Spyros Karadimas, MD, PhD

All Publications

• Sensory cortical control of movement. Nature neuroscience Karadimas, S. K., Satkunendrarajah, K., Laliberte, A. M., Ringuette, D., Weisspapir, I., Li, L., Gosgnach, S., Fehlings, M. G. 2020; 23 (1): 75-84

  Abstract

  Walking in our complex environment requires continual higher order integrated spatiotemporal information. This information is processed in the somatosensory cortex, and it has long been presumed that it influences movement via descending tracts originating from the motor cortex. Here we show that neuronal activity in the primary somatosensory cortex tightly correlates with the onset and speed of locomotion in freely moving mice. Using optogenetics and pharmacogenetics in combination with in vivo and in vitro electrophysiology, we provide evidence for a direct corticospinal pathway from the primary somatosensory cortex that synapses with cervical excitatory neurons and modulates the lumbar locomotor network independently of the motor cortex and other supraspinal locomotor centers. Stimulation of this pathway enhances speed of locomotion, while inhibition decreases locomotor speed and ultimately terminates stepping. Our findings reveal a novel pathway for neural control of movement whereby the somatosensory cortex directly influences motor behavior, possibly in response to environmental cues.

  View details for DOI 10.1038/s41593-019-0536-7

  View details for PubMedID 31740813

  View details for PubMedCentralID 4844028

• Cervical excitatory neurons sustain breathing after spinal cord injury. Nature Satkunendrarajah, K., Karadimas, S. K., Laliberte, A. M., Montandon, G., Fehlings, M. G. 2018; 562 (7727): 419-422

  Abstract

  Dysfunctional breathing is the main cause of morbidity and mortality after traumatic injury of the cervical spinal cord1,2 and often necessitates assisted ventilation, thus stressing the need to develop strategies to restore breathing. Cervical interneurons that form synapses on phrenic motor neurons, which control the main inspiratory muscle, can modulate phrenic motor output and diaphragmatic function3-5. Here, using a combination of pharmacogenetics and respiratory physiology assays in different models of spinal cord injury, we show that mid-cervical excitatory interneurons are essential for the maintenance of breathing in mice with non-traumatic cervical spinal cord injury, and are also crucial for promoting respiratory recovery after traumatic spinal cord injury. Although these interneurons are not necessary for breathing under normal conditions, their stimulation in non-injured animals enhances inspiratory amplitude. Immediately after spinal cord injury, pharmacogenetic stimulation of cervical excitatory interneurons restores respiratory motor function. Overall, our results demonstrate a strategy to restore breathing after central nervous system trauma by targeting a neuronal subpopulation.

  View details for DOI 10.1038/s41586-018-0595-z

  View details for PubMedID 30305735

• Riluzole blocks perioperative ischemia-reperfusion injury and enhances postdecompression outcomes in cervical spondylotic myelopathy. Science translational medicine Karadimas, S. K., Laliberte, A. M., Tetreault, L., Chung, Y. S., Arnold, P., Foltz, W. D., Fehlings, M. G. 2015; 7 (316): 316ra194

  Abstract

  Although surgical decompression is considered the gold standard treatment for cervical spondylotic myelopathy (CSM), a proportion of cases show postoperative decline or continue to exhibit substantial neurological dysfunction. To investigate this further, we first examined data from the prospective multicenter AOSpine North America CSM study, finding that 9.3% of patients exhibited postoperative functional decline (ΔmJOA, ≤-1) and that 44% of patients were left with substantial neurological impairment 6 months postoperatively. Notably, 4% of patients experienced perioperative neurological complications within 20 days after surgery in otherwise uneventful surgeries. To shed light on the mechanisms underlying this phenomenon and to test a combination therapeutic strategy for CSM, we performed surgical decompression in a rat model of CSM, randomizing some animals to also receive the U.S. Food and Drug Administration-approved drug riluzole. Spinal cord blood flow measurements increased after decompression surgery in rats. CSM rats showed a transient postoperative neurological decline akin to that seen in some CSM patients, suggesting that ischemia-reperfusion injury may occur after decompression surgery. Riluzole treatment attenuated oxidative DNA damage in the spinal cord and postoperative decline after decompression surgery. Mechanistic in vitro studies also demonstrated that riluzole preserved mitochondrial function and reduced oxidative damage in neurons. Rats receiving combined decompression surgery and riluzole treatment displayed long-term improvements in forelimb function associated with preservation of cervical motor neurons and corticospinal tracts compared to rats treated with decompression surgery alone.

  View details for DOI 10.1126/scitranslmed.aac6524

  View details for PubMedID 26631633

• The Impact of Postprocedural Anticoagulant Use in Patients Undergoing Woven EndoBridge: A Multicenter Propensity Score-Matched Study. Translational stroke research Musmar, B., Salim, H. A., Roy, J. M., Adeeb, N., Fuleihan, A. A., Atallah, E., Sizdahkhani, S., Koduri, S., Karadimas, S., Baba, B. E., Howard, B. M., Grossberg, J. A., Scott, K. W., Burkhardt, J. K., Srinivasan, V. M., Erazu, F., Hanel, R. A., Amllay, A., Matouk, C., MacNeil, A., Chalouhi, N., Gomez-Paz, S., Grandhi, R., Jaikumar, V., Levy, E., Siddiqui, A., Klaiman, M., Delgado, J., Hoffman, H., Arthur, A., Hasan, D. M., Notarianni, C., Cuellar, H. H., Guthikonda, B., Morcos, J., Tjoumakaris, S. I., Gooch, M. R., Rosenwasser, R. H., Jabbour, P. 2025; 16 (5): 1486-1495

  Abstract

  The Woven EndoBridge (WEB) device has become a prominent treatment for wide-neck bifurcation intracranial aneurysms since its FDA approval in 2018. However, the impact of anticoagulant therapy on its efficacy and patient outcomes remains underexplored. This study aims to evaluate the effects of postoperative anticoagulant use on aneurysm occlusion, retreatment rates, and functional outcomes following WEB device implantation. This retrospective multicenter study included 457 patients treated with the WEB device across 10 academic institutions in the United States between January 2012 and June 2024. Patients were categorized based on postoperative anticoagulant use: 91 patients (19.9%) received anticoagulants, while 366 patients (80.1%) did not. Propensity score matching (PSM) was employed to control for potential confounders, resulting in 316 matched patients (229 non-anticoagulant and 87 anticoagulant). After PSM, the anticoagulant group had lower rates of excellent functional outcomes (mRS 0-1: 73% vs. 85%, p = 0.026) and higher mortality rates (6.7% vs. 3.7%, p = 0.33), though the latter difference was not statistically significant. No significant differences in the last follow-up adequate occlusion were observed between the two groups (p = 0.7). However, patients in the anticoagulant group had lower major device compaction (> 50%) (4.9% vs. 12%, p = 0.12) and retreatment rates (4.6% vs. 12%, p = 0.045). Postoperative anticoagulant use is associated with poor functional outcomes and higher tendency for higher mortality rate. No significant differences in the last follow-up adequate occlusion rate were observed between the anticoagulant group and non-anticoagulant group. However, patients in the anticoagulant group had lower major compaction and retreatment rates. These findings suggest that the WEB mechanism of occlusion is more complex than what have been hypothesized and highlight the need for individualized management strategies to optimize outcomes in patients requiring anticoagulation post-WEB. Further studies are needed.

  View details for DOI 10.1007/s12975-024-01320-2

  View details for PubMedID 39715904

  View details for PubMedCentralID 8013102

• Vagus nerve stimulation paired with rehabilitation for post-stroke recovery: A single center experience of patient satisfaction and outcomes. Clinical neurology and neurosurgery Roy, J. M., Musmar, B., Ritz, C., Sizdahkhani, S., Karadimas, S., Papadopoulos, E., Patel, S., Wu, C., Jabbour, P., Rosenwasser, R. H., Tjoumakaris, S. I., Gooch, M. R. 2025; 257: 109043

  Abstract

  Vagus nerve stimulation (VNS) paired with rehabilitation has demonstrated the ability to aid in upper limb recovery after stroke. The Food and Drug Administration (FDA) approved the Vivistim system in 2021. Our study describes a single center experience with VNS paired with rehabilitation.This was a single center study of patients who received VNS paired with intensive rehabilitation after ischemic stroke between October 2022-September 2024. Patients with hemorrhagic stroke, those with a history of vagotomy and those who did not have access to rehabilitation after Vivistim implantation were excluded. Outcomes of interest were upper extremity Fugl-Meyer scores (FMA-UE) after completion of rehabilitation and patient satisfaction with their recovery.18 patients underwent VNS paired with rehabilitation. The mean age of the cohort was 60.4, SD (13.0) and 83.3 % (n = 15) were male. 50 % of the cohort (n = 9) had private insurance and the other 50 % (n = 9) had Medicare. Duration from physician referral to Vivistim implantation demonstrated a significant decrease over time (correlation coefficient= -.615, P < 0.01). There was an 8.9-point increase in FMA-UE scores from the first therapy session to the end of the protocol (95 % CI: 5.87-12.01, P < .001). Of 15 patients who completed telephonic follow-up, 8 reported being able to identify when the device was activated and 8 reported having a significant improvement in their quality of life from their post-stroke baseline.We report improvement in baseline FMA-UE scores with paired VNS for post-stroke recovery. Future research could help streamline the process of VNS implantation by developing a better understanding of patient-reported outcomes at long term follow-up to provide patients with expected goals of recovery over time.

  View details for DOI 10.1016/j.clineuro.2025.109043

  View details for PubMedID 40633249

• Does the volume of Onyx injected influence outcomes after middle meningeal artery embolization for subdural hematoma? Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia Roy, J. M., Musmar, B., Karadimas, S., Sizdahkhani, S., Momin, A., Pontarelli, M. K., Garg, A., Papadopoulos, E., Pedapati, V., Pannu, A., Tjoumakaris, S. I., Gooch, M. R., Rosenwasser, R. H., Jabbour, P. 2025; 142: 111651

  Abstract

  Recent literature has highlighted the efficacy of liquid embolic agents like Onyx for middle meningeal artery (MMA) embolization of subdural hematoma (SDH). Our study aims to assess whether the volume of Onyx injected affects outcomes in patients undergoing MMA embolization for SDH.This was a retrospective study of patients who underwent MMA embolization using Onyx for SDH at a single institution between March 2019- December 2024. Patients who underwent embolization using particles were excluded. Patients were dichotomized into two groups (≥0.7 ml or <0.7 ml) based on the 75th percentile of median volume of Onyx injected. The primary outcome of interest was embolization failure, defined as increase in hematoma thickness or need for surgical evacuation. The secondary outcome of interest was extended length of stay (eLOS), defined as LOS above the 75th percentile of the median.A total of 123 MMA embolization procedures were included. The mean age of the cohort was 71.7 ± 13.5 years, and 26 % (n = 32) were female. 70.7 % of patients (n = 87) received a lower volume (<0.7 ml) of Onyx. Volume of Onyx was not associated with embolization failure or eLOS. Female gender (OR: 0.24, 95 % CI: 0.06-0.89, P = 0.034) was associated with lower odds of eLOS, while baseline functional dependence was associated with higher odds of eLOS (OR: 6.34, 95 % CI: 2.24-17.97, P < 0.001).The volume of Onyx injected does not predict embolization failure or eLOS after MMA embolization for SDH. Future research could help validate our preliminary findings through prospective multicenter studies.

  View details for DOI 10.1016/j.jocn.2025.111651

  View details for PubMedID 40992199

• Outcomes of arteriovenous malformation patients with multiple versus single feeders: A multicenter retrospective study with propensity-score matching. European stroke journal Musmar, B., Adeeb, N., Abdalrazeq, H., Roy, J. M., Tjoumakaris, S. I., Salim, H. A., Kondziolka, D., Sheehan, J., Ogilvy, C. S., Riina, H., Kandregula, S., Dmytriw, A. A., El Naamani, K., Abdelsalam, A., Ironside, N., Kumbhare, D., Ataoglu, C., Essibayi, M. A., Keles, A., Muram, S., Sconzo, D., Rezai, A., Alwakaa, O., Tos, S. M., Erginoglu, U., Pöppe, J., Sen, R. D., Griessenauer, C. J., Burkhardt, J. K., Starke, R. M., Baskaya, M. K., Sekhar, L. N., Levitt, M. R., Altschul, D. J., McAvoy, M., Aslan, A., Abushehab, A., Swaid, C., Abla, A. A., Sizdahkhani, S., Koduri, S., Atallah, E., Karadimas, S., Gooch, M. R., Rosenwasser, R. H., Stapleton, C., Koch, M., Srinivasan, V. M., Chen, P. R., Blackburn, S., Cochran, J., Choudhri, O., Pukenas, B., Orbach, D., Smith, E., Mosimann, P. J., Alaraj, A., Aziz-Sultan, M. A., Patel, A. B., Cuellar, H. H., Lawton, M., Guthikonda, B., Morcos, J., Jabbour, P. 2025; 10 (3): 946-960

  Abstract

  The impact of multiple feeding arteries on clinical outcomes of cerebral arteriovenous malformations (AVMs) is not well understood. This study aims to compare outcomes between AVMs with multiple versus single feeding arteries.Data from the Multicenter International Study for Treatment of Brain AVMs (MISTA) consortium were analyzed. Propensity score matching (PSM) was used to balance cohorts. Subgroup analysis was conducted for ruptured and unruptured AVMs and different treatment options, and multivariable logistic regression was applied to assess the impact of feeding artery origin.Among 953 patients, 661(69.4%) had multiple feeding arteries, and 292 (30.6%) had a single feeding artery. After PSM, which included 422 matched patients (211 in each group), the differences in obliteration rates (68.7% vs 74.8%, OR 0.73, 95% CI: 0.48-1.12, p = 0.16) and symptomatic complications (15.6% vs 11.8%, OR 1.37, 95% CI: 0.78-2.41, p = 0.25) were not significant. Subgroup analysis comparing ruptured and unruptured AVMs and different treatment options showed no significant differences across all subgroups. Multivariable analysis identified PICA feeders as significantly associated with increased odds of all complications (OR 7.33, 95% CI: 2.14-25.1, p = 0.002).AVMs with a single feeding artery were more likely to present with rupture, but no significant differences in obliteration rates or complications were observed between the groups after PSM. These findings suggest that while the number of feeding arteries may influence the initial presentation, it does not appear to impact overall treatment success or patient prognosis. Further prospective studies are needed to confirm these findings.

  View details for DOI 10.1177/23969873251319924

  View details for PubMedID 39953956

  View details for PubMedCentralID PMC11830163

• Racial/ethnic disparities among individuals with unruptured and ruptured cerebral aneurysms: Insights from the All of Us Research Program. International journal of stroke : official journal of the International Stroke Society Roy, J. M., Musmar, B., Piper, K., Ghanem, L., Ritz, C., Karadimas, S., Koduri, S., Tjoumakaris, S. I., Gooch, M. R., Rosenwasser, R. H., Jabbour, P. 2025: 17474930251367208

  Abstract

  Race and ethnicity have been shown to affect healthcare outcomes among patients diagnosed with cerebral aneurysms. Our study analyzes baseline demographics, lifestyle, healthcare resource utilization, and perception of health status among patients with ruptured and unruptured cerebral aneurysms based on race and ethnicity.This was a cross-sectional study that utilized survey data and electronic health record (EHR) data from the All of Us Research Program. Patients with unruptured and ruptured aneurysms were identified using ICD-9/10 codes. Cohorts were classified into three categories based on self-reported race/ethnicity: Black, Hispanic, or White.A total of 2975 patients with unruptured cerebral aneurysms and 1498 ruptured cerebral aneurysms were included. Black and Hispanic patients with cerebral aneurysms reported lower income, education, and employment rates, in addition to higher rates of daily cigarette smoking compared to White patients (P < 0.001). After adjusting for confounders, Hispanic patients reported higher odds of being unable to afford specialist care (odd ratio (OR) = 1.86 [1.02-3.37], P = 0.04) and follow-up care (OR = 2.76 [1.52-5.00], P < 0.001), while Black patients reported higher odds of being unable to afford prescription medications (OR = 1.55 [1.03-2.33], P = 0.03) compared to White patients. Black and Hispanic patients reported lower odds of feeling respected by their healthcare provider (OR = 0.45 [0.21-0.94], P = 0.03 and OR = 0.32 [0.15-0.67], P < 0.01), demonstrated lower confidence in completing medical forms independently (OR = 0.58 [0.37-0.89], P = 0.01 and OR = 0.31 [0.20-0.47], P < 0.001) and were more likely to consider their provider's race/religion important compared to White patients (OR = 2.09 [1.51-2.88], P < 0.001 and OR = 2.28 [1.56-3.34], P < 0.001).Our study identified disparities in baseline characteristics, healthcare access, and perception of health status among racial/ethnic minorities with unruptured and ruptured aneurysms. Future research could emphasize on addressing these disparities by ensuring more equitable access to healthcare.

  View details for DOI 10.1177/17474930251367208

  View details for PubMedID 40751574

• Risk factors for in-stent stenosis after flow-diverter implantation for intracranial aneurysm: a single center analysis of 161 consecutive patients. Acta neurochirurgica Alshahrani, R., Karadimas, S., Alvi, M. A., Nicholson, P. J., Krings, T. 2025; 167 (1): 194

  Abstract

  Flow diverters (FD) are used for the treatment of intracranial aneurysms, by redirecting flow and serving as a scaffold for endothelial coverage of the aneurysm ostium. However, in-stent stenosis has been observed in some patients treated with these devices, the cause of which and the epidemiology remaining elusive. In the current study we aimed to elucidate potential factors leading to higher degree of in-stent stenosis including gender, location, and type of FD.The authors queried their institutional Electronic Health Record (EHR) for all patients undergoing FD for intracranial saccular aneurysms. We excluded cases where an FD was performed for a dissecting aneurysm, or other indications. We also excluded patients who had no available follow up.We identified 161 patients undergoing FD for aneurysms, with a mean age of 57.4 (SD = 12.94) and141 (87.6%) of which were females. A total of 24 patients (14.9%) had an in-stent stenosis at a median interval of 10 months; 9 (5.6%) had a severe (i.e. symptomatic or requiring treatment) stenosis. When subsetting for females, we found that females with any in-stent stenosis were significantly younger compared to those without stenosis (51.045, SD = 15.7 vs 58.5, SD = 12.31, p = 0.013). Females with severe in-stent stenosis were even younger (42.2, SD = 14.2 vs 58.3, SD = 12.54; p < 0.001) compared to the rest of the females. Patients presenting with ruptured aneurysm had a higher rate of severe in-stent stenosis (16.7%, n = 4/24, p = 0.014). Regarding devices, patients who underwent treatment with a high-braid FD were more likely to have severe in-stent stenosis (18.8%, n = 3/16; p = 0.016).Our findings indicate that younger age, presentation with rupture and high-braid FD may be associated with higher risk of severe in-stent stenosis. These findings may provide more insight into the selection of treatment modality and/or device in patients undergoing management of their cerebral aneurysms.

  View details for DOI 10.1007/s00701-025-06597-2

  View details for PubMedID 40676336

  View details for PubMedCentralID PMC12271242

• Outcomes of arteriovenous malformations with single versus multiple draining veins: A multicenter study. Journal of the neurological sciences Musmar, B., Abdalrazeq, H., Adeeb, N., Roy, J. M., Aslan, A., Tjoumakaris, S. I., Salim, H. A., Ogilvy, C. S., Baskaya, M. K., Kondziolka, D., Sheehan, J., Riina, H., Kandregula, S., Dmytriw, A. A., Abushehab, A., El Naamani, K., Abdelsalam, A., Ironside, N., Kumbhare, D., Gummadi, S., Ataoglu, C., Essibayi, M. A., Keles, A., Muram, S., Sconzo, D., Rezai, A., Alwakaa, O., Tos, S. M., Mantziaris, G., Park, M. S., Erginoglu, U., Pöppe, J., Sen, R. D., Griessenauer, C. J., Burkhardt, J. K., Starke, R. M., Sekhar, L. N., Levitt, M. R., Altschul, D. J., Haranhalli, N., McAvoy, M., Zeineddine, H. A., Abla, A. A., Sizdahkhani, S., Koduri, S., Atallah, E., Karadimas, S., Gooch, M. R., Rosenwasser, R. H., Stapleton, C., Koch, M., Srinivasan, V. M., Chen, P. R., Blackburn, S., Bulsara, K., Kim, L. J., Choudhri, O., Pukenas, B., Orbach, D., Smith, E., Mosimann, P. J., Alaraj, A., Aziz-Sultan, M. A., Patel, A. B., Savardekar, A., Notarianni, C., Cuellar, H. H., Lawton, M., Guthikonda, B., Morcos, J., Jabbour, P. 2025; 473: 123503

  Abstract

  Cerebral arteriovenous malformations (AVMs) are complex vascular lesions that pose a risk for hemorrhagic stroke. The number of draining veins has recently emerged as a significant predictor of rupture risk. This multicenter study aimed to evaluate the outcomes in adult AVM patients with single versus multiple draining veins.We conducted a retrospective analysis of 735 AVM patients from the Multicenter International Study for Treatment of Brain AVMs (MISTA) database. Patients were categorized into single draining vein (n = 430) and multiple draining veins (n = 305) groups. Logistic and linear regression models were used to assess outcomes, adjusting for baseline characteristics, including age, rupture status, Spetzler-Martin grade, and other relevant factors.After adjustment, no significant differences were observed in complete AVM obliteration at last follow-up between the multiple and single draining veins groups (OR: 1.1; 95 % CI: 0.72-1.93, p = 0.49) after any treatment type. Good functional outcomes at last follow-up (mRS 0-2) were similar between the two groups (OR: 1.00; 95 % CI: 0.48-2.09, p = 0.98), as were retreatment rates (OR: 1.68; 95 % CI: 0.74-3.83, p = 0.21). Ruptured AVMs were more common in the single draining vein group (52.0 % vs. 35.4 %, p < 0.001). Patients in the multiple draining vein group had lower odds of hemorrhagic complications compared to the single vein group (OR: 0.38; 95 % CI: 0.14-1.02, p = 0.05).Single draining vein AVMs were more likely to present with rupture, but no significant differences in obliteration rates, functional outcomes, or retreatment rates were found between the groups after adjustment. These findings suggest that while venous drainage patterns may influence initial presentation, they do not appear to affect overall treatment success or patient prognosis after any treatment type. Further studies are needed to confirm.

  View details for DOI 10.1016/j.jns.2025.123503

  View details for PubMedID 40262450

• Flow Diversion in Patients With Concurrent Anticoagulation: Multicenter Experience and Systematic Review of Literature. Operative neurosurgery (Hagerstown, Md.) Roy, J. M., Musmar, B., Koduri, S., Baldari, A., Sokol, Z., Amaravadi, C., Karadimas, S., Kozak, O., Mackenzie, L., Schmidt, R. F., Ghosh, R., Tjoumakaris, S. I., Gooch, M. R., Zarzour, H., Rosenwasser, R. H., Jabbour, P. M. 2025

  Abstract

  Dual antiplatelet therapy is used to minimize thromboembolic complications after flow diversion (FD). Oral anticoagulation (AC) has been associated with increased risk of hemorrhagic complications. Our multicenter study and systematic review of literature describes the safety and efficacy of FD in patients on concurrent AC.This was a retrospective study of patients on concurrent AC before FD for an intracranial aneurysm at 3 participating institutions between January 2018 and January 2024. Outcomes of interest were angiographic occlusion (assessed using the O'Kelly-Marotta (OKM) Grade), postoperative complications, in-stent stenosis, and functional outcome (measured using the modified Rankin Scale). PubMed was searched to identify articles that reported outcomes of interest in patients undergoing FD on AC.Nineteen patients with 20 aneurysms underwent FD while on AC. The median age of the cohort was 71%, and 89.4% were female (n = 17). Forty percentage (n = 8) of aneurysms were completely occluded (OKM grade D) and 20% (n = 4) developed clinically asymptomatic in-stent stenosis at their last follow-up. Overall, 84.2% of patients (n = 16) were functionally independent, 1 patient was lost to follow-up and 2 patients experienced mortality. Our systematic review of literature identified 2 articles describing rates of occlusion ranging from 25% to 71.4%, with increased rates of delayed rupture and retreatment among patients on AC.We report low rates of complete aneurysm obliteration after FD in patients on concurrent AC. Future research could help identify the appropriate antithrombotic regimen in this cohort.

  View details for DOI 10.1227/ons.0000000000001660

  View details for PubMedID 40459302

• Clinical impact of gradient echo MRI versus CT in detecting hemorrhagic transformation after mechanical thrombectomy. Neuroradiology Musmar, B., M Roy, J., Abdalrazeq, H., Pedapati, V., A Fuleihan, A., Koduri, S., Sizdahkhani, S., Atallah, E., Karadimas, S., I Tjoumakaris, S., Gooch, M. R., H Rosenwasser, R., Jabbour, P. 2025; 67 (6): 1395-1403

  Abstract

  Hemorrhagic transformation (HT) following mechanical thrombectomy (MT) is a critical concern in the management of ischemic stroke patients. While both CT and MRI are used to detect HT, the clinical implications of discrepancies between these modalities remain unclear. This study aims to investigate the clinical implications of discordant findings between gradient echo MRI and CT in detecting HT after MT.In this retrospective study, patients who underwent MT for ischemic stroke between 2016 and 2023 were analyzed. Patients were categorized into two groups based on imaging results: CT negative and MRI positive versus CT positive and MRI positive.A total of 286 patients were included in the study, with 104 in the CT negative and MRI positive group and 182 in the CT positive and MRI positive group. More patients in the CT negative and MRI positive group were started on antithrombotic medications in less than 2 days compared to the patients in the CT positive and MRI positive group (47.3% vs. 34.5%; OR: 1.94, 95% CI: 0.88-4.27, p = 0.09) and still exhibited significantly higher rates of good functional outcomes (mRS 0-2) at discharge (OR: 3.27, 95% CI: 1.03-10.36, p = 0.04). Additionally, the CT negative and MRI positive group had a lower, though not statistically significant, likelihood of readmission for diagnosis of intracranial hemorrhage (ICH) within 30 days (0% vs. 2.7%, p = 0.16).Gradient echo MRI can detect subtle hemorrhages not seen on CT, and both modalities offer complementary insights. In our cohort of MRI-positive patients, those with CT-negative findings had better functional outcomes and earlier antithrombotic resumption without increased risk of ICH readmission. These results suggest that in select scenarios, a negative CT may help inform safe antithrombotic management, though this does not diminish the diagnostic value of MRI. Further prospective studies are warranted to establish thresholds for MRI findings and refine clinical protocols post-MT.

  View details for DOI 10.1007/s00234-025-03638-6

  View details for PubMedID 40358713

  View details for PubMedCentralID 6288566

• Microsurgical Resection of a Left Precentral Gyrus Arteriovenous Malformation: 3-Dimensional Operative Video. Operative neurosurgery (Hagerstown, Md.) Karadimas, S. K., Morcos, J. J. 2025; 28 (4): 574

  View details for DOI 10.1227/ons.0000000000001288

  View details for PubMedID 39012144

• Comparative outcomes of endovascular vs. surgical treatment in craniocervical junction dural arteriovenous fistulas: A systematic review and meta-analysis. Journal of the neurological sciences Musmar, B., Roy, J. M., Orscelik, A., Koduri, S., Karadimas, S., Sizdahkhani, S., Atallah, E., Tjoumakaris, S. I., Gooch, M. R., Zarzour, H., Ghosh, R., Schmidt, R. F., Rosenwasser, R. H., Jabbour, P. 2025; 470: 123402

  Abstract

  Craniocervical junction dural arteriovenous fistulas (CCJ-DAVFs) are rare and complex vascular malformations that are challenging to diagnose and treat. This study aims to compare surgical and endovascular treatments for CCJ-DAVFs through a systematic review and meta-analysis.A systematic review and meta-analysis was conducted according to the PRISMA guidelines. PubMed, Scopus, and Web of Science databases were searched from inception to July 2024.Fifteen studies involving 266 patients were included. Of these, 143 (53.8 %) patients underwent surgical treatment alone and 123 (46.2 %) underwent endovascular treatment alone. In the surgical group, the complete obliteration rate at last follow-up was 89.8 %. Retreatment rate was 6.2 %. Periprocedural complications occurred in 21.6 % of cases. In the endovascular group, the complete occlusion rate at last follow-up was 73.6 %. Retreatment rate was 46.7 %. Periprocedural complications occurred in 18.8 % of cases. Comparative meta-analysis revealed that the rate of complete obliteration at last follow-up was significantly higher in the surgical group (OR: 0.24; CI: 0.07 to 0.89, p = 0.03). Surgical treatment had a significantly higher successful treatment rate (OR: 0.24; CI: 0.07 to 0.89, p = 0.03) and lower retreatment rate (OR: 37.13; CI: 6.31 to 218.59, p < 0.01). No significant differences were observed between the groups in terms of periprocedural complications or complete resolution of symptoms.Surgical treatment for CCJ-DAVFs achieves higher rates of complete obliteration with lower retreatment rates compared to endovascular treatment. However, endovascular treatment showed a tendency towards reducing periprocedural complications while increasing the likelihood of complete resolution of symptoms. Individualized treatment plans for CCJ-DAVFs, should be considered according to their anatomical location and potential surgical accessibility. Further studies are required to confirm these findings.

  View details for DOI 10.1016/j.jns.2025.123402

  View details for PubMedID 39847819

• Occipital Interhemispheric Transtentorial Approach for Microsurgical Treatment of Posterior Midbrain Arteriovenous Malformation: 2-Dimensional Operative Video. Operative neurosurgery (Hagerstown, Md.) Karadimas, S. K., Silva, M. A., Starke, R. M. 2025; 28 (3): 445-446

  View details for DOI 10.1227/ons.0000000000001273

  View details for PubMedID 38995048

• Treatment of Recurrent, Twice Coiled, Previously Ruptured Anterior Inferior Cerebellar Artery-Posterior Inferior Cerebellar Artery Aneurysm With Excision and End-to-End Anastomosis: 2-Dimensional Operative Video. Operative neurosurgery (Hagerstown, Md.) Karadimas, S. K., Wu, E. M., Elarjani, T., Morcos, J. J. 2025; 28 (2): 277

  View details for DOI 10.1227/ons.0000000000001253

  View details for PubMedID 38888312

• Comparative analysis of safety and efficacy of flow diversion with and without surface modification technology, FRED-X, FRED, PED shield and PED in 386 patients: A single center experience with systematic review and network meta analysis. Journal of the neurological sciences Roy, J. M., Musmar, B., El Naamani, K., Ahmed, M. T., Kaul, A., Amaravadi, C., Sizdahkhani, S., Karadimas, S., Gooch, M. R., Jabbour, P., Rosenwasser, R., Tjoumakaris, S. I. 2025; 468: 123336

  Abstract

  The FRED-X is a newer generation flow diverting stent (FDS) with surface modification that has demonstrated favorable efficacy in treating intracranial aneurysms. Our study provides an analysis of patients treated using FRED-X compared to FRED, PED Shield and PED.This was a retrospective single center study and a systematic review with network meta analysis of patients who underwent flow diversion using FRED-X, FRED, PED Shield or PED. Multivariate logistic regression was used to assess long-term outcomes of interest- angiographic occlusion, in-stent stenosis and functional outcome at 6- and 12-month follow up.386 patients with 386 aneurysms were included. The average age of the cohort was 56.2 years, and 81 % was female. PED had significantly higher aneurysm occlusion rates compared to FRED-X at 6- and 12-months (OR: 3.03, 95 % CI: 1.36-6.62 and OR: 4.01, 95 % CI: 1.26-12.2), with higher odds of absent in-stent stenosis (OR: 9.03, 95 % CI: 3.63-23.3 and OR: 9.58, 95 % CI: 2.56-33.8) at 6- and 12-months, respectively. Rates of stroke, TIA, ICH and mortality were not significantly different across cohorts. All patients were functionally independent on follow-up. A network meta-analysis revealed no significant difference in occlusion rates among each of the included FDS.Our study revealed comparable 12-month occlusion rates and in-stent stenosis between surface modified devices, FRED-X and PED Shield. In addition, angiographic results were comparable between FRED-X and the first generation FRED, however classic PED demonstrated higher rates of angiographic occlusion with lower in-stent stenosis.

  View details for DOI 10.1016/j.jns.2024.123336

  View details for PubMedID 39700780

• STA-MCA Bypass and Excision of a Giant Partially Thrombosed Ruptured M2 Aneurysm Journal of Neurological Surgery Part B: Skull Base Karadimas, S., Ellenbogen, Y., Alshahrani, R., Radovanovic, I. 2025
• Lateral Supraorbital Translamina Terminalis Approach for Resection of a Chiasmatic Cavernoma Journal of Neurological Surgery Part B Skull Base Karadimas, S., Radovanovic, I. 2025
• Endoscopic Trans-pterional Port Approach for Microsurgical Clipping of MCA Aneurysm Journal of Neurological Surgery Part B: Skull Base Karadimas, S., Radovanovic, I. 2025
• Retrosigmoid Transtentorial Approach with Suprameatal Drilling (Kawase from below) for Gross Total Resection of a Large Petroclival Meningioma Journal of Neurological Surgery Part B: Skull Base Karadimas, S., Chandra, A., Morcos, J. J. 2025
• Lateral Supraorbital Approach for Microsurgical Clipping of Recurrent Ruptured Fetal Posterior Communicating Artery Aneurysm Initially Treated With Woven Endobridge Embolization and Flow Diversion: 2-Dimensional Operative Video. Operative neurosurgery (Hagerstown, Md.) Karadimas, S. K., Silva, M. A., Starke, R. M. 2024; 27 (6): 789

  View details for DOI 10.1227/ons.0000000000001222

  View details for PubMedID 38847515

• Complications: skull base and cerebrovascular. Neurosurgical focus Jean, W. C., Charbel, F. T., Cohen-Gadol, A. A., Couldwell, W. T., Lawton, M. T., McDermott, M., Morcos, J. J., Spetzler, R. F., van Loveren, H. R. 2024; 57 (4): E2

  Abstract

  Neurosurgical complications are a rich source for learning, but they are grossly underutilized for the purpose of surgeon education. Details of the complications, which make them all the more powerful as teaching tools, are restricted to morbidity and mortality conferences behind closed doors, and open discussions of the topic are blurred by hypotheticals in order to shield the presenters from medicolegal risks. In this issue of Neurosurgical Focus, 9 neurosurgeons were invited to present complications they encountered along with the details and specific lessons they learned. The contributors were picked for their well-known track record of skill, experience, and candor, so readers can be confident in the lessons. The video and the accompanying written article present the clinical facts. The actions that led to the complications are demonstrated in the surgical video segments. In ancient Western civilization, the seven "deadly sins" categorized and conceptualized human malfeasance, and similarly, the neurosurgical correlate of this set of sins can provide a framework for discussing the errors that lead to unexpectedly poor outcomes. Although errors in judgment and planning grow rarer with experience, errors in execution can still occur, no matter the stage of one's career. Interestingly, even though skill and experience do not eliminate complications, they may affect the lesson that the neurosurgeon takes home. The lack of open discourse on complications may slow progress in the field and set the stage for repeating mistakes. The writing and production teams hope that this work opens a rich source of learning. The video can be found here: https://stream.cadmore.media/r10.3171/2024.7.FOCUS24379.

  View details for DOI 10.3171/2024.7.FOCUS24379

  View details for PubMedID 39666345

• Microsurgical Resection of a Left Eloquent Arteriovenous Malformation Presenting With Papilledema: 3-Dimensional Operative Video. Operative neurosurgery (Hagerstown, Md.) Karadimas, S. K., Woon, C. C., Krings, T., Sheth, S. A., Morcos, J. J. 2024; 29 (1): 153

  View details for DOI 10.1227/ons.0000000000001389

  View details for PubMedID 39311600

• Use of the neuroform atlas for stenting of intracranial atherosclerotic disease: Clinical and angiographic outcomes. Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences Ellenbogen, Y., Hendriks, E. J., Karadimas, S., O'Reilly, S., Itsekzon Hayosh, Z., Alshahrani, R., Agid, R., Schaafsma, J., Krings, T., Nicholson, P. 2023: 15910199231195134

  Abstract

  Intracranial atherosclerotic disease (ICAD) is a potential cause of ischemic stroke. Treatment of ICAD can include intracranial stenting. There are specifically designed stents for this use-case; however, less is known about the off-label use of the Neuroform Atlas stent. In this study, we describe the outcomes of the Neuroform Atlas stent for treatment of ICAD.Adult patients with symptomatic ICAD failing best medical treatment undergoing elective intracranial stenting using the Neuroform Atlas stent between November 2018 and March 2021 were included. Patient demographics, procedure-related details and clinical and imaging outcomes were analyzed.Eighteen patients met the inclusion criteria, with a mean follow-up duration of 9.6 ± 6.8 (standard deviation) months. There were two procedure-related mortalities (one massive intracranial hemorrhage and one groin site complication with sepsis). Fifteen patients were alive at the 6-month follow-up, all with satisfactory stent patency on follow-up imaging without any new ischemic events. Modified Rankin Scale at latest follow-up was 1.9 (interquartile range 5).In this single-center consecutive series, intracranial stenting with the Neuroform Atlas stent was a safe and effective treatment for symptomatic ICAD patients failing best medical management.

  View details for DOI 10.1177/15910199231195134

  View details for PubMedID 37817560

• Occipital Interhemispheric Transtentorial Approach for Microsurgical Resection of a Ruptured Vermian Arteriovenous Malformation: Three-Dimensional Operative Video. World neurosurgery Karadimas, S. K., Fierstra, J., Radovanovic, I. 2022; 168: 243

  Abstract

  Cerebellar arteriovenous malformations (AVMs) are associated with higher risk of rupture compared with cerebral AVMs.1 Microsurgical resection of a ruptured AVM, measuring 3 cm in its largest dimension, within the cerebellar vermis and right parasagittal cerebellar lobe is demonstrated in Video 1. Cerebral angiography showed major supply from both superior cerebellar arteries and minor supply from a right anterior inferior cerebellar artery-posterior inferior cerebellar artery variant. Venous drainage was through a single ectatic vermian vein draining toward the torcula. Intraoperatively, a second, thrombosed, draining vein connected to the vein of Galen was identified. A right interhemispheric occipital transtentorial approach was elected over the supracerebellar infratentorial approach for early access to the superior cerebellar artery feeding arteries and for an orthogonal rather than a tangential view. The patient was positioned in an ipsilateral lateral position with the head turned 45° toward the floor allowing for gravity retraction of the ipsilateral occipital lobe. An external ventricular drain was also inserted to allow for further relaxation of the occipital lobe. Under neuronavigation guidance, the tentorium was opened allowing immediate visualization of the AVM with early control of the superior cerebellar artery arterial feeders. The AVM was removed using standard microsurgical technique, and hematoma was evacuated. Postoperative cerebral angiography demonstrated no AVM residual. The patient was discharged to a rehabilitation institute with minor residual cerebellar deficits. The patient provided written informed consent for the procedure, video recording, and publication.

  View details for DOI 10.1016/j.wneu.2022.10.009

  View details for PubMedID 36228935

• Minimally Invasive and Outpatient Aneurysm Surgery: New Concepts. Neurosurgery clinics of North America Karadimas, S., Shakil, H., Almeida, J. P., Tymianski, M., Radovanovic, I. 2022; 33 (4): 371-382

  Abstract

  Anterior circulation aneurysms have classically been treated using the pterional (PT) craniotomy. Minimally invasive alternatives to the PT craniotomy have been successfully used to treat vascular pathologies of the anterior circulation. These approaches offer smaller incisions and reduced tissue dissection, resulting in shorter hospital stay, improved cosmetic results, and comparable outcomes for aneurysm treatment compared with classic open approaches. The supraorbital, lateral supraorbital (LSO), mini-PT, minimal interhemispheric, and endoscopic transpterional port approach (ETPA) are each best suited for different aneurysm targets. Outpatient aneurysm surgery has been possible with the use of minimally invasive approaches.

  View details for DOI 10.1016/j.nec.2022.05.005

  View details for PubMedID 36229126

• Spinal cord injury and degenerative cervical myelopathy. Handbook of clinical neurology Satkunendrarajah, K., Karadimas, S. K., Fehlings, M. G. 2022; 189: 241-257

  Abstract

  Spinal cord injury (SCI) often results in impaired respiratory function. Paresis or paralysis of inspiratory and expiratory muscles can lead to respiratory dysfunction depending on the level and severity of the injury, which can affect the management and care of SCI patients. Respiratory dysfunction after SCI is more severe in high cervical injuries, with vital capacity (VC) being an essential indicator of overall respiratory health. Respiratory complications include hypoventilation, a reduction in surfactant production, mucus plugging, atelectasis, and pneumonia. Respiratory management includes mechanical ventilation and tracheostomy in high cervical SCI, while noninvasive ventilation is more common in patients with lower cervical and thoracic injuries. Mechanical ventilation can negatively impact the function of the diaphragm and weaning should start as soon as possible. Patients can sometimes be weaned from mechanical ventilation with assistance of electrical stimulation of the phrenic nerve or the diaphragm. Respiratory muscle training regimens may also improve patients' inspiratory function following SCI. Despite the critical advances in preventing, diagnosing, and treating respiratory complications, they continue to significantly affect persons living with SCI. Additional studies of interventions to reduce respiratory complications are likely to further decrease the morbidity and mortality associated with these injuries.

  View details for DOI 10.1016/B978-0-323-91532-8.00006-9

  View details for PubMedID 36031307

• Chemogenetic stimulation of proprioceptors remodels lumbar interneuron excitability and promotes motor recovery after SCI. Molecular therapy : the journal of the American Society of Gene Therapy Gao, Z., Yang, Y., Feng, Z., Li, X., Min, C., Zhu, Z., Song, H., Hu, Y., Wang, Y., He, X. 2021; 29 (8): 2483-2498

  Abstract

  Motor recovery after severe spinal cord injury (SCI) is limited due to the disruption of direct descending commands. Despite the absence of brain-derived descending inputs, sensory afferents below injury sites remain intact. Among them, proprioception acts as an important sensory source to modulate local spinal circuits and determine motor outputs. Yet, it remains unclear whether enhancing proprioceptive inputs promotes motor recovery after severe SCI. Here, we first established a viral system to selectively target lumbar proprioceptive neurons and then introduced the excitatory Gq-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADD) virus into proprioceptors to achieve specific activation of lumbar proprioceptive neurons upon CNO administration. We demonstrated that chronic activation of lumbar proprioceptive neurons promoted the recovery of hindlimb stepping ability in a bilateral hemisection SCI mouse model. We further revealed that chemogenetic proprioceptive stimulation led to coordinated activation of proprioception-receptive spinal interneurons and facilitated transmission of supraspinal commands to lumbar motor neurons, without affecting the regrowth of proprioceptive afferents or brain-derived descending axons. Moreover, application of 4-aminopyridine-3-methanol (4-AP-MeOH) that enhances nerve conductance further improved the transmission of supraspinal inputs and motor recovery in proprioception-stimulated mice. Our study demonstrates that proprioception-based combinatorial modality may be a promising strategy to restore the motor function after severe SCI.

  View details for DOI 10.1016/j.ymthe.2021.04.023

  View details for PubMedID 33895324

  View details for PubMedCentralID PMC8353208

• Mir21 modulates inflammation and sensorimotor deficits in cervical myelopathy: data from humans and animal models. Brain communications Laliberte, A. M., Karadimas, S. K., Vidal, P. M., Satkunendrarajah, K., Fehlings, M. G. 2021; 3 (1): fcaa234

  Abstract

  Degenerative cervical myelopathy is a common condition resulting from chronic compression of the spinal cord by degenerating structures of the spine. Degenerative cervical myelopathy present a wide range of outcomes, and the biological factors underlying this variability are poorly understood. Previous studies have found elevated MIR21-5p in the sub-acute and chronic neuroinflammatory environment after spinal cord injury. As chronic spinal cord neuroinflammation is a major feature of degenerative cervical myelopathy, we hypothesized that MIR21-5p may be particularly relevant to disease pathobiology, and could serve as a potential biomarker. A prospective cohort study of 69 human degenerative cervical myelopathy patients (36 male:33 female) between the ages of 30 and 78 years was performed to identify the relationship between MIR21-5p expression, symptom severity and treatment outcomes. Results from this study identified a positive correlation between elevated plasma MIR21-5p expression, initial symptom severity and poor treatment outcomes. Subsequent validation of these relationships using a mouse model of degenerative cervical myelopathy identified a similar elevation of MIR21-5p expression at 6 and 12 weeks after onset, corresponding to moderate to severe neurological deficits. To further determine how MIR21-5p affects cervical myelopathy pathobiology, this mouse model was applied to a Mir21 knockout mouse line. Deletion of the Mir21 gene preserved locomotor function on rotarod and forced swim tests, but also resulted in increased nociception based on tail flick, Von Frey filament and electrophysiological testing. Critically, Mir21 knockout mice also had reduced spinal cord inflammation, demonstrated by the reduction of Iba1+ microglia by ∼50% relative to wild-type controls. In vitro experiments using primary microglial cultures confirmed that MIR21-5p expression was greatly increased after exposure to lipopolysaccharide (pro-inflammatory), Il4 (anti-inflammatory) and hypoxia. Mir21 knockout did not appear to alter the ability of microglia to respond to these stimuli, as expression of key pro- and anti-inflammatory response genes was not significantly altered. However, target prediction algorithms identified the IL6/STAT3 pathway as a potential downstream target of MIR21-5p, and subsequent in vitro testing found that expression of components of the IL6 receptor complex, Il6ra and Il6st, were significantly higher in Mir21 knockout microglia. In aggregate, these data show that Mir21 plays a role in the progression of motor deficits and neuroinflammatory modulation in degenerative cervical myelopathy. Given this role in neuroinflammation, and its association with poor patient outcomes, MIR21-5p represents a potential therapeutic target and a new marker for prognostication.

  View details for DOI 10.1093/braincomms/fcaa234

  View details for PubMedID 33604572

  View details for PubMedCentralID PMC7878254

• The Impact of Riluzole on Neurobehavioral Outcomes in Preclinical Models of Traumatic and Nontraumatic Spinal Cord Injury: Results From a Systematic Review of the Literature. Global spine journal Tetreault, L. A., Zhu, M. P., Wilson, J. R., Karadimas, S. K., Fehlings, M. G. 2020; 10 (2): 216-229

  Abstract

  Systematic review.To evaluate the impact of riluzole on neurobehavioral outcomes in preclinical models of nontraumatic and traumatic spinal cord injury (SCI).An extensive search of the literature was conducted in Medline, EMBASE, and Medline in Process. Studies were included if they evaluated the impact of riluzole on neurobehavioral outcomes in preclinical models of nontraumatic and traumatic SCI. Extensive data were extracted from relevant studies, including sample characteristics, injury model, outcomes assessed, timing of evaluation, and main results. The SYRCLE checklist was used to assess various sources of bias.The search yielded a total of 3180 unique citations. A total of 16 studies were deemed relevant and were summarized in this review. Sample sizes ranged from 14 to 90, and injury models included traumatic SCI (n = 9), degenerative cervical myelopathy (n = 2), and spinal cord-ischemia (n = 5). The most commonly assessed outcome measures were BBB (Basso, Beattie, Besnahan) locomotor score and von Frey filament testing. In general, rats treated with riluzole exhibited significantly higher BBB locomotor scores than controls. Furthermore, riluzole significantly increased withdrawal thresholds to innocuous stimuli and tail flick latency following application of radiant heat stimuli. Finally, rats treated with riluzole achieved superior results on many components of gait assessment.In preclinical models of traumatic and nontraumatic SCI, riluzole significantly improves locomotor scores, gait function, and neuropathic pain. This review provides the background information necessary to interpret the results of clinical trials on the impact of riluzole in traumatic and nontraumatic SCI.

  View details for DOI 10.1177/2192568219835516

  View details for PubMedID 32206521

  View details for PubMedCentralID PMC7076594

• Extended Retrosigmoid Approach for the Resection of a Pontomedullary Junction Cavernous Malformation. Journal of neurological surgery. Part B, Skull base Basma, J., Nguyen, V., Sorenson, J., Michael, L. M. 2018; 79 (Suppl 5): S418-S419

  Abstract

  Objectives  To describe an extended retrosigmoid approach for the resection of a cavernoma involving the ponto-medullary junction, with emphasis on the microsurgical anatomy and technique. Design  A retrosigmoid craniotomy is performed in the lateral decubitus position and the sigmoid sinus exposed. After opening the dura, sutures are placed medial to the sinus to allow its gentle mobilization. Cerebrospinal fluid (CSF) is drained from the cisterna magna, and cerebellopontine cistern, and dynamic retraction is used over the cerebellum. Subarachnoid dissection of the cerebellopontine angle gives access to cranial nerves IX/X, VII/VIII, and VI. Inspection of the pontomedullary junction medial to the facial nerve reveals hemosiderin staining in that region. A small pial opening is made, exposing the hemorrhagic cavity. The cavernous malformation is then identified, dissected circumferentially, and resected. Photographs of the region are borrowed from Dr Rhoton's laboratory to illustrate the microsurgical anatomy. Participants  The senior author performed the surgery. The video was edited by Drs. J.B. and V.N. Outcome Measures  Outcome was assessed with extent of resection and postoperative neurological function. Results  A gross total resection of the lesion was achieved. The patient did not develop any postoperative deficits. Conclusion  Understanding the microsurgical anatomy of the cerebellopontine angle and meticulous microneurosurgical technique are necessary to achieve a complete resection of a brainstem cavernoma. The extended retrosigmoid approach provides an adequate corridor to the pontomedullary junction. The link to the video can be found at: https://youtu.be/FIKixWJT75w .

  View details for DOI 10.1055/s-0038-1669979

  View details for PubMedID 30456048

  View details for PubMedCentralID PMC6240420

• The Natural History of Degenerative Cervical Myelopathy and the Rate of Hospitalization Following Spinal Cord Injury: An Updated Systematic Review. Global spine journal Tetreault, L. A., Karadimas, S., Wilson, J. R., Arnold, P. M., Kurpad, S., Dettori, J. R., Fehlings, M. G. 2017; 7 (3 Suppl): 28S-34S

  Abstract

  Systematic review (update).Degenerative cervical myelopathy (DCM) is a degenerative spine disease and the most common cause of spinal cord dysfunction in adults worldwide. The objective of this study is to determine the natural history of DCM by updating the systematic review by Karadimas et al. The specific aims of this review were (1) to describe the natural history of DCM and (2) to determine potential risk factors of disease progression.An updated search based on a previous protocol was conducted in PubMed and the Cochrane Collaboration library for studies published between November 2012 and February 15, 2015.The updated search yielded 3 additional citations that met inclusion criteria and reported the incidence of spinal cord injury and severe disability in patients with DCM. Based on 2 retrospective cohort studies, the incidence rate of hospitalization for spinal cord injury is 13.9 per 1000 person-years in patients with cervical spondylotic myelopathy and 4.8 per 1000 person-years in patients with myelopathy secondary to ossification of the posterior longitudinal ligament (OPLL). In a third small prospective study, the risk of being wheelchair bound or bedridden was 66.7% in DCM patients with OPLL.The overall level of evidence for these estimated rates of hospitalization following spinal cord injury was rated as low.

  View details for DOI 10.1177/2192568217700396

  View details for PubMedID 29164030

  View details for PubMedCentralID PMC5684834

• Delayed decompression exacerbates ischemia-reperfusion injury in cervical compressive myelopathy. JCI insight Vidal, P. M., Karadimas, S. K., Ulndreaj, A., Laliberte, A. M., Tetreault, L., Forner, S., Wang, J., Foltz, W. D., Fehlings, M. G. 2017; 2 (11)

  Abstract

  Degenerative cervical myelopathy (DCM) is the most common progressive nontraumatic spinal cord injury. The most common recommended treatment is surgical decompression, although the optimal timing of intervention is an area of ongoing debate. The primary objective of this study was to assess whether a delay in decompression could influence the extent of ischemia-reperfusion injury and alter the trajectory of outcome in DCM. Using a DCM mouse model, we show that decompression acutely led to a 1.5- to 2-fold increase in levels of inflammatory cytokines within the spinal cord. Delayed decompression was associated with exacerbated reperfusion injury, astrogliosis, and poorer neurological recovery. Additionally, delayed decompression was associated with prolonged elevation of inflammatory cytokines and an exacerbated peripheral monocytic inflammatory response (P < 0.01 and 0.001). In contrast, early decompression led to resolution of reperfusion-mediated inflammation, neurological improvement, and reduced hyperalgesia. Similar findings were observed in subjects from the CSM AOSpine North America and International studies, where delayed decompressive surgery resulted in poorer neurological improvement compared with patients with an earlier intervention. Our data demonstrate that delayed surgical decompression for DCM exacerbates reperfusion injury and is associated with ongoing enhanced levels of cytokine expression, microglia activation, and astrogliosis, and paralleled with poorer neurological recovery.

  View details for DOI 10.1172/jci.insight.92512

  View details for PubMedID 28570271

  View details for PubMedCentralID PMC5453710

• Rewiring of spinal respiratory neural network via cervical glutamatergic interneurons preserves respiratory function in progressive cervical spinal cord compression injury (CSM) Satkunendrarajah, K., Karadimas, S. K., Khazaei, M., Samson, P., Fehlings, M. G. FEDERATION AMER SOC EXP BIOL. 2016

  View details for Web of Science ID 000406444700346

• Cervical neurons control locomotion Karadimas, S., Satkunendrarajah, K., Sivakumaran, S., Gosgnach, S., Fehlings, M. G. FEDERATION AMER SOC EXP BIOL. 2016

  View details for Web of Science ID 000406444700319

• Riluzole promotes motor and respiratory recovery associated with enhanced neuronal survival and function following high cervical spinal hemisection. Experimental neurology Satkunendrarajah, K., Nassiri, F., Karadimas, S. K., Lip, A., Yao, G., Fehlings, M. G. 2016; 276: 59-71

  Abstract

  Cervical spinal cord injury (SCI) can result in devastating functional deficits that involve the respiratory and hand function. The mammalian spinal cord has limited ability to regenerate and restore meaningful functional recovery following SCI. Riluzole, 2-amino-6-trifluoromethoxybenzothiazole, an anti-glutamatergic drug has been shown to reduce excitotoxicity and confer neuroprotection at the site of injury following experimental SCI. Based on promising preclinical studies, riluzole is currently under Phase III clinical trial for the treatment of SCI (ClinicalTrials.gov: NCT01597518). Riluzole's anti-glutamatergic role has the potential to regulate neuronal function and provide neuroprotection and influence glutamatergic connections distal to the initial injury leading to enhanced functional recovery following SCI. In order to investigate this novel role of riluzole we used a high cervical hemisection model of SCI, which interrupts all descending input to motoneurons innervating the ipsilateral forelimb and diaphragm muscles. Following C2 spinal cord hemisection, animals were placed into one of two groups: one group received riluzole (8 mg/kg) 1 h after injury and every 12 h thereafter for 7 days at 6 mg/kg, while the second group of injured rats received vehicle solution for the same duration of time. A third group of sham injured rats underwent a C2 laminectomy without hemisection and served as uninjured control rats. Interestingly, this study reports a significant loss of motoneurons within the cervical spinal cord caudal to C2 hemisection injury. Disruption of descending input led to a decrease in glutamatergic synapses and motoneurons caudal to the injury while riluzole treatment significantly limited this decline. Functionally, Hoffmann reflex recordings revealed an increase in the excitability of the remaining ipsilateral cervical motoneurons and significant improvements in skilled and unskilled forelimb function and respiratory motor function in the riluzole-treated animals. In conclusion, using a C2 hemisection injury model, this study provides novel evidence of motoneuron loss caudal to the injury and supports riluzole's capacity to promote neuronal preservation and function of neural network caudal to the SCI resulting in early and sustained functional improvements.

  View details for DOI 10.1016/j.expneurol.2015.09.011

  View details for PubMedID 26394202

• Degenerative Cervical Myelopathy: Epidemiology, Genetics, and Pathogenesis. Spine Nouri, A., Tetreault, L., Singh, A., Karadimas, S. K., Fehlings, M. G. 2015; 40 (12): E675-93

  Abstract

  Review.To formally introduce "degenerative cervical myelopathy" (DCM) as the overarching term to describe the various degenerative conditions of the cervical spine that cause myelopathy. Herein, the epidemiology, pathogenesis, and genetics of conditions falling under this hypernym are carefully described.Nontraumatic, degenerative forms of cervical myelopathy represent the commonest cause of spinal cord impairment in adults and include cervical spondylotic myelopathy, ossification of the posterior longitudinal ligament, ossification of the ligamentum flavum, and degenerative disc disease. Unfortunately, there is neither a specific term nor a specific diagnostic International Classification of Diseases, Tenth Revision code to describe this collection of clinical entities. This has resulted in the inconsistent use of diagnostic terms when referring to patients with myelopathy due to degenerative disease of the cervical spine.Narrative review.The incidence and prevalence of myelopathy due to degeneration of the spine are estimated at a minimum of 41 and 605 per million in North America, respectively. Incidence of cervical spondylotic myelopathy-related hospitalizations has been estimated at 4.04/100,000 person-years, and surgical rates seem to be rising. Pathophysiologically, myelopathy results from static compression, spinal malalignment leading to altered cord tension and vascular supply, and dynamic injury mechanisms. Occupational hazards, including transportation of goods by weight bearing on top of the head, and other risk factors may accelerate DCM development. Potential genetic factors include those related to MMP-2 and collagen IX for degenerative disc disease, and collagen VI and XI for ossification of the posterior longitudinal ligament. In addition, congenital anomalies including spinal stenosis, Down syndrome, and Klippel-Feil syndrome may predispose to the development of DCM.Although DCMs can present as separate diagnostic entities, they are highly interrelated, frequently manifest concomitantly, present similarly from a clinical standpoint, and seem to be in part a response to compensate and improve stability due to progressive age and wear of the cervical spine. The use of the term "degenerative cervical myelopathy" is advocated.5.

  View details for DOI 10.1097/BRS.0000000000000913

  View details for PubMedID 25839387

• Pathobiology of cervical spondylotic myelopathy. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society Karadimas, S. K., Gatzounis, G., Fehlings, M. G. 2015; 24 Suppl 2: 132-8

  Abstract

  In this narrative review, we aim to outline what is currently known about the pathophysiology of cervical spondylotic myelopathy (CSM), the most common cause of spinal cord dysfunction. In particular, we note the unique factors that distinguish it from acute spinal cord injury. Despite its common occurrence, the reasons why some patients develop severe symptomatology while others have few or no symptoms despite radiographic evidence confirming similar degrees of compression is poorly understood. Neither is there a clear understanding of why certain patients have a stable clinical myelopathy and others present with only mild myelopathy. Moreover, the precise molecular mechanisms which contribute to the pathogenesis of the disease are incompletely understood. The current treatment method is decompression of the spinal cord but a lack of clinically relevant models of CSM have hindered the understanding of the full pathophysiology which would aid the development of new therapeutic avenues of investigation. Further elucidation of the role of ischemia, currently a source of debate, as well as the complex cascade of biomolecular events as a result of the unique pathophysiology in this disease will pave the way for further neuroprotective strategies to be developed to attenuate the physiological consequences of surgical decompression and augment its benefits.

  View details for DOI 10.1007/s00586-014-3264-4

  View details for PubMedID 24626958

• Bilateral contusion-compression model of incomplete traumatic cervical spinal cord injury. Journal of neurotrauma Forgione, N., Karadimas, S. K., Foltz, W. D., Satkunendrarajah, K., Lip, A., Fehlings, M. G. 2014; 31 (21): 1776-88

  Abstract

  Despite the increasing incidence and prevalence of cervical spinal cord injury (cSCI), we lack clinically relevant animal models that can be used to study the pathomechanisms of this injury and test new therapies. Here, we characterize a moderate cervical contusion-compression model in rats that is similar to incomplete traumatic cSCI in humans. We characterized the effects of 18-g clip-compression injury at cervical level C6 over an 8-week recovery period. Using Luxol fast blue/hematoxylin-eosin staining in combination with quantitative stereology, we determined that 18-g injury results in loss of gray matter (GM), white matter (WM), as well as in cavity formation. Magnetization transfer and T2-weighted magnetic resonance imaging were used to analyze lesion dynamics in vivo. This analysis demonstrated that both techniques are able to differentiate between the injury epicenter, subpial rim, and WM distal to the injury. Neurobehavioral assessment of locomotor function using Basso, Beattie, and Bresnahan (BBB) scoring and CatWalk revealed limited recovery from clip-compression injury at C6. Testing of forelimb function using grip strength demonstrated significant forelimb dysfunction, similar to the loss of upper-limb motor function observed in human cSCI. Sensory-evoked potentials recorded from the forelimb and Hoffman reflex recorded from the hindlimb confirmed the fore- and hindlimb deficits observed in our neurobehavioral analysis. Here, we have characterized a clip-compression model of incomplete cSCI that closely models this condition in humans. This work directly addresses the current lack of clinically relevant models of cSCI and will thus contribute to improved success in the translation of putative therapies into the clinic.

  View details for DOI 10.1089/neu.2014.3388

  View details for PubMedID 24949719

  View details for PubMedCentralID PMC4186801

• Delayed administration of a bio-engineered zinc-finger VEGF-A gene therapy is neuroprotective and attenuates allodynia following traumatic spinal cord injury. PloS one Figley, S. A., Liu, Y., Karadimas, S. K., Satkunendrarajah, K., Fettes, P., Spratt, S. K., Lee, G., Ando, D., Surosky, R., Giedlin, M., Fehlings, M. G. 2014; 9 (5): e96137

  Abstract

  Following spinal cord injury (SCI) there are drastic changes that occur in the spinal microvasculature, including ischemia, hemorrhage, endothelial cell death and blood-spinal cord barrier disruption. Vascular endothelial growth factor-A (VEGF-A) is a pleiotropic factor recognized for its pro-angiogenic properties; however, VEGF has recently been shown to provide neuroprotection. We hypothesized that delivery of AdV-ZFP-VEGF--an adenovirally delivered bio-engineered zinc-finger transcription factor that promotes endogenous VEGF-A expression--would result in angiogenesis, neuroprotection and functional recovery following SCI. This novel VEGF gene therapy induces the endogenous production of multiple VEGF-A isoforms; a critical factor for proper vascular development and repair. Briefly, female Wistar rats--under cyclosporin immunosuppression--received a 35 g clip-compression injury and were administered AdV-ZFP-VEGF or AdV-eGFP at 24 hours post-SCI. qRT-PCR and Western Blot analysis of VEGF-A mRNA and protein, showed significant increases in VEGF-A expression in AdV-ZFP-VEGF treated animals (p<0.001 and p<0.05, respectively). Analysis of NF200, TUNEL, and RECA-1 indicated that AdV-ZFP-VEGF increased axonal preservation (p<0.05), reduced cell death (p<0.01), and increased blood vessels (p<0.01), respectively. Moreover, AdV-ZFP-VEGF resulted in a 10% increase in blood vessel proliferation (p<0.001). Catwalk™ analysis showed AdV-ZFP-VEGF treatment dramatically improves hindlimb weight support (p<0.05) and increases hindlimb swing speed (p<0.02) when compared to control animals. Finally, AdV-ZFP-VEGF administration provided a significant reduction in allodynia (p<0.01). Overall, the results of this study indicate that AdV-ZFP-VEGF administration can be delivered in a clinically relevant time-window following SCI (24 hours) and provide significant molecular and functional benefits.

  View details for DOI 10.1371/journal.pone.0096137

  View details for PubMedID 24846143

  View details for PubMedCentralID PMC4028194

• Synergistic effects of self-assembling peptide and neural stem/progenitor cells to promote tissue repair and forelimb functional recovery in cervical spinal cord injury. Biomaterials Iwasaki, M., Wilcox, J. T., Nishimura, Y., Zweckberger, K., Suzuki, H., Wang, J., Liu, Y., Karadimas, S. K., Fehlings, M. G. 2014; 35 (9): 2617-29

  Abstract

  While neural stem/progenitor cells (NPCs) show promise for traumatic spinal cord injury (SCI), their efficacy in cervical SCI remains to be established. Moreover, their application to SCI is limited by the challenges posed by the lesion including the glial scar and the post-traumatic cavitation. Given this background, we sought to examine the synergistic effect of self-assembling peptide (SAP) molecules, designed to optimize the post-traumatic CNS microenvironment, and NSCs in a clinically-relevant model of contusive/compressive cervical SCI. We injected K2(QL)6K2 (QL6) SAPs into the lesion epicenter 14 days after bilateral clip compression-induced cervical SCI in rats, combined with simultaneous transplantation of neural stem/progenitor cells (NPCs) intraspinally adjacent to the lesion epicenter. The QL6 SAPs reduced the volume of cystic cavitation in the spinal cord lesion. Simultaneously engrafted NPCs preserved motor neurons and attenuated perilesional inflammation. The combination of QL6 and NPCs promoted forelimb neurobehavioral recovery and was associated with significant improvement in forelimb print area and stride length. In summary, we report for the first time histologic and functional benefits in a clinically-relevant model of cervical SCI through the synergistic effects of combined SAP and NPCs.

  View details for DOI 10.1016/j.biomaterials.2013.12.019

  View details for PubMedID 24406216

• Riluzole attenuates neuropathic pain and enhances functional recovery in a rodent model of cervical spondylotic myelopathy. Neurobiology of disease Moon, E. S., Karadimas, S. K., Yu, W. R., Austin, J. W., Fehlings, M. G. 2014; 62: 394-406

  Abstract

  Cervical spondylotic myelopathy (CSM) is the commonest cause of spinal cord impairment worldwide and despite surgical treatment, it is commonly associated with chronic neuropathic pain and neurological impairment. Based on data suggesting a key role of sodium and glutamate mediated cellular injury in models of spinal cord compression, we examined whether riluzole, a sodium channel/glutamate blocker, could improve neurobehavioral outcomes in a rat model of CSM. To produce chronic progressive compression of the cervical spinal cord, we used an established model of graded mechanical cord compromise developed in our laboratory. The chronic (8weeks) mechanical compression of the cervical spinal cord resulted in persistent mechanical allodynia and thermal hyperalgesia at 8weeks. Moreover, we found increased expression of phosphorylated NR1 and NR2B in the dorsal horns as well as astrogliosis and increased microglia expression in the dorsal horns after mechanical compression. Following daily systemic administration for 7weeks after the induction of compression, riluzole (8mg/kg) significantly attenuated forelimb and hindlimb mechanical allodynia and alleviated thermal hyperalgesia in the tail. Importantly, riluzole led to a decrease in swing phase duration, an increase in hind leg swing speed and an increase paw intensity in gait analysis. Riluzole also decreased the number of phosphorylated NR1 and phosphorylated NR2B positive cells in the dorsal horns and the microglia activation in the dorsal horns. Together, our results indicate that systemic riluzole administration during chronic cervical spinal cord compression is effective at protecting spinal cord tissue, preserving neurobehavioral function and alleviating neuropathic pain, possibly by decreasing NMDA receptor phosphorylation in astrocytes and by eliminating microglia activation. As such, riluzole represents a promising clinical treatment for CSM.

  View details for DOI 10.1016/j.nbd.2013.10.020

  View details for PubMedID 24184328

• Pathophysiology and natural history of cervical spondylotic myelopathy. Spine Karadimas, S. K., Erwin, W. M., Ely, C. G., Dettori, J. R., Fehlings, M. G. 2013; 38 (22 Suppl 1): S21-36

  Abstract

  This study is a combination of narrative and systematic review.Clinicians who deal with cervical spondylotic myelopathy (CSM) should be up-to-date with the emerging knowledge related to the cascade of pathobiological secondary events that take place under chronic cervical spinal cord compression. Moreover, by performing a systematic review, we aim to (1) describe the natural history and (2) determine potential risk factors that affect the progression of CSM.The pathophysiology, natural history, as well as the factors associated with clinical deterioration have not been fully described in CSM.For the first part of the study, a literature review was performed. To answer key questions 1 and 2 of the second goal, a systematic search was conducted in PubMed and the Cochrane Collaboration Library for articles published between January 1, 1956, and November 7, 2012. We included all articles that described the progression and outcomes of CSM for which no surgical intervention was given.By performing a narrative literature review, we found that the assumption that acute traumatic spinal cord injury and CSM share a similar series of cellular and molecular secondary injury events was made in the past. However, recent advances in basic research have shown that the chronic mechanical compression results in secondary injury mechanisms that have distinct characteristics regarding the nature and the temporal profile compared with those of spinal cord injury. For the purpose of the systematic review, 10 studies yielding 16 publications met inclusion criteria for key questions 2 and 3. Moderate-strength evidence related to the natural history of CSM suggests that 20% to 60% of patients will deteriorate neurologically over time without surgical intervention. Finally, there is low-strength evidence indicating that the area of circumferential compression is associated with deteriorating neurological symptoms.CSM has unique pathobiological mechanisms that mainly remain unexplored. Although the natural history of CSM can be mixed, surgical intervention eliminates the chances of the neurological deterioration. EVIDENCE-BASED CLINICAL RECOMMENDATIONS:Evidence concerning the natural history of CSM suggests that 20% to 60% of patients will deteriorate neurologically over time without surgical intervention. Therefore, we recommend that patients with mild CSM be counseled regarding the natural history of CSM and have the option of surgical decompression explained.Moderate.Strong. SUMMARY STATEMENTS: Chronic compression of the spinal cord results in progressive neural cell loss related to secondary mechanisms including apoptosis, neuroinflammation, and vascular disruption.

  View details for DOI 10.1097/BRS.0b013e3182a7f2c3

  View details for PubMedID 23963004

• Clinical evaluation of a neuroprotective drug in patients with cervical spondylotic myelopathy undergoing surgical treatment: design and rationale for the CSM-Protect trial. Spine Fehlings, M. G., Wilson, J. R., Karadimas, S. K., Arnold, P. M., Kopjar, B. 2013; 38 (22 Suppl 1): S68-75

  Abstract

  Descriptive article and narrative review.To explain the rationale and design of the cervical spondylotic myelopathy (CSM)-Protect clinical trial that aims to elucidate the efficacy and safety of riluzole in the context of CSM.CSM is the most common cause of spinal cord-related dysfunction internationally. Although surgery is effective in preventing the progression of impairment, and in some cases improving functional outcomes, many patients continue to exhibit significant disability in the postoperative setting. Evidence from preclinical studies suggests that glutamate-related excitotoxicity may contribute to the pathology of CSM and that administration of the sodium and glutamate-blocking medication riluzole, when combined with spinal cord decompression, may mitigate this effect and improve neurobehavioral outcomes. Although riluzole is FDA approved and has been shown to be safe and effective in the context of amyotrophic lateral sclerosis, its efficacy and safety in the context of CSM remain unknown.Descriptive article with narrative review of the literature.In addition to providing pertinent preclinical background on the topic, this descriptive article and narrative review discusses the design and current status of an ongoing phase III randomized controlled trial evaluating the efficacy and safety of riluzole, combined with surgical decompression, in the treatment of CSM.On the basis of current projections, we estimate that the interim analysis for this study will take place in the spring of 2014, at which time an adaptive sample size adjustment may take place.

  View details for DOI 10.1097/BRS.0b013e3182a7e9b0

  View details for PubMedID 23962993

• Cervical spondylotic myelopathy: the clinical phenomenon and the current pathobiology of an increasingly prevalent and devastating disorder. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry Kalsi-Ryan, S., Karadimas, S. K., Fehlings, M. G. 2013; 19 (4): 409-21

  Abstract

  Cervical spondylotic myelopathy (CSM) is a common disorder involving chronic progressive compression of the cervical spinal cord due to degenerative disc disease, spondylosis, or other degenerative pathology. CSM is the most common form of spinal cord impairment and causes functional decline leading to reduced independence and quality of life. Despite a sound understanding of the disease process, clinical presentation and management, a universal definition of CSM and a standardized index of severity are not currently used universally. Work is required to develop a definition and establish clinical predictors of progression to improve management of CSM. Despite advances in decompressive and reconstructive surgery, patients are often left with residual disability. Gaps in knowledge of the pathobiology of CSM have limited therapeutic advances to complement surgery. Although the histopathologic and pathophysiologic similarities between CSM and traumatic spinal cord injury have long been acknowledged, the unique pathomechanisms of CSM remain unexplored. Increased efforts to elucidate CSM pathobiology could lead to the discovery of novel therapeutic targets for human CSM and other spinal cord diseases. Here, the natural history of CSM, epidemiology, clinical presentation, and current methods of clinical management are reported, along with the current state of basic scientific research in the field.

  View details for DOI 10.1177/1073858412467377

  View details for PubMedID 23204243

• A novel experimental model of cervical spondylotic myelopathy (CSM) to facilitate translational research. Neurobiology of disease Karadimas, S. K., Moon, E. S., Yu, W. R., Satkunendrarajah, K., Kallitsis, J. K., Gatzounis, G., Fehlings, M. G. 2013; 54: 43-58

  Abstract

  Cervical spondylotic myelopathy (CSM) is the most common form of spinal cord impairment in adults. However critical gaps in our knowledge of the pathobiology of this disease have limited therapeutic advances. To facilitate progress in the field of regenerative medicine for CSM, we have developed a unique, clinically relevant model of CSM in rats. To model CSM, a piece of synthetic aromatic polyether, to promote local calcification, was implanted microsurgically under the C6 lamina in rats. We included a sham group in which the material was removed 30s after the implantation. MRI confirmed postero-anterior cervical spinal cord compression at the C6 level. Rats modeling CSM demonstrated insidious development of a broad-based, ataxic, spastic gait, forelimb weakness and sensory changes. No neurological deficits were noted in the sham group during the course of the study. Spasticity of the lower extremities was confirmed by a significantly greater H/M ratio in CSM rats in H reflex recordings compared to sham. Rats in the compression group experienced significant gray and white matter loss, astrogliosis, anterior horn cell loss and degeneration of the corticospinal tract. Moreover, chronic progressive posterior compression of the cervical spinal cord resulted in compromise of the spinal cord microvasculature, blood-spinal cord barrier disruption, inflammation and activation of apoptotic signaling pathways in neurons and oligodendrocytes. Finally, CSM rats were successfully subjected to decompressive surgery as confirmed by MRI. In summary, this novel rat CSM model reproduces the chronic and progressive nature of human CSM, produces neurological deficits and neuropathological features accurately mimicking the human condition, is MRI compatible and importantly, allows for surgical decompression.

  View details for DOI 10.1016/j.nbd.2013.02.013

  View details for PubMedID 23466695

• Immunohistochemical profile of NF-κB/p50, NF-κB/p65, MMP-9, MMP-2, and u-PA in experimental cervical spondylotic myelopathy. Spine Karadimas, S. K., Klironomos, G., Papachristou, D. J., Papanikolaou, S., Papadaki, E., Gatzounis, G. 2013; 38 (1): 4-10

  Abstract

  The immunohistochemical profile of nuclear factor-κ B (NF-κB)/p50, NF-κB/p65, matrix metalloproteinase (MMP)-9, MMP-2, and urokinase-type plasminogen activator (u-PA) proteins was examined in spinal cord tissues coming from rabbits, which underwent chronic cervical spinal cord compression.To study the potential role of NF-κB and extracellular matrix proteins under the chronic mechanical compression of the cervical spinal cord.Cervical spondylotic myelopathy (CSM) is the most common cause of spinal cord dysfunction among adults older than 55 years. Neuronal loss, myelin destruction, axonal degeneration, and glial scar formation are the principal neuropathological features of CSM. However, the biologic pathways that lead to these features remain unclear.In this study, we used a new animal experimental model of CSM developed in our laboratory. Briefly, after posterior cervical laminectomy, gradual and progressive compression (during 20 weeks) was achieved by introducing a piece of aromatic polyether (0.07 mm thick) under the C6 lamina in 15 New Zealand rabbits. In control animals (n = 15), the aromatic polyether was implanted and then removed after 60 seconds (sham operation). The immunoreactivity of p50 and p65 subunits of NF-kB, as well as that of MMP-2, MMP-9, and u-PA, was evaluated in paraffin-embedded spinal cord sections coming from both groups. The evaluation was performed using immunohistochemistry technique and the results were analyzed using SPSS for Windows, release 12.0 (SPSS Inc., Chicago, IL).Increased immunoreactivity of both NF-κB subunits, p50 and p65, as well as MMP-2, MMP-9, and u-PA was demonstrated in animals with CSM in comparison with controls. Statistical analysis of the results revealed strong positive correlation between NF-κB subunits immunoreactivity and that of MMP-9, MMP-2, and u-PA.There is a strong correlation between the immunoexpression of NF-κB/p50, NF-κB/p65, MMP-2, MMP-9, u-PA, and CSM.

  View details for DOI 10.1097/BRS.0b013e318261ea6f

  View details for PubMedID 22673181

• The Sodium Channel/Gluatamate Blocker Riluzole is Complementary to Decompression in a Preclinical Experimental Model of Cervical Spondylotic Myelopathy (CSM): Implications for Translational Clinical Application Karadimas, S., Moon, E., Fehlings, M. G. LIPPINCOTT WILLIAMS & WILKINS. 2012: E543

  View details for DOI 10.1227/01.neu.0000417691.81552.81

  View details for Web of Science ID 000307109300019

• New experimental rabbit animal model for cervical spondylotic myelopathy. Spinal cord Klironomos, G., Karadimas, S., Mavrakis, A., Mirilas, P., Savvas, I., Papadaki, E., Papachristou, D. J., Gatzounis, G. 2011; 49 (11): 1097-102

  Abstract

  Cervical spondylotic myelopathy (CSM) represents the most commonly acquired cause of spinal cord dysfunction among individuals over 55 years old. The pathophysiology of the disease involves static and dynamic mechanical factors, which are the result of chronic degeneration. The clinical course of the disease remains unpredictable. In the past, many experimental animal models have been developed to study the cellular and molecular mechanisms underlining the pathophysiology of the disease.To create a new animal model of CSM, which will reproduce the temporal course of the disease and the local microenvironment at the site of spinal cord compression.We performed posterior laminectomy to New Zealand rabbits at the level of C7, and a thin sheet (5-7 μm) of aromatic polyether was implanted with microsurgical technique at the epidural space underneath C5-C6 laminae. Motor function evaluation was performed after the operation and once a week thereafter.After 20 weeks, the animals were killed, and the histological evaluation of spinal cord at the site of compression above and below it, using eosin hematoxylin, immonohistochemistry and Kluver-Barrera techniques reveals axonal swelling and demyelination, interstitial edema and myelin sheet fragmentation. Moreover, histological evaluation of C5 and C6 laminae reveals osteophyte formation.We believe that this CSM model reproduces the temporal evolution of the disease and creates a local microenvironment at the site of spinal cord compression, which shares the same characteristics with that of human disease.

  View details for DOI 10.1038/sc.2011.71

  View details for PubMedID 21788956

• The role of oligodendrocytes in the molecular pathobiology and potential molecular treatment of cervical spondylotic myelopathy. Current medicinal chemistry Karadimas, S. K., Gialeli, C. H., Klironomos, G., Tzanakakis, G. N., Panagiotopoulos, E., Karamanos, N. K., Gatzounis, G. 2010; 17 (11): 1048-58

  Abstract

  Cervical spondylotic myelopathy (CSM) is a very common and debilitating disease; however, its underlying pathocellular process remains uncertain. Attempts have been made to reproduce CSM in experimental animal models in order to deepen the knowledge on the molecular pathobiology of this disease. The up-to-date observations have established the apoptosis of oligodendrocytes (OLGs) as the principal pathocellular process of CSM. Since favorable neurological recovery cannot be obtained in afflicted patients, even after the decompression surgery, elucidation of the apoptotic cascade in OLGs may unveil possible molecular treatments which could inhibit demyelination and ameliorate the neurological deficits. Moreover, additional therapeutic benefits may include improvement of myelin self-repair capability by stimulating OLG progenitor cells to become mature and finally, myelinating OLGs. This review focuses on the factors and mechanisms of crucial importance for developing antiapoptotic treatments. Critical evaluations of the role of OLGs in molecular pathobiology of CSM as well as strategies for potential remyelination of CSM are also provided. The analyses and evaluations of the experimental findings can possibly lead to treatment of CSM as well as to development of novel biopharmacenticals.

  View details for DOI 10.2174/092986710790820598

  View details for PubMedID 20156160