Biographies of international women leaders in neurosurgery.

We received so many biographies of women neurosurgery leaders for this issue that only a selection could be condensed here. In all of them, the essence of a leader shines through. Many are included as "first" of their country or color or other achievement. All of them are included as outstanding-in clinical, academic, and organized neurosurgery. Two defining features are tenacity and service. When faced with shocking discrimination, or numbing indifference, they ignored it or fought valiantly. When choosing their life's work, they chose service, often of the most neglected-those with pain, trauma, and disability. These women inspire and point the way to a time when the term "women leaders" as an exception is unnecessary.-Katharine J. Drummond, MD, on behalf of this month's topic editors.

A large animal model of spinal muscular atrophy and correction of phenotype.

OBJECTIVES: Spinal muscular atrophy (SMA) is caused by reduced levels of survival motor neuron (SMN) protein, which results in motoneuron loss. Therapeutic strategies to increase SMN levels including drug compounds, antisense oligonucleotides, and scAAV9 gene therapy have proved effective in mice. We wished to determine whether reduction of SMN in postnatal motoneurons resulted in SMA in a large animal model, whether SMA could be corrected after development of muscle weakness, and the response of clinically relevant biomarkers. METHODS: Using intrathecal delivery of scAAV9 expressing an shRNA targeting pig SMN1, SMN was knocked down in motoneurons postnatally to SMA levels. This resulted in an SMA phenotype representing the first large animal model of SMA. Restoration of SMN was performed at different time points with scAAV9 expressing human SMN (scAAV9-SMN), and electrophysiology measurements and pathology were performed. RESULTS: Knockdown of SMN in postnatal motoneurons results in overt proximal weakness, fibrillations on electromyography indicating active denervation, and reduced compound muscle action potential (CMAP) and motor unit number estimation (MUNE), as in human SMA. Neuropathology showed loss of motoneurons and motor axons. Presymptomatic delivery of scAAV9-SMN prevented SMA symptoms, indicating that all changes are SMN dependent. Delivery of scAAV9-SMN after symptom onset had a marked impact on phenotype, electrophysiological measures, and pathology. INTERPRETATION: High SMN levels are critical in postnatal motoneurons, and reduction of SMN results in an SMA phenotype that is SMN dependent. Importantly, clinically relevant biomarkers including CMAP and MUNE are responsive to SMN restoration, and abrogation of phenotype can be achieved even after symptom onset.

A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse.

Spinal muscular atrophy (SMA) is an autosomal-recessive disorder characterized by α-motor neuron loss in the spinal cord anterior horn. SMA results from deletion or mutation of the Survival Motor Neuron 1 gene (SMN1) and retention of SMN2. A single nucleotide difference between SMN1 and SMN2 results in exclusion of exon 7 from the majority of SMN2 transcripts, leading to decreased SMN protein levels and development of SMA. A series of splice enhancers and silencers regulate incorporation of SMN2 exon 7; these splice motifs can be blocked with antisense oligomers (ASOs) to alter SMN2 transcript splicing. We have evaluated a morpholino (MO) oligomer against ISS-N1 [HSMN2Ex7D(-10,-29)], and delivered this MO to postnatal day 0 (P0) SMA pups (Smn-/-, SMN2+/+, SMNΔ7+/+) by intracerebroventricular (ICV) injection. Survival was increased markedly from 15 days to >100 days. Delayed CNS MO injection has moderate efficacy, and delayed peripheral injection has mild survival advantage, suggesting that early CNS ASO administration is essential for SMA therapy consideration. ICV treatment increased full-length SMN2 transcript as well as SMN protein in neural tissue, but only minimally in peripheral tissue. Interval analysis shows a decrease in alternative splice modification over time. We suggest that CNS increases of SMN will have a major impact on SMA, and an early increase of the SMN level results in correction of motor phenotypes. Finally, the early introduction by intrathecal delivery of MO oligomers is a potential treatment for SMA patients.

Burden and Risk Factors of Cervical Spine Conditions in Military Aircrew From 1997 to 2015: A Retrospective Cohort Study.

INTRODUCTION: Military aviators may have increased risk of cervical spine injuries because of exposure to supraphysiologic forces and vibration during dynamic flight. Aviator medical attrition impairs mission readiness, decreases operational capabilities, increases overall DoDcosts, and decreases retention of seasoned aviators. This study evaluated incidence and risk factors for cervical spine conditions in U.S. military aviators from 1997 to 2015. MATERIALS AND METHODS: The Defense Medical Epidemiological Database was queried for aviators with a diagnosis of cervical spine conditions. Pertinent ICD-9 codes for cervical spine pathology were ascertained from U.S. Army, Air Force, and Naval Air Forces aeromedical references. Negative binomial regressions assessed sex, age, service, aircraft, and year on incidence of conditions. Rates were compared to non-aviator controls. The study was approved by the Institutional Review Board at the Naval Health Research Center (NHRC.2020.0205-NHSR). RESULTS: Incidence rates were 9.78 to 12.57/1,000 person-years for neck pain, 2.04 to 3.89/1,000 person-years for degenerative conditions without neurological involvement, and 0.94 to 1.36/1,000 person-years for degenerative conditions with neurological involvement. Aviation occupation (relative risk [RR] 1.41-2.05), female sex (RR 3.32-7.89), age over 40 (RR 2.39-4.62), and service in the Army or Marine Corps (RR 1.62-2.14) were risk factors. CONCLUSIONS: Military aviators had a statistically significant increase in risk of neck pain and medically disqualifying degenerative cervical spine conditions compared to non-aviator controls. Rates of neck pain increased in all aviators over the study epoch. Possible explanations could be related to the operational demands and the increased use of forward helmet-mounted display systems during the study period, a supposition that requires further investigation. There was no significant difference in rates of neck pain or degenerative cervical conditions between aircraft platforms (fighter/bomber, other fixed wing, and rotary wing). Female sex, age over 40 years, and Army/Marine Corps service were the greatest risk factors for neck pain and degenerative cervical spine conditions. Targeted prevention programs and expanded treatment modalities are necessary to reduce aviator attrition and Department of Defense cost burden.

Cranioplasty in the deployed environment: experience for host-country nationals.

OBJECTIVE: Decompressive craniectomy (DC) is the definitive neurosurgical treatment for managing refractory malignant cerebral edema and intracranial hypertension due to combat-related severe traumatic brain injury (TBI). To date, the long-term outcomes and sequelae of this procedure on host-country national (HCN) populations during Operation Iraqi Freedom (Iraq, 2003-2011), Operation Enduring Freedom (Afghanistan, 2001-2014), and Operation Freedom's Sentinel (Afghanistan, 2015-2021) have not been described, specifically the process and results of delayed custom synthetic cranioplasty. The Joint Trauma System's Clinical Practice Guidelines (JTS-CPG) for severe head injury counsels surgeons to discard the cranial osseous explant when treating coalition service members. Ongoing political and healthcare system instabilities often preclude opportunities for delayed cranioplasty by host-country assets. Various surgical options (such as hinge craniectomy) are inadequate in the setting of complicated cranial comminution from blast or missile injuries, severe cerebral edema, grossly contaminated wounds, complex polytrauma, and tissue devitalization. Delayed cranioplasty with a custom synthetic implant is a viable but logistically challenging alternative. In this retrospective review, the authors present the first patient series describing delayed custom synthetic cranioplasty in an HCN population performed during active military conflict. METHODS: Patients were identified through the Joint Trauma System/Theater Medical Data Store, and subgroup analyses were performed to include mechanisms of injury, surgical complications, and clinical outcomes. RESULTS: Twenty-five patients underwent DC between 2012 and 2020 to treat penetrating, blast, and high-energy closed head injuries per JTS-CPG criteria. The average time from injury to surgery was 1.4 days, although 6 patients received delayed care (3-6 days) due to protracted evacuation from local hospitals. Delayed care correlated with an increased rate of intracranial abscess and empyema. The average time to cranioplasty was 134 days due to a lack of robust mechanisms for patient follow-up, tracking, and access to NATO hospitals. HCN patients who recovered from DC demonstrated overall benefit from custom synthetic cranioplasty, although formal statistical analysis was impeded by a lack of long-term follow-up. CONCLUSIONS: This review demonstrates that cranioplasty with a custom synthetic implant is a safe and feasible treatment for vulnerable HCN patients who survive their index DC surgery. This unique paradigm of care highlights the capabilities of deployed neurosurgical healthcare teams working in partnership with the prosthetics laboratory at Walter Reed National Military Medical Center.

Effect of Fusion and Arthroplasty for Cervical Degenerative Disc Disease in Active Duty Service Members Performed at an Overseas Military Treatment Facility: A 2-Year Retrospective Analysis.

INTRODUCTION: Among U.S. military active duty service members, cervicalgia, cervical radiculopathy, and myelopathy are common causes of disability, effecting job performance and readiness, often leading to medical separation from the military. Among surgical therapies, anterior cervical discectomy and fusion (ACDF) and cervical disc arthroplasty (CDA) are options in select cases; however, elective surgeries performed while serving overseas (OCONUS) have not been studied. MATERIALS AND METHODS: A retrospective analysis of a prospectively collected surgical database from an OCONUS military treatment facility over a 2-year period (2019-2021) was queried. Patient and procedural data were collected to include ACDF or CDA surgery, military rank, age, tobacco use, pre- and post-operative visual analogue scales for pain, and presence of radiographic fusion after surgery for ACDF patients or heterotopic ossification for CDA patients. Chi-square and Student t-test analyses were performed to identify variables associated with return to full duty. RESULTS: A total of 47 patients (25 ACDF and 22 CDA) underwent surgery with an average follow-up of 192.1 days (range 7-819 days). Forty-one (87.2%) patients were able to return to duty without restrictions; 10.6% of patients remained on partial or limited duty at latest follow-up and one patient was medically separated from the surgical cohort. There was one complication and one patient required tour curtailment from overseas duty for ongoing symptoms. CONCLUSIONS: Both ACDF and CDA are effective and safe surgical procedures for active duty patients with cervicalgia, cervical radiculopathy, and cervical myelopathy. They can be performed OCONUS with minimal interruption to the patient, their family, and the military unit, while helping to maintain surgical readiness for the surgeon and the military treatment facility.

Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders.

Adeno-associated virus type 9 (AAV9) is a powerful tool for delivering genes throughout the central nervous system (CNS) following intravenous injection. Preclinical results in pediatric models of spinal muscular atrophy (SMA) and lysosomal storage disorders provide a compelling case for advancing AAV9 to the clinic. An important translational step is to demonstrate efficient CNS targeting in large animals at various ages. In the present study, we tested systemically injected AAV9 in cynomolgus macaques, administered at birth through 3 years of age for targeting CNS and peripheral tissues. We show that AAV9 was efficient at crossing the blood-brain barrier (BBB) at all time points investigated. Transgene expression was detected primarily in glial cells throughout the brain, dorsal root ganglia neurons and motor neurons within the spinal cord, providing confidence for translation to SMA patients. Systemic injection also efficiently targeted skeletal muscle and peripheral organs. To specifically target the CNS, we explored AAV9 delivery to cerebrospinal fluid (CSF). CSF injection efficiently targeted motor neurons, and restricted gene expression to the CNS, providing an alternate delivery route and potentially lower manufacturing requirements for older, larger patients. Our findings support the use of AAV9 for gene transfer to the CNS for disorders in pediatric populations.

Perspectives on Cervical Arthroplasty in Navy and Marine Corps Tactical Jet Aircrew.

Symptomatic cervical spondylosis is a progressive degenerative condition of the cervical spine commonly resulting in functionally-limiting pain, weakness, and/or limited dexterity. Symptomatic cervical spondylosis is believed to occur at higher rates in military aviators than civilian counterparts and is a disqualifying condition for all Navy and Marine Corps aircrew. This condition is non-waiverable for tactical jet (ejection-seat-based) aviators. Medical attrition of experienced tactical jet aircrew from the military aviation community results in substantial cost to the U.S. Government, reduces fleet combat capability, and adversely impacts career progression and retention. The clinical maturation of cervical total disc replacement (TDR) technology over the last 2 decades has revolutionized the treatment of symptomatic cervical spondylosis and enabled a return to duty for hundreds of military service members in non-aviation fields. TDR studies demonstrate equal or superior functional outcomes, rates of symptom resolution, reduced complication and reoperation rates, and lower long-term cost compared to traditional Anterior Cervical Discectomy and Fusion (ACDF). Although initial computational modeling studies have evaluated cervical arthroplasty performance during rotary-wing crash impacts, safety within the dynamic tactical jet environment has not yet been established. The purpose of this article is to review factors relevant to TDR safety and outcomes and to propose a framework to evaluate the safety of TDR in Navy and Marine Corps tactical jet aircrew, to ultimately inform aeromedical algorithms regarding return to flight after TDR.

Lumbar Fusion for Active Duty Service Members Performed at an Overseas Military Treatment Facility: A 2-Year Retrospective Analysis.

INTRODUCTION: Among U.S. Military active duty service members, low back pain (LBP) and lumbar radiculopathy are common causes of disability and effect job performance and readiness and can lead to medical separation from the military. Among surgical therapies, lumbar fusion is an option in select cases; however, elective lumbar fusion performed while serving overseas has not been studied extensively. MATERIALS AND METHODS: A retrospective analysis of a prospectively collected surgical database from an overseas military treatment facility (MTF) over a 2-year period (2019-2021) was queried. Patient and procedural data were collected to include single and 2-level lumbar fusion, indications for surgery, military rank, age, tobacco use, pre- and postoperative Visual Analog Scale (VAS) scores for pain, and the presence of radiographic fusion after surgery. Chi-square and Student's t-test analyses were performed to identify variables associated with return to full duty. RESULTS: A total of 21 patients underwent lumbar fusion with an average follow-up of 303.2 days (110-832 days). Eleven (52.4%) were able to return to full duty without restriction. Four (19%) patients ultimately required medical separation from the military, and six (28.6%) remained in a partial or limited duty status. Three (14.3%) patients required tour curtailment and return from overseas duty prematurely. Older age (40.2 ± 5.9 years), rank of E7 or greater, and reduction in VAS of 50% postoperatively were all associated with return to full unrestricted active duty. Three surgical complications occurred; all patients were able to recover overseas within a 3-month postoperative period. CONCLUSIONS: Low back pain (LBP) and lumbar radiculopathy may ultimately require treatment with instrumented lumbar fusion and decompression. In this series, we demonstrate that overseas duty with treatment at a community-sized MTF does not preclude this therapy and should be considered among treatment options.

Attitudes Toward Neurosurgery Education for the Nonneurosurgeon: A Survey Study and Critical Analysis of U.S. Military Training Techniques and Future Prospects.

BACKGROUND: The U.S. military requires medical readiness to support forward-deployed combat operations. Because time and distance to neurosurgical capabilities vary within the deployed trauma system, nonneurosurgeons are required to perform emergent cranial procedures in select cases. It is unclear whether these surgeons have sufficient training in these procedures. METHODS: This quality-improvement study involved a voluntary, anonymized specialty-specific survey of active-duty surgeons about their experience and attitudes toward U.S. military emergency neurosurgical training. RESULTS: Survey responses were received from 104 general surgeons and 26 neurosurgeons. Among general surgeons, 81% have deployed and 53% received training in emergency neurosurgical procedures before deployment. Only 16% of general surgeons reported participating in craniotomy/craniectomy procedures in the last year. Nine general surgeons reported performing an emergency neurosurgical procedure while on deployment/humanitarian mission, and 87% of respondents expressed interest in further predeployment emergency neurosurgery training. Among neurosurgeons, 81% had participated in training nonneurosurgeons and 73% believe that more comprehensive training for nonneurosurgeons before deployment is needed. General surgeons proposed lower procedure minimums for competency for external ventricular drain placement and craniotomy/craniectomy than did neurosurgeons. Only 37% of general surgeons had used mixed/augmented reality in any capacity previously; for combat procedures, most (90%) would prefer using synchronous supervision via high-fidelity video teleconferencing over mixed reality. CONCLUSIONS: These survey results show a gap in readiness for neurosurgical procedures for forward-deployed general surgeons. Capitalizing on capabilities such as mixed/augmented reality would be a force multiplier and a potential means of improving neurosurgical capabilities in the forward-deployed environments.

Carole A. Miller, MD: Matriarch of the Ohio State University's Department of Neurosurgery.

Carole A. Miller, M.D., was born (May 7, 1939) and raised in Kalamazoo, Michigan. She obtained her undergraduate and medical degrees at the Ohio State University. She went on to complete her neurosurgical training at the Ohio State University Medical Center. After her first faculty role at the University of Michigan (1971), she returned to the Ohio State University Medical Center (1975) where she spent nearly 4 decades. She thrived in the specialty, achieving in every facet of academic practice including scientific contributions, graduate medical education, clinical care, and leadership roles within her academic department, locally, and at the national level of organized neurosurgery. Dr. Miller passed away peacefully, on October 28, 2015, after a courageous battle with cancer. Based on her essential programmatic and specialty-related contributions, she is remembered as the 'founding mother' of neurosurgery at the Ohio State University.

Adult presentation of spinal dysraphism and tandem diastematomyelia.

BACKGROUND CONTEXT: Diastematomyelia is a split-cord malformation often accompanied by other cord or column anomalies. PURPOSE: To report on an adult patient with diastematomyelia and discuss the embryological basis and related developmental sequelae of this split-cord malformation. STUDY DESIGN: Case report. METHODS: A summary of the management of a 54-year-old woman with recent clinical symptomatology related to an undiagnosed split-cord malformation is presented with accompanying literature review. RESULTS: A rare adult presentation of diastematomyelia with accompanying intradural extramedullary epidermoid tumor was repaired with resection of the soft-tissue mass and excision of the fibro-osseous septum. CONCLUSION: Initial presentation of diastematomyelia is rarely seen in adults; accompanying pathology includes scoliosis, tethered cord, and intradural tumors. Effective treatment involves identification of the primary pathology.

Nontraumatic cervicothoracic syrinx as a cause of progressive neurologic dysfunction.

BACKGROUND/OBJECTIVE: Syringomyelia is characterized by a fluid-filled cavity within the spinal cord. While its pathogenesis is currently debated, the relationship of syringomyelia with other conditions, such as Chiari I malformation and cord/column trauma, is well accepted. Despite these common associations, a nidus for syrinx formation has not been identified in a subset of patients. We report 2 patients with idiopathic cervicothoracic syringomyelia who presented with progressive neurologic dysfunction. Diagnostic and treatment algorithms used in the care of these patients are presented. METHODS: Retrospective review, including preoperative and postoperative studies, intraoperative findings, and the patients' surgical outcomes. RESULTS: Patients underwent laminectomy, lysis of adhesions, untethering of spinal cord, fenestration of syrinx, and duraplasty after preoperative studies demonstrated evidence of focal cerebrospinal fluid flow block at the level of the syrinx. One patient's neurologic condition improved after surgery, whereas the other's remained unchanged without further deterioration; both showed radiographic decrease in the syrinx on immediate postoperative magnetic resonance imaging. CONCLUSIONS: These 2 cases illustrate patients who develop a cervicothoracic syrinx in the absence of any trauma, infection, previous manipulation of the neuraxis, or malformations known to be associated with a syringomyelia. Whereas there is no consensus on the optimal management of these patients, the patients reported here experienced arrest in deterioration or improvement of their neurologic examination, making the identification of this condition important as a potentially reversible cause of neurologic deficits. Long-term follow-up is required to determine the efficacy, durability, and lifestyle impact of the procedure.

Electrophysiological Biomarkers in Spinal Muscular Atrophy: Preclinical Proof of Concept.

OBJECTIVE: Preclinical therapies that restore survival motor neuron (SMN) protein levels can dramatically extend survival in spinal muscular atrophy (SMA) mouse models. Biomarkers are needed to effectively translate these promising therapies to clinical trials. Our objective was to investigate electrophysiological biomarkers of compound muscle action potential (CMAP), motor unit number estimation (MUNE) and electromyography (EMG) using an SMA mouse model. METHODS: Sciatic CMAP, MUNE, and EMG were obtained in SMNΔ7 mice at ages 3-13 days and at 21 days in mice with SMN selectively reduced in motor neurons (ChATCre ). To investigate these measures as biomarkers of treatment response, measurements were obtained in SMNΔ7 mice treated with antisense oligonucleotide (ASO) or gene therapy. RESULTS: CMAP was significantly reduced in SMNΔ7 mice at days 6-13 (p<0.01), and MUNE was reduced at days 7-13 (p<0.01). Fibrillations were present on EMG in SMNΔ7 mice but not controls (p=0.02). Similar findings were seen at 21 days in ChATCre mice. MUNE in ASO-treated SMNΔ7 mice were similar to controls at day 12 and 30. CMAP reduction persisted in ASO-treated SMNΔ7 mice at day 12 but was corrected at day 30. Similarly, CMAP and MUNE responses were corrected with gene therapy to restore SMN. INTERPRETATION: These studies confirm features of preserved neuromuscular function in the early postnatal period and subsequent motor unit loss in SMNΔ7 mice. SMN restoring therapies result in preserved MUNE and gradual repair of CMAP responses. This provides preclinical evidence for the utilization of CMAP and MUNE as biomarkers in future SMA clinical trials.

Antisense oligonucleotides for the treatment of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive disease affecting ∼1 in 10,000 live births. The most striking component is the loss of α-motor neurons in the ventral horn of the spinal cord, resulting in progressive paralysis and eventually premature death. There is no current treatment paradigm other than supportive care, though the past 15 years has seen a striking advancement in understanding of both SMA genetics and molecular mechanisms. A variety of disease-modifying interventions are rapidly bridging the translational gap from the laboratory to clinical trials, including the application of antisense oligonucleotide (ASO) therapy for the correction of aberrant RNA splicing characteristic of SMA. Survival motor neuron (SMN) is a ubiquitously expressed 38-kD protein. Humans have two genes that produce SMN, SMN1 and SMN2, the former of which is deleted or nonfunctional in the majority of patients with SMA. These two genes are nearly identical with one exception, a C to T transition (C6T) within exon 7 of SMN2. C6T disrupts a modulator of splicing, leading to the exclusion of exon 7 from ∼90% of the mRNA transcript. The resultant truncated Δ7SMN protein does not oligomerize efficiently and is rapidly degraded. SMA can therefore be considered a disease of too little SMN protein. A number of cis-acting splice modifiers have been identified in the region of exon 7, the steric block of which enhances the retention of the exon and a resultant full-length mRNA sequence. ASOs targeted to these splice motifs have shown impressive phenotype rescue in multiple SMA mouse models.

Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: towards a treatment for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is caused by loss of the Survival Motor Neuron 1 (SMN1) gene, resulting in reduced SMN protein. Humans possess the additional SMN2 gene (or genes) that does produce low level of full length SMN, but cannot adequately compensate for loss of SMN1 due to aberrant splicing. The majority of SMN2 gene transcripts lack exon 7 and the resultant SMNΔ7 mRNA is translated into an unstable and non-functional protein. Splice intervention therapies to promote exon 7 retention and increase amounts of full-length SMN2 transcript offer great potential as a treatment for SMA patients. Several splice silencing motifs in SMN2 have been identified as potential targets for antisense oligonucleotide mediated splice modification. A strong splice silencer is located downstream of exon 7 in SMN2 intron 7. Antisense oligonucleotides targeting this motif promoted SMN2 exon 7 retention in the mature SMN2 transcripts, with increased SMN expression detected in SMA fibroblasts. We report here systematic optimisation of phosphorodiamidate morpholino oligonucleotides (PMO) that promote exon 7 retention to levels that rescued the phenotype in a severe mouse model of SMA after intracerebroventricular delivery. Furthermore, the PMO gives the longest survival reported to date after a single dosing by ICV.