Lucas P. Carlstrom

Bidirectional remodeling of β1-integrin adhesions during chemotropic regulation of nerve growth

BackgroundChemotropic factors in the extracellular microenvironment guide nerve growth by acting on the growth cone located at the tip of extending axons. Growth cone extension requires the coordination of cytoskeleton-dependent membrane protrusion and dynamic adhesion to the extracellular matrix, yet how chemotropic factors regulate these events remains an outstanding question. We demonstrated previously that the inhibitory factor myelin-associated glycoprotein (MAG) triggers endocytic removal of the adhesion receptor β1-integrin from the growth cone surface membrane to negatively remodel substrate adhesions during chemorepulsion. Here, we tested how a neurotrophin might affect integrin adhesions.ResultsWe report that brain-derived neurotropic factor (BDNF) positively regulates the formation of substrate adhesions in axonal growth cones during stimulated outgrowth and prevents removal of β1-integrin adhesions by MAG. Treatment of Xenopus spinal neurons with BDNF rapidly triggered β1-integrin clustering and induced the dynamic formation of nascent vinculin-containing adhesion complexes in the growth cone periphery. Both the formation of nascent β1-integrin adhesions and the stimulation of axon extension by BDNF required cytoplasmic calcium ion signaling and integrin activation at the cell surface. Exposure to MAG decreased the number of β1-integrin adhesions in the growth cone during inhibition of axon extension. In contrast, the BDNF-induced adhesions were resistant to negative remodeling by MAG, correlating with the ability of BDNF pretreatment to counteract MAG-inhibition of axon extension. Pre-exposure to MAG prevented the BDNF-induced formation of β1-integrin adhesions and blocked the stimulation of axon extension by BDNF.ConclusionsAltogether, these findings demonstrate the neurotrophin-dependent formation of integrin-based adhesions in the growth cone and reveal how a positive regulator of substrate adhesions can block the negative remodeling and growth inhibitory effects of MAG. Such bidirectional remodeling may allow the growth cone to rapidly adjust adhesiveness to the extracellular matrix as a general mechanism for governing axon extension. Techniques for manipulating integrin internalization and activation state may be important for overcoming local inhibitory factors after traumatic injury or neurodegenerative disease to enhance regenerative nerve growth.

Deadly falls: operative versus nonoperative management of Type II odontoid process fracture in octogenarians

OBJECTIVE Type II odontoid fracture is a common injury among elderly patients, particularly given their predisposition toward low-energy falls. Previous studies have demonstrated a survival advantage following early surgery among patients older than 65 years, yet octogenarians represent a medically distinct and rapidly growing population. The authors compared operative and nonoperative management in patients older than 79 years. METHODS A single-center prospectively maintained trauma database was reviewed using ICD-9 codes to identify octogenarians with C-2 cervical fractures between 1998 and 2014. Cervical CT images were independently reviewed by blinded neurosurgeons to confirm a Type II fracture pattern. Prospectively recorded outcomes included Glasgow Coma Scale (GCS) score, Abbreviated Injury Scale (AIS) score, Injury Severity Score (ISS), additional cervical fracture, and cord injury. Primary end points were mortality at 30 days and at 1 year. Statistical tests included the Student t-test, chi-square test, Fishers exact test, Kaplan-Meier test, and Cox proportional hazard. RESULTS A total of 111 patients met inclusion criteria (94 nonoperative and 17 operative [15 posterior and 2 anterior]). Mortality data were available for 100% of patients. The mean age was 87 years (range 80-104 years). Additional cervical fracture, spinal cord injury, GCS score, AIS score, and ISS were not associated with either management strategy at the time of presentation. The mean time to death or last follow-up was 22 months (range 0-129 months) and was nonsignificant between operative and nonoperative groups (p = 0.3). Overall mortality was 13% in-hospital, 26% at 30 days, and 41% at 1 year. Nonoperative and operative mortality rates were not significant at any time point (12% vs 18%, p = 0.5 [in-hospital]; 27% vs 24%, p = 0.8 [30-day]; and 41% vs 41%, p = 1.0 [1-year]). Kaplan-Meier analysis did not demonstrate a survival advantage for either management strategy. Spinal cord injury, GCS score, AIS score, and ISS were significantly associated with 30-day and 1-year mortality; however, Cox modeling was not significant for any variable. Additional cervical fracture was not associated with increased mortality. The rate of nonhome disposition was not significant between the groups. CONCLUSIONS Type II odontoid fracture is associated with high morbidity among octogenarians, with 41% 1-year mortality independent of intervention-a dramatic decrease from actuarial survival rates for all 80-, 90-, and 100-year-old Americans. Poor outcome is associated with spinal cord injury, GCS score, AIS score, and ISS.

Differential Role of PTEN Phosphatase in Chemotactic Growth Cone Guidance

Background: The phosphatase PTEN is implicated in suppressing neuroregeneration following injury. Results: Chemorepulsion of axons by distinct cues, but not chemoattraction, correlates with PTEN activity, depression of phosphatidylinositol signaling, and remodeling of integrin adhesions. Conclusion: PTEN mediates chemorepulsion selectively. Significance: Suppressing PTEN activity may block repulsion by negative cues after injury while permitting attractive guidance of regenerating axons. Negatively targeting the tumor suppressor and phosphoinositide phosphatase PTEN (phosphatase and tensin homologue) promotes axon regrowth after injury. How PTEN functions in axon guidance has remained unknown. Here we report the differential role of PTEN in chemotactic guidance of axonal growth cones. Down-regulating PTEN expression in Xenopus laevis spinal neurons selectively abolished growth cone chemorepulsion but permitted chemoattraction. These findings persisted during cAMP-dependent switching of turning behaviors. Live cell imaging using a GFP biosensor revealed rapid PTEN-dependent depression of phosphatidylinositol 3,4,5-trisphosphate levels in the growth cone induced by the repellent myelin-associated glycoprotein. Moreover, down-regulating PTEN expression blocked negative remodeling of β1-integrin adhesions triggered by myelin-associated glycoprotein, yet permitted integrin clustering by a positive chemotropic treatment. Thus, PTEN negatively regulates growth cone phosphatidylinositol 3,4,5-trisphosphate levels and mediates chemorepulsion, whereas chemoattraction is PTEN-independent. Regenerative therapies targeting PTEN may therefore suppress growth cone repulsion to soluble cues while permitting attractive guidance, an essential feature for re-forming functional neural circuits.

Incidence and Risk Factors of Delayed Facial Palsy After Vestibular Schwannoma Resection.

BACKGROUND Preservation of facial nerve function following vestibular schwannoma surgery is a high priority. Even those patients with normal to near-normal function in the early postoperative period remain at risk for delayed facial palsy (DFP). OBJECTIVE To evaluate the incidence and prognosis of DFP and to identify risk factors for its occurrence. METHODS A retrospective cohort study of 489 patients who underwent vestibular schwannoma resection at our institution between 2000 and 2014. Delayed facial palsy was defined as deterioration in facial function of at least 2 House-Brackmann (HB) grades between postoperative days 5 to 30. Only patients with a HB grade of I to III by postoperative day 5 were eligible for study inclusion. RESULTS One hundred twenty-one patients with HB grade IV to VI facial weakness at postoperative day 5 were excluded from analysis. Of the remaining 368, 60 (16%) patients developed DFP (mean 12 days postoperatively, range: 5-25 days). All patients recovered function to HB grade I to II by a mean of 33 days (range: 7-86 days). Patients that developed DFP had higher rates of gross total resections (83% vs 71%, P = .05) and retrosigmoid approaches (72% vs 52%, P < .01). There was no difference in recovery time between patients who received treatment with steroids, steroids with antivirals, or no treatment at all (P = .530). CONCLUSION Patients with a gross total tumor resection or undergoing a retrosigmoid approach may be at higher risk of DFP. The prognosis is favorable, with patients likely recovering to normal or near-normal facial function within 1 month of onset.

Characterizing and predicting the Nelson-Salassa syndrome.

OBJECTIVE Nelson-Salassa syndrome (NSS) is a rare consequence of bilateral adrenalectomy (ADX) for refractory hypercortisolism due to Cushing disease (CD). Although classically defined by rapid growth of a large, invasive, adrenocorticotropin hormone (ACTH)-secreting pituitary tumor after bilateral ADX that causes cutaneous hyperpigmentation, visual disturbance, and high levels of ACTH, clinical experience suggests more variability. METHODS The authors conducted a retrospective chart review of all patients 18 years and older with a history of bilateral ADX for CD, adequate pituitary MRI, and at least 2 years of clinical follow-up. Statistical tests included Students t-test, chi-square test, Fishers exact test, multivariate analysis, and derived receiver operating characteristic curves. RESULTS Between 1956 and 2015, 302 patients underwent bilateral ADX for the treatment of hypercortisolism caused by CD; 88 had requisite imaging and follow-up (mean 16 years). Forty-seven patients (53%) had radiographic progression of pituitary disease and were diagnosed with NSS. Compared with patients who did not experience progression, those who developed NSS were significantly younger at the time of CD diagnosis (33 vs 44 years, p = 0.007) and at the time of bilateral ADX (35 vs 49 years, p = 0.007), had larger tumors at the time of CD diagnosis (6 mm vs 1 mm, p = 0.03), and were more likely to have undergone external-beam radiation therapy (EBRT, 43% vs 12%, p = 0.005). Among NSS patients, the mean tumor growth was 7 mm/yr (SE 6 mm/yr); the median tumor growth was 3 mm/yr. Prevalence of pathognomonic symptoms was low; the classic triad occurred in 9%, while hyperpigmentation without visual field deficit was observed in 23%, and 68% remained asymptomatic despite radiographic disease progression. NSS required treatment in 14 patients (30%). CONCLUSIONS NSS is a prevalent sequela of CD after bilateral ADX and affects more than 50% of patients. However, although radiological evidence of NSS is common, it is most often clinically indolent, with only a small minority of patients developing the more aggressive disease phenotype characterized by clinically meaningful symptoms and indications for treatment. Young age at the time of CD diagnosis or treatment with bilateral ADX, large tumor size at CD diagnosis, and EBRT are associated with progression to NSS and may be markers of aggressiveness.

Synergy and convergence of pathways controlling functional regeneration in the spinal cord

Barriers to regeneration in the mammalian central nervous system (CNS) include the presence of inhibitory factors like myelin-associated glycoprotein (MAG) that block re-growth of injured axons. Inhibition by MAG antagonizes the induction of integrin-based substrate adhesions in axonal growth cones by brain-derived neurotrophic factor (BDNF). Here, using a novel approach to overcome inhibitory actions of MAG by activating integrins, we provide cellular and molecular evidence that integrin activity modulates the actions of chemotropic cues on substrate adhesions and supports axon regeneration in vertebrates. Potentiating integrin activity in cultured spinal neurons blocked negative integrin remodeling and inhibition of axon outgrowth induced by MAG, but also restored BDNF-dependent integrin clustering and stimulated outgrowth. In a zebrafish complete spinal cord transection model, combined integrin activation and BDNF treatment synergistically triggered functional regeneration of long projection axons that lack regenerative capacity from the hindbrain. The combined treatment also promoted functional repair even in the presence of exogenous mammalian inhibitory factors, including MAG, which alone impaired recovery of swimming movements. Thus, integrin activation state plays complementary roles in modulating the output activity of opposing cues on integrin-based adhesions and supports functional nerve regeneration in vivo. Our findings reveal effective reversal of downstream actions of inhibitory cues, thereby overcoming a major barrier to regeneration in the mammalian CNS, while simultaneously supporting neurotrophin-stimulated outgrowth. Discovery of therapeutic strategies targeting integrin activation state therefore holds promise for promoting axon regeneration after traumatic injury, which is a critical step in restoring connectivity and functional recovery.

Trigeminal Nerve Schwannoma of the Cerebellopontine Angle

Introduction  Large and even moderate sized, extra-axial cerebellopontine angle (CPA) tumors may fill this restricted space and distort the regional anatomy. It may be difficult to determine even with high resolution magnetic resonance imaging (MRI) if the tumor is dural-based, or what the nerve of origin is if a schwannoma. While clinical history and exam are helpful, they are not unequivocal, particularly since many patients present with a myriad of symptoms, or conversely an incidental finding. We present an atypical appearing, asymptomatic CPA tumor, ultimately identified at surgery to be a trigeminal schwannoma. Case History  A 40-year-old man presented with new-onset seizure. MRI identified an incidental heterogeneously contrast-enhancing CPA lesion ( Fig. 1A – D ). The tumor was centered on the internal auditory canal (IAC) with no tumor extension into Meckels cave, IAC or jugular foramen. Audiometry demonstrated 10db of relative left-sided hearing loss with 100% word recognition. Physical examination was negative for focal neurologic deficits. A retrosigmoid craniotomy was performed and an extra-axial, yellow-hued mass was encountered and resected, which was ultimately confirmed to originate from the trigeminal nerve ( Video 1 ). Gross total resection was achieved, and the patient recovered from surgery with partial ipsilateral trigeminal sensory loss and no other new neurologic deficits. Conclusion  Pure CPA trigeminal schwannomas are rare, but should be considered in the differential for enhancing CPA lesions. Although, Meckels cave involvement is frequently observed, it is not universal, and pure CPA schwannomas of all cranial nerves IV–XII have been reported in the literature. The link to the video can be found at: https://youtu.be/AlodYCu70F8 .

Microarteriovenous Malformations—Value of Indocyanine Green Fluorescence and Nuances of Surgical Excision: 2-Dimensional Operative Video

MicroAVMs (microarteriovenous malformation) are arteriovenous shunts with a nidus smaller than 1 centimeter.1 They are typically diagnosed after hemorrhage. When the nidus is very small, diagnosis can be challenging even on catheter angiography and careful examination of the arterial and capillary phases is required to identify the early shunt. Because of the very small size, identification and localization of the actual AV shunt can be problematic during surgical exploration. Advances in frameless stereotactic neuronavigation and the introduction of intraoperative indocyanine green (ICG) fluorescein provide useful adjuncts in the surgical treatment of these relatively uncommon lesions. In this video, we present 2 cases which document the value of intraoperative ICG fluorescein as well as some of the surgical pitfalls in the treatment of these lesions.

Spontaneous Regression of a Retroodontoid Transverse Ligament Cyst: A Case Report

BACKGROUND AND IMPORTANCE Transverse ligament cysts (TLC) are rare, surgically complex lesions arising posterior to the odontoid process of C2. Direct compression of the cervicomedullary junction is a devastating consequence of untreated lesions. We report the first case of spontaneous TLC regression without surgical intervention. CLINICAL PRESENTATION A 75-yr-old woman presented to an outside hospital with acute episodes of left face and upper extremity numbness. Magnetic resonance imaging (MRI) demonstrated a well-circumscribed 5.8 mm cystic mass at the atlantoaxial junction, posterior to the odontoid process, most consistent with a TLC. She presented to our institution 1 yr later with symptoms of progressive occipital neuralgia seeking surgical treatment. No evidence of cervical myelopathy was identified on clinical examination. Repeat MRI showed near doubling of the cyst, with no brainstem edema. The patient elected for surveillance of the cyst with a transforaminal steroid injection at C1-C2 for her occipital neuralgia. One year later, symptoms of occipital neuralgia had resolved and she remained neurologically intact; MRI of the cervical spine showed near complete involution of the cyst. CONCLUSION Symptomatic TLCs are often managed with surgical decompression and, in selected cases, fusion with good functional outcome. However, these interventions carry high risk of postoperative morbidity, particularly in the elderly. Conservative surveillance is rarely reported as a viable option. We present the first case of spontaneous TLC regression in the absence surgery or neck bracing. In select patients without acute myelopathy, clinical and radiographic surveillance may be considered for the management of TLCs.

Nervus intermedius and the surgical management of geniculate neuralgia

OBJECTIVEGeniculate neuralgia (GN) is an uncommon craniofacial pain syndrome attributable to nervus intermedius (NI) dysfunction. Diagnosis and treatment can be challenging, due to the complex nature of ear sensory innervation, resulting in clinical overlap with trigeminal neuralgia (TN) and glossopharyngeal neuralgia (GPN).METHODSA retrospective review of a prospective neurosurgical database at our institution was performed, 2000-2017, with a corresponding systematic literature review. Pain outcomes were dichotomized as unfavorable for unchanged/worsened symptoms versus favorable if improved/resolved. Eight formalin-fixed brains were examined to describe NI at the brainstem.RESULTSEleven patients were surgically treated for GN-9 primary, 2 reoperations. The median age was 48, 7 patients were female, and the median follow-up was 11 months (range 3-143). Seven had ≥ 2 probable cranial neuralgias. NI was sectioned in 9 and treated via microvascular decompression (MVD) in 2. Five patients underwent simultaneous treatment for TN (4 MVD; 1 rhizotomy) and 5 for GPN (3 MVD; 2 rhizotomy). Eleven reported symptomatic improvement (100%); 8 initially reported complete resolution (73%). Pain outcomes at last contact were favorable in 8 (73%)-all among the 9 primary operations (89% vs 0%, p = 0.054). Six prior series reported outcomes in 111 patients.CONCLUSIONSGN is rare, and diagnosis is confounded by symptomatic overlap with TN/GPN. Directed treatment of all possible neuralgias improved pain control in almost all primary operations. Repeat surgery seems a risk factor for an unfavorable outcome. NI is adherent to superomedial VIII at the brainstem; the intermediate/cisternal portion is optimal for visualization and sectioning.