transection in a Spina Bifida Adult.

BACKGROUND: Spinal cord transection is a radical but effective treatment for highly selective cases of symptomatic spinal retethering in paraplegic spina bifida patients. Autonomic dysreflexia (AD) is a potentially life-threatening syndrome involving a dysregulated sympathetic discharge reflex commonly seen following cervical and high thoracic spinal cord injury, leading to a disconnect between autonomic pathways above and below the lesion that can lead to severe complications including uncontrolled hypertension, bradycardia, stroke, and potentially death. Herein we present a case in which a paraplegic spina bifida patient presenting with symptomatic spinal retethering experienced autonomic dysreflexia following an elective spinal cord transection. CASE DESCRIPTION: A 51-year-old male with a history of complex spina bifida presented with an active cerebrospinal fluid leak. Physical examination revealed a thin covering of abnormal epidermis over the large placode. Magnetic resonance imaging revealed a large myelomeningocele defect with posterior element defects spanning from L2 to the sacrum with evidence of tethering. The patient underwent an intradural transection of the spinal cord with a "blind-pouch" closure of the dura at the level of T12/L1. Postoperatively, the patient developed intermittent episodes of hypertension, bradycardia, headaches, altered mental status, severe perspiration, and red flushing of the upper torso, face, and arms. The diagnosis of AD was made clinically and managed with a positive response to a combination of beta- and alpha-blockade along with patient education on avoidance of common AD triggers. At 5-year follow-up the patient has continued to do well on medication. CONCLUSION: This case highlights a potential major side effect from elective transection of the spinal cord. If unrecognized and untreated, AD can cause significant distress and morbidity. We hope this first case report serves to supplement existing data and aid in future surgical and medical decision-making.

Short- and Long-Term Outcomes of Deep Brain Stimulation in Patients 70 Years and Older with Parkinson Disease.

BACKGROUND: Parkinson disease (PD) is a common neurodegenerative disease in elderly patients that may be treated with deep brain stimulation (DBS). DBS is an accepted surgical treatment in PD patients <70 years that demonstrates marked improvement in disease symptomology. Patients ≥70 years historically have been excluded from DBS therapy. Our objective is to evaluate the short- and long-term outcomes in patients with PD ≥70 years who underwent DBS at our center. METHODS: In our single-center study, we retrospectively assessed a prospective registry of patients with PD treated with DBS who were ≥70 years old at the time of their procedure. Univariate analyses and 1-sample paired t test were used to evaluate data. Motor scores were evaluated with the Unified Parkinson's Disease Rating Scale III, and the effects on medication requirements were evaluated with levodopa equivalence daily doses (LEDD). RESULTS: Thirty-seven patients were followed for an average of 42.2 months post-DBS. The average ages at diagnosis and at the time of DBS surgery were 63.05 years and 72.45 years, respectively. Significant reductions in the average Unified Parkinson's Disease Rating Scale III score were observed (preoperative 31.8; postoperative 15.6; P < 0.0001). Significant reductions in the average LEDD (preoperative 891.94 mg; postoperative 559.6 mg; P = 0.0008) and medication doses per day (preoperative 11.54; postoperative 7.97; P = 0.0112) also were present. CONCLUSION: DBS is effective in treating elderly patients with PD. Patients experienced improvement in motor function, LEDD, and medication doses per day after DBS. Our results suggest that DBS is an effective treatment modality in elderly patients with PD.

Primary High-Grade Osteosarcoma of the Clivus: A Case Report and Literature Review.

BACKGROUND: Osteosarcoma is the second most common primary tumor of the skeletal system and the most common primary bone tumor. Usually occurring at the metaphysis of long bones, osteosarcomas are highly aggressive lesions that comprise osteoid-producing spindle cells. Craniofacial osteosarcomas comprise <8% and are believed to be less aggressive and lower grade. Primary osteosarcomas of the skull and skull base comprise <2% of all skull tumors. Osteosarcomas originating from the clivus are rare. We present a case of a primar, high-grade clival osteosarcoma. CASE DESCRIPTION: A 29-year-old man presented to our institution with a progressively worsening right frontal headache for 3 weeks. There were no sensory or cranial nerve deficits. Computed tomography revealed a destructive mass involving the clivus with extension into the left sphenoid sinus. Magnetic resonance imaging revealed a homogenously enhancing lesion measuring 2.7 × 2.5 × 3.2 cm. The patient underwent endonasal transphenoidal surgery for gross total resection. The histopathologic analysis revealed proliferation of malignant-appearing spindled and epithelioid cells with associated osteoclast-like giant cells and a small area of osteoid production. The analysis was consistent with high-grade osteosarcoma. The patient did well and was discharged on postoperative day 2. He was referred for adjuvant radiation therapy and chemotherapy. Two-year follow-up showed postoperative changes and clival expansion caused by packing material. CONCLUSIONS: Osteosarcoma is a highly malignant neoplasm. These lesions are usually found in the extremities; however, they may rarely present in the craniofacial region. Clival osteosarcomas are relatively infrequent. We present a case of a primary clival osteosarcoma with high-grade pathology.

Insular and Sylvian Fissure Dermoid Cyst with Giant Cell Reactivity: Case Report and Review of Literature.

BACKGROUND: Dermoid cysts are rare intracranial tumors that are most commonly found infratentorially and along the midline. Characterized by slow growth and often found incidentally, these lesions can nonetheless have severe complications, notably rupture leading to chemical meningitis. They infrequently present as a supratentorial and lateralized mass. As such, sylvian fissure dermoid cysts are exquisitely rare. We present a rare case of a dermoid cyst with giant cell reactivity suggestive of focal rupture and chronic inflammation. CASE DESCRIPTION: A 61-year-old female presented with new-onset seizures. Magnetic resonance imaging revealed a right insular mass measuring 4.3 × 4.5 cm with compression of the ipsilateral frontal and temporal lobes. The mass was nonenhancing; however, it was bright on diffusion-weighted imaging, suggesting a dermoid cyst. She underwent craniotomy for tumor resection. Histologic analysis revealed keratinizing squamous epithelium, sebaceous glands, and hair follicles associated with giant cell reaction involving the capsule of the cyst consisted with dermoid cyst. At 2.5 years post operation, she is seizure free and without evidence of recurrence. CONCLUSION: The dermoid cyst in our patient was not grossly ruptured, but histopathologic analysis revealed giant cell reactivity, which may indicate focal rupture or chronic inflammation. The relationship between rupture of dermoid cysts and inflammation is not well elucidated. It is not known whether symptoms occur immediately after rupture or as an acute manifestation of a chronic process following rupture. As these lesions are quite rare and rupture is even rarer, more diligence on our part regarding details of histopathology for dermoid cysts is necessary.

Role of chronic Schwann cell denervation in poor functional recovery after nerve injuries and experimental strategies to combat it.

OBJECTIVE: To present our data about the role of chronic denervation (CD) of the distal nerve stumps as compared with muscle denervation atrophy and experimental strategies to promote better functional recovery. METHODS: A rat model of nerve injury and repair was used. The common peroneal branch of the sciatic nerve was subjected to 0 to 24 weeks of CD before cross-suture with the tibial motoneurons. Our outcome measures included the numbers of motoneurons that regenerated their axons and the numbers that reinnervated muscle targets (motor units). To overcome the effects of CD, we used subcutaneous injection of FK506 and in vitro reactivation of Schwann cells that had been subjected to 24 weeks of CD with transforming growth factor beta. RESULTS: Numbers of regenerated motoneurons and reinnervated motor units decreased as a function of duration of CD. However, axons that regenerated through the distal nerve stumps reinnervated the muscle targets and even formed enlarged motor unit size regardless of the duration of CD. FK506 doubled the numbers of tibial motoneurons that regenerated their axons into the common peroneal nerve even after delayed repair. Reactivation of chronically denervated Schwann cells with transforming growth factor beta significantly increased their capacity to support axonal regeneration. CONCLUSION: CD of the distal nerve stumps is the primary factor that results in poor axonal regeneration and subsequently poor functional recovery. Acceleration of the rate of axonal regeneration and/or reactivation of Schwann cells of the distal nerve stumps are effective experimental strategies to promote axonal regeneration and functional recovery.

Nerve transfer surgery for adult brachial plexus injury: a 10-year experience at Louisiana State University.

OBJECTIVE: To review the clinical outcomes in our patients who have undergone nerve transfer operations for brachial plexus reconstruction at the Louisiana State University (LSU) over a 10-year period. A secondary objective is to compare clinical outcomes in patients who had only nerve transfer operations as compared with patients whose nerve transfers were supplemented with direct repair of brachial plexus elements. METHODS: Retrospective review of the medical records, imaging, and electrodiagnostic studies (electromyographic and nerve conduction studies) of patients with brachial plexus injuries who underwent nerve transfer operations at LSU over a period of 10 years. RESULTS: A total of 81 patients were treated between 1995 to 2005 at the LSU Health Sciences Center; 7 of these patients were lost to follow-up, leaving 74 patients, with an average follow-up of 3.5 years, for review. We evaluated recovery of elbow flexion and shoulder abduction. Ninety percent of patients with medial pectoral to musculocutaneous nerve transfers recovered to LSU grade 2 (Medical Research Council grade 3), and 60% of those patients with intercostal to musculocutaneous nerve transfer regained similar strength in elbow flexion. Shoulder abduction recovery to LSU grade 2 (Medical Research Council grade 3) after spinal accessory to suprascapular and/or thoracodorsal to axillary nerve transfer, was 95% and 36%, respectively. There was a tendency for better motor recovery when nerve transfer operations were combined with direct repair of plexus elements. CONCLUSION: Nerve transfers for repair of brachial plexus injuries result in excellent recovery of elbow and shoulder functions. Patients who had direct repair of brachial plexus elements in addition to nerve transfers tended to do better than those who had only nerve transfer operations.

Accelerating axon growth to overcome limitations in functional recovery after peripheral nerve injury.

OBJECTIVE: Injured peripheral nerves regenerate at very slow rates. Therefore, proximal injury sites such as the brachial plexus still present major challenges, and the outcomes of conventional treatments remain poor. This is in part attributable to a progressive decline in the Schwann cells' ability to provide a supportive milieu for the growth cone to extend and to find the appropriate target. These challenges are compounded by the often considerable delay of regeneration across the site of nerve laceration. Recently, low-frequency electrical stimulation (as brief as an hour) has shown promise, as it significantly accelerated regeneration in animal models through speeding of axon growth across the injury site. METHODS: To test whether this might be a useful clinical tool, we carried out a randomized controlled trial in patients who had experienced substantial axonal loss in the median nerve owing to severe compression in the carpal tunnel. To further elucidate the potential mechanisms, we applied rolipram, a cyclic adenosine monophosphate agonist, to rats after axotomy of the femoral nerve. RESULTS: We demonstrated that effects similar to those observed in animal studies could also be attained in humans. The mechanisms of action of electrical stimulation likely operate through up-regulation of neurotrophic factors and cyclic adenosine monophosphate. Indeed, the application of rolipram significantly accelerated nerve regeneration. CONCLUSION: With new mechanistic insights into the influencing factors of peripheral nerve regeneration, the novel treatments described above could form part of an armament of synergistic therapies that could make a meaningful difference to patients with peripheral nerve injuries.

Transforming growth factor-beta and forskolin attenuate the adverse effects of long-term Schwann cell denervation on peripheral nerve regeneration in vivo.

Transforming growth factor-beta (TGF-beta) plays a central role in the regulation of Schwann cell (SC) proliferation and differentiation and is essential for the neurotrophic effects of several neurotrophic factors (reviewed by Unsicker and Krieglstein, 2000; Unsicker and Strelau, 2000). However, its role in peripheral nerve regeneration in vivo is not yet understood. Our studies were carried out to characterize (1) the effects of duration of regeneration, and chronic SC denervation on the number of tibial (TIB) motor neurons that regenerated axons over a fixed distance (25 mm into distal common peroneal [CP] nerve stumps), and (2) the effect of in vitro incubation of 6-month chronically denervated sciatic nerve explants with TGF-beta and forskolin on their capacity to support axonal regeneration in vivo. TIB--CP cross-suture in Silastic tubing was used, and regeneration into 0-24-week chronically denervated CP stumps was allowed for either 1.5 or 3 months. Chronically denervated rat sciatic nerve explants (3 x 3 mm(2)) were incubated in vitro with either DMEM and 15% fetal calf serum (D-15) plus TGF-beta/forskolin or D-15 alone for 48 h and placed into a 10-mm Silastic tube that bridged the proximal and distal nerve stumps of a freshly cut TIB nerve. The number of tibial motor neurons that regenerated axons through the explants and 25 mm into the distal nerve stump after 6 months, and TIB regeneration into the CP nerve stumps, were assessed using retrograde tracers, fluorogold, or fluororuby. We found that all tibial motor neurons regenerate their axons 25 mm into 0-4-week denervated CP nerve stumps after a regeneration period of 3 months. Reducing regeneration time to 1.5 months and chronic denervation, reduced the number of motor neurons that regenerated axons over 25 mm. Exposure of 6-month denervated nerve explants to TGF-beta/forskolin increased the number of motor neurons that regenerated through them from 258 +/-13; mean +/- SE to 442 +/- 22. Hence, acute treatment of atrophic SC with TGF-beta can reactivate the growth-permissive SC phenotype to support axonal regeneration.

FK506 increases peripheral nerve regeneration after chronic axotomy but not after chronic schwann cell denervation.

Poor functional recovery after peripheral nerve injury is attributable, at least in part, to chronic motoneuron axotomy and chronic Schwann cell (SC) denervation. While FK506 has been shown to accelerate the rate of nerve regeneration following a sciatic nerve crush or immediate nerve repair, for clinical application, it is important to determine whether the drug is effective after chronic nerve injuries. Two models were employed in the same adult rats using cross-sutures: chronic axotomy and chronic denervation of SCs. For chronic axotomy, a chronically (2 months) injured proximal tibial (TIB) was sutured to a freshly cut common peroneal (CP) nerve. For chronic denervation, a chronically (2 months) injured distal CP nerve was sutured to a freshly cut TIB nerve. Rats were given subcutaneous injections of FK506 or saline (5 mg/kg/day) for 3 weeks. In the chronic axotomy model, FK506 doubled the number of regenerated motoneurons identified by retrograde labeling (from 205 to 414 TIB motoneurons) and increased the numbers of myelinated axons (from 57 to 93 per 1000 microm2) and their myelin sheath thicknesses (from 0.42 to 0.78 microm) in the distal nerve stump. In contrast, after chronic denervation, FK506 did not improve the reduced capacity of SCs to support axonal regeneration. Taken together, the results suggest that FK506 acts directly on the neuron (as opposed to the denervated distal nerve stump) to accelerate and promote axonal regeneration of neurons whose regenerative capacity is significantly reduced by chronic axotomy.

Chronic Schwann cell denervation and the presence of a sensory nerve reduce motor axonal regeneration.

Motor axonal regeneration is compromised by chronic distal nerve stump denervation, induced by delayed repair or prolonged regeneration distance, suggesting that the pathway for regeneration is progressively impaired with time and/or distance. In the present experiments, we tested the impacts of (i) chronic distal sensory nerve stump denervation on axonal regeneration and (ii) sensory or motor innervation of a nerve graft on the ability of motoneurons to regenerate their axons from the opposite end of the graft. Using the motor and sensory branches of rat femoral nerve and application of neuroanatomical tracers, we evaluated the numbers of regenerated femoral motoneurons and nerve fibers when motoneurons regenerated (i) into freshly cut and 2-month chronically denervated distal sensory nerve stump, (ii) alone into a 4-cm-long distally ligated sensory autograft (MGL) and, (iii) concurrently as sensory (MGS) or motor (MGM) nerves regenerated into the same autograft from the opposite end. We found that all (315 +/- 24: mean +/- SE) the femoral motoneurons regenerated into a freshly cut distal sensory nerve stump as compared to 254 +/- 20 after 2 months of chronic denervation. Under the MGL condition, 151 +/- 5 motoneurons regenerated, which was not significantly different from the MGM group (134 +/- 13) but was significantly reduced to 99 +/- 2 in the MGS group (P < 0.05). The number of regenerated nerve fibers was 1522 +/- 81 in the MGL group, 888 +/- 18 in the MGM group, and 516 +/- 44 in the MGS group, although the high number of nerve fibers in the MGL group was due partly to the elaboration of multiple sprouts. Nerve fiber number and myelination were reduced in the MGS group and increased in the MGM group. These results demonstrate that both chronic denervation and the presence of sensory nerve axons reduced desired motor axonal regeneration into sensory pathways. A common mechanism may involve reduced responsiveness of sensory Schwann cells within the nerve graft or chronically denervated distal nerve stump to regenerating motor axons. The findings confirm that motor regeneration is optimized by avoiding even short-term denervation. They also imply that repairing pure motor nerves (without their cutaneous sensory components) to distal nerve stumps should be considered clinically when motor recovery is the main desired outcome.