- Email: [email protected]
Intravenous Stem Cell Therapy for High-Grade Aneurysmal Subarachnoid Hemorrhage: Case Report and Literature Review
Case Report
Intravenous Stem Cell Therapy for High-Grade Aneurysmal Subarachnoid Hemorrhage: Case Report and Literature Review Marie-Christine Brunet1, Stephanie H. Chen1, Priyank Khandelwal4, Joshua M. Hare1, Robert M. Starke1,2, Eric C. Peterson1, Dileep R. Yavagal1,3
Key words Aneurysm - Stem cells - Stroke - Subarachnoid hemorrhage -
Abbreviations and Acronyms MSC: Mesenchymal stem cell SAH: Subarachnoid hemorrhage From the Departments of 1Neurological Surgery, 2Radiology, and 3Neurology, University of Miami Miller School of Medicine, Miami, Florida; and 4Department of Neurological Surgery, New Jersey Medical School, Newark, New Jersey, USA To whom correspondence should be addressed: Dileep R. Yavagal, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2019) 128:573-575. https://doi.org/10.1016/j.wneu.2019.04.055 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
INTRODUCTION Aneurysmal subarachnoid hemorrhage (SAH) affects >30,000 patients every year in the United States. Despite a progressive decrease in case-fatality rate after SAH during the last 3 decades due to more accurate diagnostics and improved management, mortality (30%e40%) and morbidity remain high; >15%e20% of survivors experience severe physical, neurologic, and psychological deficits associated with significant loss of quality of life.1-3 Aneurysm rupture results in blood extravasation into the subarachnoid space, which triggers multiple pathophysiologic mechanisms, including cerebral edema, increased intracranial pressure, vasospasm, influxes of immune cells, and decreases in cerebral perfusion and oxygen tension.2 These pathophysiologic processes are highly amplified in Hunt and Hess grade 4e5 SAH and lead to dismal functional outcomes despite early and effective
- BACKGROUND:
Aneurysmal subarachnoid hemorrhage (SAH) is associated with high mortality (30%e40%) and morbidity with long-term physical, neurologic, and psychological impairments; most patients present with high initial Hunt and Hess grade. In view of the great need for efficacious therapies for highgrade SAH, recent animal studies have demonstrated improved outcomes with administration of mesenchymal stem cells (MSCs) as a potential neuroregenerative strategy. We present the first case of human intravenous administration of MSCs after aneurysmal SAH.
- CLINICAL
PRESENTATION: An 80-year-old man presented with sudden severe headache with nausea and vomiting. Computed tomography demonstrated SAH with hydrocephalus from a ruptured basilar tip aneurysm. Initial examination of the patient showed Hunt and Hess grade 5 and World Federation of Neurosurgical Societies grade 5. The patient was treated with external ventricular drain placement and coiling of aneurysm. The patient received an infusion of intravenous bone marrowederived allogeneic MSCs on day 3 postbleed. The patient made a better recovery than anticipated with a modified Rankin Scale score of 3 at 6 months.
- CONCLUSIONS:
Several studies using models of ischemic brain injury have found that administration of MSCs may improve functional neurologic recovery and decrease brain lesion volume. Although there have been limited human studies in patients with stroke, the role of stem cell therapy for aneurysmal SAH remains unclear. This is the first case of use of MSCs in a patient for treatment of aneurysmal SAH. In conjunction with the promising results in animal studies, this encouraging preliminary case report supports the need for additional clinical trials.
aneurysm occlusion and modern neurocritical care. In view of the great need for efficacious therapies for highgrade SAH, few recent animal studies have demonstrated improved outcome with administration of mesenchymal stem cells (MSCs) as a regenerative strategy. We present the first case of human intravenous administration of MSCs.
vomiting. The patient quickly became unconscious and was brought to another hospital, where brain computed tomography scan demonstrated SAH with hydrocephalus. The patient progressed to a comatose state and was transferred to our service for further management.
Examination CASE DESCRIPTION History An 80-year-old man with a past medical history of diabetes, hypertension, and cardiac bypass experienced sudden onset of severe headache with nausea and
WORLD NEUROSURGERY 128: 573-575, AUGUST 2019
Initial examination revealed an intubated patient with flexor posturing to pain, 2- to 3-mm nonreactive pupils, positive corneal reflexes, and no gag reflex. This examination correlated with Hunt and Hess grade 5 and World Federation of Neurosurgical Societies grade 5.
www.journals.elsevier.com/world-neurosurgery
573
CASE REPORT MARIE-CHRISTINE BRUNET ET AL.
Therapeutic Intervention An emergent external ventricular drain was placed to treat hydrocephalus. After the external ventricular drain was in place, the patient was transferred to the neurointerventional suite for emergency diagnostic cerebral angiography and potential aneurysm embolization. Cerebral angiography showed a dysmorphic wide-based basilar tip aneurysm measuring 11 mm 8 mm. This aneurysm was considered to be the source of SAH, and successful stent-assisted coiling was performed. MSC Therapy An emergency compassionate use (expanded access) investigational and unlabeled new drug authorization for this single patient was obtained from the U.S. Food and Drug Administration for infusion of intravenous bone marrowederived allogeneic MSCs. The MSCs were produced by the Good Manufacturing Practiceecertified cell manufacturing facility at Interdisciplinary Stem Cell Institute at the University of Miami Miller School of Medicine, Miami, Florida. The source of the cells was healthy donors 18e 40 years of age. After obtaining institutional review board approval and informed consent, on day 3 postbleed, the patient received 100 million allogeneic human MSCs in 80 mL via intravenous infusion at a rate of 2 mL/minute over 45 minutes. No cell-related allergic or any other adverse effect was observed during the cell infusion or 24 hours after infusion. Clinical Outcome The patient was intubated and remained stable for 2 weeks with extension of all extremities; decerebrate posturing. During hospitalization, the patient underwent placement of an inferior vena cava filter for deep venous thrombosis, tracheostomy tube, percutaneous gastrojejunostomy feeding tube, and ventriculoperitoneal shunt after failure to wean the external ventricular drain. Three weeks after SAH, the patient began to show mild improvements in consciousness level with eye opening and withdrawal of the upper extremities. At 5 weeks, the patient’s eyes were opening spontaneously, and he was tracking and following commands intermittently. The patient was discharged to rehabilitation at 5 weeks. Following rehabilitation, the patient had regained the
574
www.SCIENCEDIRECT.com
STEM CELL INFUSION FOR ANEURYSMAL SAH
ability to speak and was caring for himself with some assistance; his overall modified Rankin Scale score at 6 months was 3. DISCUSSION Several studies using animal models of ischemic stroke, intracranial hemorrhage, and SAH have found that different types of stem cells have the potential to induce or improve functional recovery after brain injury.4-11 However, the results in human clinical trials have remained mixed. The STARTING (Stem cell Application Researches and Trials In NeuroloGy) trial randomly assigned 85 patients to intravenous autologous culture-expanded MSCs or control and found a significantly lower modified Rankin Scale score in the MSC group compared with the control group.12 However, in the InveST (Intravenous Autologous Bone Marrow Mononuclear Cell Therapy for Ischemic Stroke) trial, investigators found no difference in neurologic function at 180 days or infarct volume between patients infused with intravenous autologous bone marrow cells and control subjects.13 Although this trial failed to show effectiveness, there were no significant differences in adverse outcomes, such as findings of tumor growth on positron emission tomography or seizures on electroencephalography. Most recently, a meta-analysis of 9 studies (194 patients and 191 control subjects) by Detante et al.14 suggested that cell therapy had an overall beneficial effect on outcomes at 6 months. Additionally, the safety profile appeared to be benign with only rare adverse events that were self-limited and resolved spontaneously or with appropriate management. The most common events were seizures, headache, and events associated with procedures used for administering these therapies.15 Despite this trend toward improvement across various domains of functional impairment in patients with stroke, it is still very difficult to draw any meaningful conclusion given the high level of heterogeneity among studies and the small number of patients involved. This heterogeneity is due to the baseline differences in patients as well as differences in cell types used and the route, dose, and time of administration that vary from 1 trial to another.15 In a
meta-analysis by Nagpal et al.,6 the most common route of delivery of stem cells was intravenous followed by intracerebral and intra-arterial. To target the brain, stem cells have also been applied through the nasal route.16 It was demonstrated that in neonatal mice with hypoxia-ischemia brain injury, intranasal treatment with MSCs significantly decreased brain damage and improved functional outcome, and MSCs were capable of migrating selectively from the cribriform plate toward the ipsilateral cerebral lesion site in 2e24 hours.16 Several mechanisms have been explored to explain the positive pathophysiologic effects of MSC in stroke and SAH models. Similar to ischemic stroke, SAH results in the abolishment of the blood-brain barrier by the release of matrix metalloproteinases and other proteases from endothelial cells. This leads to the infiltration and generation of reactive oxygen species and inflammation, which result in irreversible brain injury.1 It was noted that the number of surviving grafted or differentiated cells was very small and therefore may not be the main contributor to beneficial effect of MSCs. Rather than cell replacement, the mechanisms of action principally involve stimulation of endogenous repair processes, promotion of brain plasticity and synaptic reorganization, immunomodulation, and reduction in secondary injury.10,17,18 Compared with intracerebral transplantation, systemic delivery obtains better distribution into the injured brain areas, has a more extensive neuroprotective effect, and avoids the process of invasive surgery. Despite the growing evidence of beneficial effect of cell therapy in stroke, the role of stem cell therapy for aneurysmal SAH is still not adequately established, as very few groups have studied this distinct population of patients. Ghonim et al.19 performed a meta-analysis of 4 preclinical studies with 181 animal subjects that showed a decrease in neural apoptosis and inflammation, improvement of ultrastructural integrity of cerebral tissue, and improvement of sensorimotor function after SAH. In a recent study, Nijboer et al.7 demonstrated that intranasal administration of MSCs at 6 days after severe SAH was associated with improved sensorimotor function and decreased lesion size in rats compared
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.04.055
CASE REPORT MARIE-CHRISTINE BRUNET ET AL.
with control animals. They also observed that the neuroinflammation associated with SAH, assessed by astrocyte and microglia/macrophage activation, was significantly reduced by MSC treatment. CONCLUSIONS At the present time, there is no documented case of human subjects treated with stem cell therapy in the context of aneurysmal SAH in the literature. The 80year-old patient presented in this article achieved an unexpectedly rapid and favorable recovery with a modified Rankin Scale score of 3 following a high-grade SAH from a ruptured top of basilar aneurysm with initial Hunt and Hess grade 5. The promising results of this case report, in conjunction with other human trials demonstrating the safety of stem cell therapy for stroke, encourages further investigation of the efficacy of stem cell therapy for SAH. REFERENCES 1. Hao L, Zou Z, Tian H, Zhang Y, Zhou H, Liu L. Stem cell-based therapies for ischemic stroke. Biomed Res Int. 2014;2014:468748. 2. Kocsis JD, Honmou O. Bone marrow stem cells in experimental stroke. Prog Brain Res. 2012;201: 79-98. 3. Lovelock CE, Rinkel GJ, Rothwell PM. Time trends in outcome of subarachnoid hemorrhage: population-based study and systematic review. Neurology. 2010;74:1494-1501. 4. Donega V, van Velthoven C, Nijboer CH, Kavelaars A, Heijnen CJ. The endogenous regenerative capacity of the damaged newborn brain: boosting neurogenesis with mesenchymal stem cell treatment. J Cereb Blood Flow Metab. 2013;33: 625-634.
STEM CELL INFUSION FOR ANEURYSMAL SAH
5. Hop JW, Rinkel GJ, Algra A, Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage. Stroke. 1997;28:660-664. 6. Nagpal A, Choy FC, Howell S, et al. Safety and effectiveness of stem cell therapies in early-phase clinical trials in stroke: a systematic review and meta-analysis. Stem Cell Res Ther. 2017;8:191. 7. Nijboer CH, Koijman E, van Velthoven CT, et al. Intranasal stem cell treatment as a novel therapy for subarachnoid hemorrhage. Stem Cells Dev. 2018; 27:313-325. 8. Onda T, Honmou O, Harada K, Houkin K, Hamada H, Koscis JD. Therapeutic benefits by human mesenchymal stem cells (hMSCs) and Ang-1 gene-modified hMSCs after cerebral ischemia. J Cereb Blood Flow Metab. 2007;28: 329-340. 9. Tewari M, Agarwal A, Mathuriya S, Gupta V. The outcome after aneurysmal subarachnoid hemorrhage: a study of various factors. Ann Neurosci. 2015;22:78-80. 10. Scheibe F, Ladhoff J, Huck J, et al. Immune effects of mesenchymal stomal cells in experimental stroke. J Cereb Blood Flow Metab. 2012;32:1578-1588. 11. van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Repeated mesenchymal stem cell treatment after neonatal hypoxia-ischemia has distinct effects on formation and maturation of new neurons and oligodendrocytes leading to restoration of damage, corticospinal mortor tract activity and sensorimotor function. J Neurosci. 2010; 30:9603-9611. 12. Lee JS, Hong JM, Moon GJ, et al. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells. 2010;28: 1099-1106.
15. Khalili MA, Anvari M, Hekmati-Moghadam SH, Sadeghian-Nodoushan F, Fesahat F, Miresmaeli SM. Therapeutic benefit of intravenous transplantation of mesenchymal stem cells after experimental subarachnoid hemorrhage in rats. J Stroke Cerebrovasc Dis. 2012;21:445-451. 16. Donega V, van Velthoven C, Nijboer CH, van Bel F, Kavelaars A, Heijnen CJ. Intranasal mesenchymal stem cell treatment for neonatal brain damage: long-term cognitive and sensorimotor improvement. PLoS One. 2013;8:e51253. 17. Savitz SI, Cramer SC, Wechsler L. Stem cell as an emerging paradigm in stroke 3: enhancing the development of clinical trials. Stroke. 2013;45: 634-639. 18. Zhang ZG, Chopp M. Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol. 2009;8:491-500. 19. Ghonim HT, Shah SS, Thompson JW, Ambekar S, Peterson EC, Elhammady MS. Stem cells as a potential adjunctive therapy in aneurysmal subarachnoid hemorrhage. J Vasc Interv Neurol. 2016;8: 30-37.
Conflict of interest statement: D. R. Yavagal is a consultant for Medtronic Neurovascular, Cerenovus, Rapid Medical, and Neural Analytics; R. M. Starke is a consultant for Medtronic Neurovascular, Penumbra, Cerenovus, and Abbott; E. C. Peterson is a consultant for Stryker Neurovascular, Penumbra, Medtronic Neurovascular, and Cerenovus and a stockholder in RIST Neurovascular; and J. M. Hare reported holding a patent for cardiac cell -based therapy. He is a consultant, is a member of the advisory board, and holds equity in Vestion Inc. He is the Chief Scientific Officer, a compensated consultant, and an advisory board member for Longeveron and holds equity in Longeveron. He is also the co-inventor of the intellectual property licensed to Longeveron. Received 5 March 2019; accepted 5 April 2019
13. Prasad K, Sharma A, Garg A, et al. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric randomized trial. Stroke. 2014;45:3618-3624. 14. Detante O, Moisan A, Hommel M, Jaillard A. Controlled clinical trials of cell therapy in stroke: meta-analysis at six months after treatment. Int J Stroke. 2017;12:748-751.
WORLD NEUROSURGERY 128: 573-575, AUGUST 2019
Citation: World Neurosurg. (2019) 128:573-575. https://doi.org/10.1016/j.wneu.2019.04.055 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
www.journals.elsevier.com/world-neurosurgery
575
Intravenous Stem Cell Therapy for High-Grade Aneurysmal Subarachnoid Hemorrhage: Case Report and Literature Review Marie-Christine Brunet1, Stephanie H. Chen1, Priyank Khandelwal4, Joshua M. Hare1, Robert M. Starke1,2, Eric C. Peterson1, Dileep R. Yavagal1,3
Key words Aneurysm - Stem cells - Stroke - Subarachnoid hemorrhage -
Abbreviations and Acronyms MSC: Mesenchymal stem cell SAH: Subarachnoid hemorrhage From the Departments of 1Neurological Surgery, 2Radiology, and 3Neurology, University of Miami Miller School of Medicine, Miami, Florida; and 4Department of Neurological Surgery, New Jersey Medical School, Newark, New Jersey, USA To whom correspondence should be addressed: Dileep R. Yavagal, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2019) 128:573-575. https://doi.org/10.1016/j.wneu.2019.04.055 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
INTRODUCTION Aneurysmal subarachnoid hemorrhage (SAH) affects >30,000 patients every year in the United States. Despite a progressive decrease in case-fatality rate after SAH during the last 3 decades due to more accurate diagnostics and improved management, mortality (30%e40%) and morbidity remain high; >15%e20% of survivors experience severe physical, neurologic, and psychological deficits associated with significant loss of quality of life.1-3 Aneurysm rupture results in blood extravasation into the subarachnoid space, which triggers multiple pathophysiologic mechanisms, including cerebral edema, increased intracranial pressure, vasospasm, influxes of immune cells, and decreases in cerebral perfusion and oxygen tension.2 These pathophysiologic processes are highly amplified in Hunt and Hess grade 4e5 SAH and lead to dismal functional outcomes despite early and effective
- BACKGROUND:
Aneurysmal subarachnoid hemorrhage (SAH) is associated with high mortality (30%e40%) and morbidity with long-term physical, neurologic, and psychological impairments; most patients present with high initial Hunt and Hess grade. In view of the great need for efficacious therapies for highgrade SAH, recent animal studies have demonstrated improved outcomes with administration of mesenchymal stem cells (MSCs) as a potential neuroregenerative strategy. We present the first case of human intravenous administration of MSCs after aneurysmal SAH.
- CLINICAL
PRESENTATION: An 80-year-old man presented with sudden severe headache with nausea and vomiting. Computed tomography demonstrated SAH with hydrocephalus from a ruptured basilar tip aneurysm. Initial examination of the patient showed Hunt and Hess grade 5 and World Federation of Neurosurgical Societies grade 5. The patient was treated with external ventricular drain placement and coiling of aneurysm. The patient received an infusion of intravenous bone marrowederived allogeneic MSCs on day 3 postbleed. The patient made a better recovery than anticipated with a modified Rankin Scale score of 3 at 6 months.
- CONCLUSIONS:
Several studies using models of ischemic brain injury have found that administration of MSCs may improve functional neurologic recovery and decrease brain lesion volume. Although there have been limited human studies in patients with stroke, the role of stem cell therapy for aneurysmal SAH remains unclear. This is the first case of use of MSCs in a patient for treatment of aneurysmal SAH. In conjunction with the promising results in animal studies, this encouraging preliminary case report supports the need for additional clinical trials.
aneurysm occlusion and modern neurocritical care. In view of the great need for efficacious therapies for highgrade SAH, few recent animal studies have demonstrated improved outcome with administration of mesenchymal stem cells (MSCs) as a regenerative strategy. We present the first case of human intravenous administration of MSCs.
vomiting. The patient quickly became unconscious and was brought to another hospital, where brain computed tomography scan demonstrated SAH with hydrocephalus. The patient progressed to a comatose state and was transferred to our service for further management.
Examination CASE DESCRIPTION History An 80-year-old man with a past medical history of diabetes, hypertension, and cardiac bypass experienced sudden onset of severe headache with nausea and
WORLD NEUROSURGERY 128: 573-575, AUGUST 2019
Initial examination revealed an intubated patient with flexor posturing to pain, 2- to 3-mm nonreactive pupils, positive corneal reflexes, and no gag reflex. This examination correlated with Hunt and Hess grade 5 and World Federation of Neurosurgical Societies grade 5.
www.journals.elsevier.com/world-neurosurgery
573
CASE REPORT MARIE-CHRISTINE BRUNET ET AL.
Therapeutic Intervention An emergent external ventricular drain was placed to treat hydrocephalus. After the external ventricular drain was in place, the patient was transferred to the neurointerventional suite for emergency diagnostic cerebral angiography and potential aneurysm embolization. Cerebral angiography showed a dysmorphic wide-based basilar tip aneurysm measuring 11 mm 8 mm. This aneurysm was considered to be the source of SAH, and successful stent-assisted coiling was performed. MSC Therapy An emergency compassionate use (expanded access) investigational and unlabeled new drug authorization for this single patient was obtained from the U.S. Food and Drug Administration for infusion of intravenous bone marrowederived allogeneic MSCs. The MSCs were produced by the Good Manufacturing Practiceecertified cell manufacturing facility at Interdisciplinary Stem Cell Institute at the University of Miami Miller School of Medicine, Miami, Florida. The source of the cells was healthy donors 18e 40 years of age. After obtaining institutional review board approval and informed consent, on day 3 postbleed, the patient received 100 million allogeneic human MSCs in 80 mL via intravenous infusion at a rate of 2 mL/minute over 45 minutes. No cell-related allergic or any other adverse effect was observed during the cell infusion or 24 hours after infusion. Clinical Outcome The patient was intubated and remained stable for 2 weeks with extension of all extremities; decerebrate posturing. During hospitalization, the patient underwent placement of an inferior vena cava filter for deep venous thrombosis, tracheostomy tube, percutaneous gastrojejunostomy feeding tube, and ventriculoperitoneal shunt after failure to wean the external ventricular drain. Three weeks after SAH, the patient began to show mild improvements in consciousness level with eye opening and withdrawal of the upper extremities. At 5 weeks, the patient’s eyes were opening spontaneously, and he was tracking and following commands intermittently. The patient was discharged to rehabilitation at 5 weeks. Following rehabilitation, the patient had regained the
574
www.SCIENCEDIRECT.com
STEM CELL INFUSION FOR ANEURYSMAL SAH
ability to speak and was caring for himself with some assistance; his overall modified Rankin Scale score at 6 months was 3. DISCUSSION Several studies using animal models of ischemic stroke, intracranial hemorrhage, and SAH have found that different types of stem cells have the potential to induce or improve functional recovery after brain injury.4-11 However, the results in human clinical trials have remained mixed. The STARTING (Stem cell Application Researches and Trials In NeuroloGy) trial randomly assigned 85 patients to intravenous autologous culture-expanded MSCs or control and found a significantly lower modified Rankin Scale score in the MSC group compared with the control group.12 However, in the InveST (Intravenous Autologous Bone Marrow Mononuclear Cell Therapy for Ischemic Stroke) trial, investigators found no difference in neurologic function at 180 days or infarct volume between patients infused with intravenous autologous bone marrow cells and control subjects.13 Although this trial failed to show effectiveness, there were no significant differences in adverse outcomes, such as findings of tumor growth on positron emission tomography or seizures on electroencephalography. Most recently, a meta-analysis of 9 studies (194 patients and 191 control subjects) by Detante et al.14 suggested that cell therapy had an overall beneficial effect on outcomes at 6 months. Additionally, the safety profile appeared to be benign with only rare adverse events that were self-limited and resolved spontaneously or with appropriate management. The most common events were seizures, headache, and events associated with procedures used for administering these therapies.15 Despite this trend toward improvement across various domains of functional impairment in patients with stroke, it is still very difficult to draw any meaningful conclusion given the high level of heterogeneity among studies and the small number of patients involved. This heterogeneity is due to the baseline differences in patients as well as differences in cell types used and the route, dose, and time of administration that vary from 1 trial to another.15 In a
meta-analysis by Nagpal et al.,6 the most common route of delivery of stem cells was intravenous followed by intracerebral and intra-arterial. To target the brain, stem cells have also been applied through the nasal route.16 It was demonstrated that in neonatal mice with hypoxia-ischemia brain injury, intranasal treatment with MSCs significantly decreased brain damage and improved functional outcome, and MSCs were capable of migrating selectively from the cribriform plate toward the ipsilateral cerebral lesion site in 2e24 hours.16 Several mechanisms have been explored to explain the positive pathophysiologic effects of MSC in stroke and SAH models. Similar to ischemic stroke, SAH results in the abolishment of the blood-brain barrier by the release of matrix metalloproteinases and other proteases from endothelial cells. This leads to the infiltration and generation of reactive oxygen species and inflammation, which result in irreversible brain injury.1 It was noted that the number of surviving grafted or differentiated cells was very small and therefore may not be the main contributor to beneficial effect of MSCs. Rather than cell replacement, the mechanisms of action principally involve stimulation of endogenous repair processes, promotion of brain plasticity and synaptic reorganization, immunomodulation, and reduction in secondary injury.10,17,18 Compared with intracerebral transplantation, systemic delivery obtains better distribution into the injured brain areas, has a more extensive neuroprotective effect, and avoids the process of invasive surgery. Despite the growing evidence of beneficial effect of cell therapy in stroke, the role of stem cell therapy for aneurysmal SAH is still not adequately established, as very few groups have studied this distinct population of patients. Ghonim et al.19 performed a meta-analysis of 4 preclinical studies with 181 animal subjects that showed a decrease in neural apoptosis and inflammation, improvement of ultrastructural integrity of cerebral tissue, and improvement of sensorimotor function after SAH. In a recent study, Nijboer et al.7 demonstrated that intranasal administration of MSCs at 6 days after severe SAH was associated with improved sensorimotor function and decreased lesion size in rats compared
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.04.055
CASE REPORT MARIE-CHRISTINE BRUNET ET AL.
with control animals. They also observed that the neuroinflammation associated with SAH, assessed by astrocyte and microglia/macrophage activation, was significantly reduced by MSC treatment. CONCLUSIONS At the present time, there is no documented case of human subjects treated with stem cell therapy in the context of aneurysmal SAH in the literature. The 80year-old patient presented in this article achieved an unexpectedly rapid and favorable recovery with a modified Rankin Scale score of 3 following a high-grade SAH from a ruptured top of basilar aneurysm with initial Hunt and Hess grade 5. The promising results of this case report, in conjunction with other human trials demonstrating the safety of stem cell therapy for stroke, encourages further investigation of the efficacy of stem cell therapy for SAH. REFERENCES 1. Hao L, Zou Z, Tian H, Zhang Y, Zhou H, Liu L. Stem cell-based therapies for ischemic stroke. Biomed Res Int. 2014;2014:468748. 2. Kocsis JD, Honmou O. Bone marrow stem cells in experimental stroke. Prog Brain Res. 2012;201: 79-98. 3. Lovelock CE, Rinkel GJ, Rothwell PM. Time trends in outcome of subarachnoid hemorrhage: population-based study and systematic review. Neurology. 2010;74:1494-1501. 4. Donega V, van Velthoven C, Nijboer CH, Kavelaars A, Heijnen CJ. The endogenous regenerative capacity of the damaged newborn brain: boosting neurogenesis with mesenchymal stem cell treatment. J Cereb Blood Flow Metab. 2013;33: 625-634.
STEM CELL INFUSION FOR ANEURYSMAL SAH
5. Hop JW, Rinkel GJ, Algra A, Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage. Stroke. 1997;28:660-664. 6. Nagpal A, Choy FC, Howell S, et al. Safety and effectiveness of stem cell therapies in early-phase clinical trials in stroke: a systematic review and meta-analysis. Stem Cell Res Ther. 2017;8:191. 7. Nijboer CH, Koijman E, van Velthoven CT, et al. Intranasal stem cell treatment as a novel therapy for subarachnoid hemorrhage. Stem Cells Dev. 2018; 27:313-325. 8. Onda T, Honmou O, Harada K, Houkin K, Hamada H, Koscis JD. Therapeutic benefits by human mesenchymal stem cells (hMSCs) and Ang-1 gene-modified hMSCs after cerebral ischemia. J Cereb Blood Flow Metab. 2007;28: 329-340. 9. Tewari M, Agarwal A, Mathuriya S, Gupta V. The outcome after aneurysmal subarachnoid hemorrhage: a study of various factors. Ann Neurosci. 2015;22:78-80. 10. Scheibe F, Ladhoff J, Huck J, et al. Immune effects of mesenchymal stomal cells in experimental stroke. J Cereb Blood Flow Metab. 2012;32:1578-1588. 11. van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Repeated mesenchymal stem cell treatment after neonatal hypoxia-ischemia has distinct effects on formation and maturation of new neurons and oligodendrocytes leading to restoration of damage, corticospinal mortor tract activity and sensorimotor function. J Neurosci. 2010; 30:9603-9611. 12. Lee JS, Hong JM, Moon GJ, et al. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells. 2010;28: 1099-1106.
15. Khalili MA, Anvari M, Hekmati-Moghadam SH, Sadeghian-Nodoushan F, Fesahat F, Miresmaeli SM. Therapeutic benefit of intravenous transplantation of mesenchymal stem cells after experimental subarachnoid hemorrhage in rats. J Stroke Cerebrovasc Dis. 2012;21:445-451. 16. Donega V, van Velthoven C, Nijboer CH, van Bel F, Kavelaars A, Heijnen CJ. Intranasal mesenchymal stem cell treatment for neonatal brain damage: long-term cognitive and sensorimotor improvement. PLoS One. 2013;8:e51253. 17. Savitz SI, Cramer SC, Wechsler L. Stem cell as an emerging paradigm in stroke 3: enhancing the development of clinical trials. Stroke. 2013;45: 634-639. 18. Zhang ZG, Chopp M. Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol. 2009;8:491-500. 19. Ghonim HT, Shah SS, Thompson JW, Ambekar S, Peterson EC, Elhammady MS. Stem cells as a potential adjunctive therapy in aneurysmal subarachnoid hemorrhage. J Vasc Interv Neurol. 2016;8: 30-37.
Conflict of interest statement: D. R. Yavagal is a consultant for Medtronic Neurovascular, Cerenovus, Rapid Medical, and Neural Analytics; R. M. Starke is a consultant for Medtronic Neurovascular, Penumbra, Cerenovus, and Abbott; E. C. Peterson is a consultant for Stryker Neurovascular, Penumbra, Medtronic Neurovascular, and Cerenovus and a stockholder in RIST Neurovascular; and J. M. Hare reported holding a patent for cardiac cell -based therapy. He is a consultant, is a member of the advisory board, and holds equity in Vestion Inc. He is the Chief Scientific Officer, a compensated consultant, and an advisory board member for Longeveron and holds equity in Longeveron. He is also the co-inventor of the intellectual property licensed to Longeveron. Received 5 March 2019; accepted 5 April 2019
13. Prasad K, Sharma A, Garg A, et al. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric randomized trial. Stroke. 2014;45:3618-3624. 14. Detante O, Moisan A, Hommel M, Jaillard A. Controlled clinical trials of cell therapy in stroke: meta-analysis at six months after treatment. Int J Stroke. 2017;12:748-751.
WORLD NEUROSURGERY 128: 573-575, AUGUST 2019
Citation: World Neurosurg. (2019) 128:573-575. https://doi.org/10.1016/j.wneu.2019.04.055 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
www.journals.elsevier.com/world-neurosurgery
575