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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., (Published by Elsevier Inc.)

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.

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.

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., (© 2014 American Neurological Association.)

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 ( ChAT Cre ). 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 ChAT Cre 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.

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.

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.

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.