Nicholas Theodore

A Phase I/IIa Clinical Trial of a Recombinant Rho Protein Antagonist in Acute Spinal Cord Injury

Multiple lines of evidence have validated the Rho pathway as important in controlling the neuronal response to growth inhibitory proteins after central nervous system (CNS) injury. A drug called BA-210 (trademarked as Cethrin(®)) blocks activation of Rho and has shown promise in pre-clinical animal studies in being used to treat spinal cord injury (SCI). This is a report of a Phase I/IIa clinical study designed to test the safety and tolerability of the drug, and the neurological status of patients following the administration of a single dose of BA-210 applied during surgery following acute SCI. Patients with thoracic (T2-T12) or cervical (C4-T1) SCI were sequentially recruited for this dose-ranging (0.3 mg to 9 mg Cethrin), multi-center study of 48 patients with complete American Spinal Injury Association assessment (ASIA) A. Vital signs; clinical laboratory tests; computed tomography (CT) scans of the spine, head, and abdomen; magnetic resonance imaging (MRI) of the spine, and ASIA assessment were performed in the pre-study period and in follow-up periods out to 1 year after treatment. The treatment-emergent adverse events that were reported were typical for a population of acute SCI patients, and no serious adverse events were attributed to the drug. The pharmacokinetic analysis showed low levels of systemic exposure to the drug, and there was high inter-patient variability. Changes in ASIA motor scores from baseline were low across all dose groups in thoracic patients (1.8±5.1) and larger in cervical patients (18.6±19.3). The largest change in motor score was observed in the cervical patients treated with 3 mg of Cethrin in whom a 27.3±13.3 point improvement in ASIA motor score at 12 months was observed. Approximately 6% of thoracic patients converted from ASIA A to ASIA C or D compared to 31% of cervical patients and 66% for the 3-mg cervical cohort. Although the patient numbers are small, the observed motor recovery in this open-label trial suggests that BA-210 may increase neurological recovery after complete SCI. Further clinical trials with Cethrin in SCI patients are planned, to establish evidence of efficacy.

Pharmacological Therapy for Acute Spinal Cord Injury

• Administration of methylprednisolone (MP) for the treatment of acute spinal cord injury (SCI) is not recommended. Clinicians considering MP therapy should bear in mind that the drug is not Food and Drug Administration (FDA) approved for this application. There is no Class I or Class II medical evidence supporting the clinical benefit of MP in the treatment of acute SCI. Scattered reports of Class III evidence claim inconsistent effects likely related to random chance or selection bias. However, Class I, II, and III evidence exists that high-dose steroids are associated with harmful side effects including death. • Administration of GM-1 ganglioside (Sygen) for the treatment of acute SCI is not recommended.

Guidelines for the management of acute cervical spine and spinal cord injuries: 2013 update.

In 2002, an author group selected and sponsored by the Joint Section on Spine and Peripheral Nerves of the American Association of Neurological Surgeons and Congress of Neurological Surgeons published the first evidence-based guidelines for the management of patients with acute cervical spinal cord injuries (SCIs). In the spirit of keeping up with changes in information available in the medical literature that might provide more contemporary and more robust medical evidence, another author group was recruited to revise and update the guidelines. The review process has been completed and is published and can be once again found as a supplement to Neurosurgery. The purpose of this article is to provide an overview of the changes in the recommendations as a result of new evidence or broadened scope.

Safety and accuracy of bedside external ventricular drain placement.

OBJECTIVE To study the safety and accuracy of ventriculostomy by neurosurgical trainees. METHODS Initial computed tomographic studies of 346 consecutive patients who underwent bedside ventriculostomy were reviewed retrospectively. Diagnosis, catheter tip location, midline shift, and procedural complications were tabulated. To analyze catheter placement, we used a new grading system: Grade 1, optimal placement in the ipsilateral frontal horn or third ventricle; Grade 2, functional placement in the contralateral lateral ventricle or noneloquent cortex; and Grade 3, suboptimal placement in the eloquent cortex or nontarget cerebrospinal fluid space, with or without functional drainage. Statistical analysis was performed using Fishers exact test and a weighted κ coefficient. RESULTS Diagnoses included the following: subarachnoid hemorrhage, n = 153 (44%); trauma, n = 64 (18%); intracerebral hemorrhage/intraventricular hemorrhage, n = 63 (18%); and other, n = 66 (20%). There were 266 (77%) Grade 1, 34 (10%) Grade 2, and 46 (13%) Grade 3 catheter placements. Hemorrhagic complications occurred in 17 (5%). Four patients (1.2%) were symptomatic, with two (0.6%) requiring surgery. Inter- and intraobserver agreement was almost perfect (κ = 0.846 and 0.922, respectively) as applied to our grading system. Rates of suboptimal placement were highest in patients with midline shift (P = 0.059) and trauma (P = 0.0001). Rates of optimal placement were highest in patients with subarachnoid hemorrhage (P = 0.003) and when the catheter was placed ipsilateral to the side of midline shift (P = 0.063). Neither the residents training experience nor the side of placement seemed to affect accuracy. CONCLUSION Bedside ventriculostomy is a safe and accurate procedure for intracranial pressure monitoring and cerebrospinal fluid drainage.

Blood supply and vascular reactivity of the spinal cord under normal and pathological conditions

The authors present a review of spinal cord blood supply, discussing the anatomy of the vascular system and physiological aspects of blood flow regulation in normal and injured spinal cords. Unique anatomical functional properties of vessels and blood supply determine the susceptibility of the spinal cord to damage, especially ischemia. Spinal cord injury (SCI), for example, complicating thoracoabdominal aortic aneurysm repair is associated with ischemic trauma. The rate of this devastating complication has been decreased significantly by instituting physiological methods of protection. Traumatic SCI causes complex changes in spinal cord blood flow, which are closely related to the severity of injury. Manipulating physiological parameters such as mean arterial blood pressure and intrathecal pressure may be beneficial for patients with an SCI. Studying the physiopathological processes of the spinal cord under vascular compromise remains challenging because of its central role in almost all of the bodys hemodynamic and neurofunctional processes.

The Acute Cardiopulmonary Management of Patients With Cervical Spinal Cord Injuries

M anagement of patients with an acute cervical spinal cord injury in an intensive care unit or similar monitored setting is recommended. • Use of cardiac, hemodynamic, and respiratory monitoring devices to detect cardiovascular dysfunction and respiratory insufficiency in patients following acute spinal cord injury is recommended. • Correction of hypotension in spinal cord injury (systolic blood pressure , 90 mm Hg) when possible and as soon as possible is recommended. • Maintenance of mean arterial blood pressure between 85 and 90 mm Hg for the first 7 days following an acute spinal cord injury is recommended.

Intraoperative Iso-C C-arm Navigation in Cervical Spinal Surgery : Review of the First 52 Cases

Study Design. Fifty-two study participants underwent cervical spine surgery using intraoperative Iso-C imaging with or without spinal navigation. Objectives. To evaluate prospectively the feasibility, advantages, limitations, and applications of Iso-C in cervical spine surgery. Summary of Background Data. Existing stereotactic spinal navigational systems images must be acquired before surgery and typically require cumbersome point-to-point registration. Intraoperative computed tomography (CT) and magnetic resonance imaging (MRI) provide real-time information but can restrict access to the patient, preclude the use of traditional operating room tables, and are time-consuming. The Iso-C allows quick, CT-quality, real-time data acquisition without restricting access to the patient. The data acquired can be automatically transferred to navigational systems with the immediate ability to navigate for anterior or posterior cervical spine procedures. Methods. High-resolution isotropic three-dimensional data sets were acquired using the Iso-C intraoperative fluoroscopy in 52 cervical spine cases. In 30 cases, the data were imported automatically to the StealthStation Treon to support neuronavigation. In 22 cases, a postprocedural intraoperative CT was obtained with the Iso-C primarily to assess the extent of osseous decompression and/or the accuracy of implants or instrumentation. In most cases, a postoperative high-resolution CT image was obtained and compared with the Iso-C data. Results. Successful automated registration suitable for navigation was attained for all anterior and posterior cervical spinal cases. The postprocedural intraoperative Iso-C data were 100% concordant with those of postoperative high-resolution CT as determined by a blinded neuroradiologist. Conclusions. Iso-C intraoperative fluoroscopy is an accurate and rapid way to perform CT-quality image-guided navigation in cervical spinal surgery. In most cases, it obviates the need for postoperative imaging.

2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patients individual circumstances.Coccidioidomycosis, also known as San Joaquin Valley fever, is a systemic infection endemic to parts of the southwestern United States and elsewhere in the Western Hemisphere. Residence in and recent travel to these areas are critical elements for the accurate recognition of patients who develop this infection. In this practice guideline, we have organized our recommendations to address actionable questions concerning the entire spectrum of clinical syndromes. These can range from initial pulmonary infection, which eventually resolves whether or not antifungal therapy is administered, to a variety of pulmonary and extrapulmonary complications. Additional recommendations address management of coccidioidomycosis occurring for special at-risk populations. Finally, preemptive management strategies are outlined in certain at-risk populations and after unintentional laboratory exposure.

Management of Pediatric Cervical Spine and Spinal Cord Injuries

DIAGNOSTIC STANDARDS There is insufficient evidence to support diagnostic standards. GUIDELINES In children who have experienced trauma and are alert, conversant, have no neurological deficit, no midline cervical tenderness, and no painful distracting injury, and are not intoxicated, cervical spine x-rays are not necessary to exclude cervical spine injury and are not recommended. In children who have experienced trauma and who are either not alert, nonconversant, or have neurological deficit, midline cervical tenderness, or painful distracting injury, or are intoxicated, it is recommended that anteroposterior and lateral cervical spine x-rays be obtained. OPTIONS In children younger than age 9 years who have experienced trauma, and who are nonconversant or have an altered mental status, a neurological deficit, neck pain, or a painful distracting injury, are intoxicated, or have unexplained hypotension, it is recommended that anteroposterior and lateral cervical spine x-rays be obtained. In children age 9 years or older who have experienced trauma, and who are nonconversant or have an altered mental status, a neurological deficit, neck pain, or a painful distracting injury, are intoxicated, or have unexplained hypotension, it is recommended that anteroposterior, lateral, and open-mouth cervical spine x-rays be obtained. Computed tomographic scanning with attention to the suspected level of neurological injury to exclude occult fractures or to evaluate regions not seen adequately on plain x-rays is recommended. Flexion/extension cervical x-rays or fluoroscopy may be considered to exclude gross ligamentous instability when there remains a suspicion of cervical spine instability after static x-rays are obtained. Magnetic resonance imaging of the cervical spine may be considered to exclude cord or nerve root compression, evaluate ligamentous integrity, or provide information regarding neurological prognosis. TREATMENT STANDARDS There is insufficient evidence to support treatment standards. GUIDELINES There is insufficient evidence to support treatment guidelines. OPTIONS Thoracic elevation or an occipital recess to prevent flexion of the head and neck when restrained supine on an otherwise flat backboard may allow for better neutral alignment and immobilization of the cervical spine in children younger than 8 years because of the relatively large head in these younger children and is recommended. Closed reduction and halo immobilization for injuries of the C2 synchondrosis between the body and odontoid is recommended in children younger than 7 years. Consideration of primary operative therapy is recommended for isolated ligamentous injuries of the cervical spine with associated deformity.

Dysphagia After Anterior Cervical Spine Surgery: Incidence and Risk Factors

OBJECTIVE To evaluate risk factors for the development of dysphagia after anterior cervical surgery. METHODS The records of 249 patients who underwent anterior cervical surgery were reviewed. The presence and severity of dysphagia were assessed with the Dysphagia Disability Index 6 weeks and 3, 6, and 12 months after surgery. Age; sex; ethnicity; cigarette smoking; previous cervical surgeries; reoperation for same pathology; type of procedure, incision, and instrumentation; number and levels involved; side of procedure, length of surgery; and use of postoperative bracing were analyzed. RESULTS During the first 6 months after surgery, 27 (10.8%) patients developed dysphagia. From these patients the presence of dysphagia at 6 weeks and at 3 and 6 months was 88.8%, 29.6%, and 7.4%, respectively. By 12 months, dysphagia had resolved in all cases. The mean age of patients with dysphagia was 55 years (SD 12.98) and 50 years (SD 12.07) in patients without dysphagia (P = 0.05). Dysphagic patients had an average of 2.2 (SD 1.15) levels operated compared with 1.84 (SD 0.950) in nondysphagic patients (P = 0.05). Patients who developed dysphagia were most often treated at C4-5 (67%) and C5-6 (81%: P < 0.001). Although mean operative time was slightly longer in patients with dysphagia (186 minutes) compared with those without (169 minutes), the difference was not significant. CONCLUSIONS In our patients, the incidence of dysphagia was low, and it had completely resolved at 12 months in all cases. Risk factors for dysphagia were multilevel procedures, involvement of C4-5 and C5-6, and age.