Craniocervical instability in patients with Ehlers-Danlos syndromes: outcomes analysis following occipito-cervical fusion.

Craniocervical instability (CCI) is increasingly recognized in hereditary disorders of connective tissue and in some patients following suboccipital decompression for Chiari malformation (CMI) or low-lying cerebellar tonsils (LLCT). CCI is characterized by severe headache and neck pain, cervical medullary syndrome, lower cranial nerve deficits, myelopathy, and radiological metrics, for which occipital cervical fusion (OCF) has been advocated. We conducted a retrospective analysis of patients with CCI and Ehlers-Danlos syndrome (EDS) to determine whether the surgical outcomes supported the criteria by which patients were selected for OCF. Fifty-three consecutive subjects diagnosed with EDS, who presented with severe head and neck pain, lower cranial nerve deficits, cervical medullary syndrome, myelopathy, and radiologic findings of CCI, underwent open reduction, stabilization, and OCF. Thirty-two of these patients underwent suboccipital decompression for obstruction of cerebral spinal fluid flow. Questionnaire data and clinical findings were abstracted by a research nurse. Follow-up questionnaires were administered at 5-28 months (mean 15.1). The study group demonstrated significant improvement in headache and neck pain (p < 0.001), decreased use of pain medication (p < 0.0001), and improved Karnofsky Performance Status score (p < 0.001). Statistically significant improvement was also demonstrated for nausea, syncope (p < 0.001), speech difficulties, concentration, vertigo, dizziness, numbness, arm weakness, and fatigue (p = 0.001). The mental fatigue score and orthostatic grading score were improved (p < 0.01). There was no difference in pain improvement between patients with CMI/LLCT and those without. This outcomes analysis of patients with disabling CCI in the setting of EDS demonstrated significant benefits of OCF. The results support the reasonableness of the selection criteria for OCF. We advocate for a multi-center, prospective clinical trial of OCF in this population.

Refractory Syncope and Presyncope Associated with Atlantoaxial Instability: Preliminary Evidence of Improvement Following Surgical Stabilization.

BACKGROUND: The proclivity to atlantoaxial instability (AAI) has been widely reported for conditions such as rheumatoid arthritis and Down syndrome. Similarly, we have found a higher than expected incidence of AAI in hereditary connective tissue disorders. We demonstrate a strong association of AAI with manifestations of dysautonomia, in particular syncope and lightheadedness, and make preliminary observations as to the salutary effect of surgical stabilization of the atlantoaxial motion segment. METHODS: In an institutional review board-approved retrospective study, 20 subjects (16 women, 4 men) with hereditary connective tissue disorders had AAI diagnosed by computed tomography. Subjects underwent realignment (reduction), stabilization, and fusion of the C1-C2 motion segment. All subjects completed preoperative and postoperative questionnaires in which they were asked about performance, function, and autonomic symptoms, including lightheadedness, presyncope, and syncope. RESULTS: All patients with AAI reported lightheadedness, and 15 had refractory syncope or presyncope despite maximal medical management and physical therapy. Postoperatively, subjects reported a statistically significant improvement in lightheadedness (P = 0.003), presyncope (P = 0.006), and syncope (P = 0.03), and in the frequency (P < 0.05) of other symptoms related to autonomic function, such as nausea, exercise intolerance, palpitations, tremors, heat intolerance, gastroesophageal reflux, and sleep apnea. CONCLUSIONS: This study draws attention to the potential for AAI to present with syncope or presyncope that is refractory to medical management, and for surgical stabilization of AAI to lead to improvement of these and other autonomic symptoms.

Atlanto-axial rotary instability (Fielding type 1): characteristic clinical and radiological findings, and treatment outcomes following alignment, fusion, and stabilization.

Atlanto-axial instability (AAI) is common in the connective tissue disorders, such as rheumatoid arthritis, and increasingly recognized in the heritable disorders of Stickler, Loeys-Dietz, Marfan, Morquio, and Ehlers-Danlos (EDS) syndromes, where it typically presents as a rotary subluxation due to incompetence of the alar ligament. This retrospective, IRB-approved study examines 20 subjects with Fielding type 1 rotary subluxation, characterized by anterior subluxation of the facet on one side, with a normal atlanto-dental interval. Subjects diagnosed with a heritable connective tissue disorder, and AAI had failed non-operative treatment and presented with severe headache, neck pain, and characteristic neurological findings. Subjects underwent a modified Goel-Harms posterior C1-C2 screw fixation and fusion without complication. At 15 months, two subjects underwent reoperation following a fall (one) and occipito-atlantal instability (one). Patients reported improvement in the frequency or severity of neck pain (P < 0.001), numbness in the hands and lower extremities (P = 0.001), headaches, pre-syncope, and lightheadedness (all P < 0.01), vertigo and arm weakness (both P = 0.01), and syncope, nausea, joint pain, and exercise tolerance (all P < 0.05). The diagnosis of Fielding type 1 AAI requires directed investigation with dynamic imaging. Alignment and stabilization is associated with improvement of pain, syncopal and near-syncopal episodes, sensorimotor function, and exercise tolerance.

The Neurosurgical Intraoperative Checklist for Surgery of the Craniocervical Junction and Spine.

Many sectors within healthcare have adapted checklists to improve quality control. Notwithstanding the reported successful implementation of surgical checklists in the operating theater, a dearth of literature addresses the specific challenges posed by complex surgery in the craniocervical junction and spine. The authors devised an intraoperative checklist to address the common errors and verify the completion of objectives unique to these surgeries. The data over six years is presented retrospectively; no historical control for comparison is available, as those omissions and surgical errors addressed by the checklist are not generally registered in any morbidity and mortality reports. Through six years and approximately 1200 surgeries, the checklist was implemented with 98% compliance. The checklist eliminated the occurrences of mundane surgical errors, minimized iatrogenic complications, and ensured completion of specific objectives. We discuss that preoperative checklists, now in general use in all hospitals, have not addressed the most common, intraoperative omissions. These technical omissions result in part from the complexity of spine surgery and directly impact the surgical outcome. The Neurosurgical Intraoperative Checklist is a practical, rapid, and comprehensive means to prevent common, avoidable errors and iatrogenic complications inherent to spine surgery.

Optimizing Alignment Parameters During Craniocervical Stabilization and Fusion: A Technical Note.

Proper craniocervical alignment during craniocervical reduction, stabilization, and fusion optimizes cerebrospinal fluid (CSF) flow through the foramen magnum, establishes the appropriate "gaze angle", avoids dysphagia and dyspnea, and, most importantly, normalizes the clival-axial angle (CXA) to reduce ventral brainstem compression. To illustrate the metrics of reduction that include CXA, posterior occipital cervical angle, orbital-axial or "gaze angle", and mandible-axial angle, we present a video illustration of a patient presenting with signs and symptoms of the cervical medullary syndrome along with concordant radiographic findings of craniocervical instability as identified on dynamic imaging and through assessment of the CXA, Harris, and Grabb-Oakes measurements.

Endoscopic trans-iliac approach to L5-S1 disc and foramen - a report on clinical experience.

BACKGROUND: The lumbosacral junction is a difficult area for spine surgery because of the complex anatomy. In the era of minimally invasive spine surgery, the presence of the iliac wing has, at the level of lumbosacral junction, created a major obstacle in the paths of two of the major approaches, namely, the direct lateral and percutaneous posterolateral endoscopic approaches. A trans-iliac cadaver study published by the senior author and co-workers in 1997, suggested the possibility of an alternative approach to the lumbosacral junction. PURPOSE: To determine the feasibility of percutaneous, endoscopic trans-iliac approach to the L5-S1 disc and foramen. STUDY DESIGN: Prospective case series study. MATERIALS AND METHODS: 15 consecutive patients undergoing the transiliac approach to L5-S1 disc and foramen were included in the study. Pre- and postoperative visual analogue scale (VAS); Oswestry Disability Index (ODI); and intra-operative blood loss and operative time, were obtained for the study. Preoperative MRI or CT scan was used to determine the need for trans-iliac access. The procedure was performed with the patient in prone position and under monitored sedation for decompression. Endotracheal anesthesia was used for fusion cases. The transiliac access was established with a cannulated drill or core drill through the iliac wing. Once the trans-iliac window had been created, the rest of the procedure proceeded as for percutaneous endoscopic transforaminal decompression and fusion. RESULTS: 15 patients (9 male and 6 female) participated in the study. The VAS for back and leg pain significantly improved in all patients. The ODI dropped by more than 50%. There was minimal blood loss, and transient post-operative dysesthesia in 2 cases which resolved after 3 weeks. CONCLUSION: Endoscopic trans-iliac approach to the L5-S1 disc and foramen is feasible and safe. Decompression can be performed safely via trans-iliac access with minimal blood loss, and in a short operative time.

Nortriptyline protects mitochondria and reduces cerebral ischemia/hypoxia injury.

BACKGROUND AND PURPOSE: Nortriptyline, an antidepressant, was identified as a strong inhibitor of mitochondrial permeability transition by our screening of a library of 1040 drugs. Because mitochondrial permeability transition and consequent mitochondrial dysfunction have been implicated in acute neuronal death, we proposed to investigate the possible neuroprotective effects of nortriptyline in cerebral ischemia. METHODS: The effects of nortriptyline were first studied in oxygen/glucose deprivation-induced death of primary cerebrocortical neurons, a cellular model of cerebral ischemia. Mitochondrial membrane potential, mitochondrial factor release, and caspase 3 activation were evaluated after its treatment. Nortriptyline was also studied in a mouse model, which was established by occlusion of the middle cerebral artery. The infarct volume, neurological function, and biochemical events were examined in the absence or the presence of nortriptyline. RESULTS: Nortriptyline inhibits oxygen/glucose deprivation-induced cell death, loss of mitochondrial membrane potential, downstream release of mitochondrial factors, and activation of caspase 3 in primary cerebrocortical neurons. Furthermore, it decreases infarct size and improves neurological scores after middle cerebral artery occlusion in mice. CONCLUSIONS: The ability of nortriptyline to inhibit mitochondrial factor release and caspase activation and further protect the animals correlates to its inhibitory effect on mitochondrial permeability transition in isolated mitochondria. This study indicated that nortriptyline is neuroprotective against cerebral ischemia. It also suggested mitochondrial permeability transition might be a valuable therapeutic target for acute neurodegeneration.

Craniopharyngiomas: an update.

Craniopharyngiomas have been challenging practitioners for over 100 years. These benign cystic tumors are thought to be a part of a continuum of ectodermal cystic lesions found in the suprasellar region. They are rare tumors found in both the adult and pediatric populations. Patients most often present with findings associated with ventricular outflow obstruction causing hydrocephalus, optic chiasm compression resulting in visual dysfunction or hypothalamic/pituitary compression leading to endocrinopathy. The mainstay of treatment involves a combination of radical or limited surgery followed by radiotherapy. Other adjunctive strategies include cyst fenestration, Ommaya catheter implantation and brachytherapy. Patients in general have high long-term survival but can have significant tumor- and treatment-associated morbidity requiring a lifetime of medical and psychological management.

Protective role of Cop in Rip2/caspase-1/caspase-4-mediated HeLa cell death.

CARD only protein (Cop) was recently identified as a protein with significant homology with the CARD of caspase-1. We have conducted functional studies on Cop and report on its role as an inhibitor of cell death in a broad range of cell death paradigms. A notable exception in the ability of Cop to inhibit cell death pertains to its inability to inhibit ER stress-mediated cell death. Furthermore, in addition to the known interaction of Cop and caspase-1, we demonstrated a novel interaction of Cop with caspase-4. We propose that Cop's action to prevent TNF-alpha-induced cell death may operate independently of the mitochondrial death pathway. Furthermore, Cop overexpression inhibits Bid cleavage. In summary, Cop inhibition of cell death, at least to a certain extent, results from its interference with the activation of caspase-1 and caspase-4. Understanding the mechanistic details modulating caspase cell death pathways should provide important information for the development of therapies for diseases featuring aberrant caspase activation. Cop, as an inhibitor of an important apical caspase cell death axis, may provide a tool for modulating pathological cell death.

The mitochondrial permeability transition as a target for neuroprotection.

Mitochondria serve as checkpoints and amplifiers on cell death pathways. In the central nervous system, mitochondrial involvement seems essential for normal expression of cell death phenotypes, and interference with these pathways thus seems a reasonable approach to neuroprotection. We have been involved in examining the potential involvement of the mitochondrial permeability transition (mPT) as one of several possible mechanisms by which mitochondria may be drawn into these death cascades. This possibility, though still controversial, is supported by evidence that factors that may stimulate mPT induction are associated with some forms of cell death (e.g., in stroke) and are modulated by diseases of the central nervous system (e.g., Huntington's). Evidence of neuroprotection seen with compounds such as N -Met-Val cyclosporine also support this possibility.

Clinically approved heterocyclics act on a mitochondrial target and reduce stroke-induced pathology.

Substantial evidence indicates that mitochondria are a major checkpoint in several pathways leading to neuronal cell death, but discerning critical propagation stages from downstream consequences has been difficult. The mitochondrial permeability transition (mPT) may be critical in stroke-related injury. To address this hypothesis, identify potential therapeutics, and screen for new uses for established drugs with known toxicity, 1,040 FDA-approved drugs and other bioactive compounds were tested as potential mPT inhibitors. We report the identification of 28 structurally related drugs, including tricyclic antidepressants and antipsychotics, capable of delaying the mPT. Clinically achievable doses of one drug in this general structural class that inhibits mPT, promethazine, were protective in both in vitro and mouse models of stroke. Specifically, promethazine protected primary neuronal cultures subjected to oxygen-glucose deprivation and reduced infarct size and neurological impairment in mice subjected to middle cerebral artery occlusion/reperfusion. These results, in conjunction with new insights provided to older studies, (a) suggest a class of safe, tolerable drugs for stroke and neurodegeneration; (b) provide new tools for understanding mitochondrial roles in neuronal cell death; (c) demonstrate the clinical/experimental value of screening collections of bioactive compounds enriched in clinically available agents; and (d) provide discovery-based evidence that mPT is an essential, causative event in stroke-related injury.

Fundamental role of the Rip2/caspase-1 pathway in hypoxia and ischemia-induced neuronal cell death.

Caspase-1 plays a key role in inflammatory pathways by processing pro-IL-1beta into the active cytokine mature IL-1beta. Given its sequence similarity with the Caenorhabditis elegans cell death gene ced-3,it has long been speculated that caspase-1 may also play a role in cell death. However, an unequivocal role for caspase-1 in cell death has been questioned, and not definitively demonstrated. Furthermore, if caspase-1 does play a role in cell death, its position in the apoptotic hierarchy has not been clearly defined. Previous studies have shown that caspase-1 knockout (KO) mice and transgenic mice expressing a dominant-negative caspase-1 construct are resistant to ischemic brain injury. We provide direct evidence that caspase-1 plays a key role in neuronal cell death and that caspase-1 is an apical activator of the cell death pathway in the premitochondrial collapse stage. Furthermore, we demonstrate that Rip2/Cardiak/Rick is a stress-inducible upstream modulator of pro-caspase-1 apoptotic activation. We provide evidence that Bid cleavage appears to be an important downstream effector of caspase-1-mediated cell death. Our data demonstrate that caspase-1 is an apical mediator of neuronal cell death during in vitro hypoxia, and confirmed in vivo in ischemia, and provide insights into the sequence of events involved in this pathological cell death process.

Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS.

The known neuroprotective effects of minocycline and creatine in animal models of amyotrophic lateral sclerosis (ALS) led us to examine whether the combination of these agents would result in increased neuroprotection. As previously reported, we confirmed in ALS mice that either minocycline or creatine treatment results in improvement in motor performance and extended survival. We report that combination of minocycline and creatine resulted in additive neuroprotection, suggesting this to be a novel potential strategy for the treatment of ALS. To our knowledge, this is the first report demonstrating additive neuroprotection of a combinatorial approach in a mouse model of ALS. Adding relevancy to our findings, minocycline and creatine, are relatively safe, cross the blood-brain barrier, and are currently available for human evaluation.