Comparison of Endovascular and Intraventricular Gene Therapy With Adeno-Associated Virus–α-L-Iduronidase for Hurler Disease
Abstract BACKGROUND: Hurler disease (mucopolysaccharidosis type I [MPS-I]) is an inherited metabolic disorder characterized by deficiency of the lysosomal enzyme α-L-iduronidase (IDUA). Currently, the only therapies for MPS-I, enzyme replacement and hematopoietic stem cell transplantation, are gener...
Gespeichert in:
| Veröffentlicht in: | Neurosurgery 2014-01, Vol.74 (1), p.99-111 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 111 |
|---|---|
| container_issue | 1 |
| container_start_page | 99 |
| container_title | Neurosurgery |
| container_volume | 74 |
| creator | Janson, Christopher G. Romanova, Liudmila G. Leone, Paola Nan, Zhenhong Belur, Lalitha McIvor, R. Scott Low, Walter C. |
| description | Abstract
BACKGROUND:
Hurler disease (mucopolysaccharidosis type I [MPS-I]) is an inherited metabolic disorder characterized by deficiency of the lysosomal enzyme α-L-iduronidase (IDUA). Currently, the only therapies for MPS-I, enzyme replacement and hematopoietic stem cell transplantation, are generally ineffective for central nervous system manifestations.
OBJECTIVE:
To test whether brain-targeted gene therapy with recombinant adeno-associated virus (rAAV5)-IDUA vectors in an MPS-I transgenic mouse model would reverse the pathological hallmarks.
METHODS:
Gene therapy approaches were compared using intraventricular or endovascular delivery with a marker (rAAV5-green fluorescent protein) or therapeutic (rAAV5-IDUA) vector. To improve the efficiency of brain delivery, we tested different applications of hyperosmolar mannitol to disrupt the blood-brain barrier or ependymal-brain interface.
RESULTS:
Intraventricular delivery of 1 × 1011 viral particles of rAAV5-IDUA with systemic 5 g/kg mannitol co-administration resulted in IDUA expression throughout the brain, with global enzyme activity >200% of the baseline level in age-matched, wild-type mice. Endovascular delivery of 1 × 1012 viral particles of rAAV5-IDUA to the carotid artery with 29.1% mannitol blood-brain barrier disruption resulted in mainly ipsilateral brain IDUA expression and ipsilateral brain enzyme activity 42% of that in wild-type mice. Quantitative assays for glycosaminoglycans showed a significant decrease in both hemispheres after intraventricular delivery and in the ipsilateral hemisphere after endovascular delivery compared with untreated MPS-I mice. Immunohistochemistry for ganglioside GM3, another disease marker, showed reversal of neuronal inclusions in areas with IDUA co-expression in both delivery methods.
CONCLUSION:
Physiologically relevant biochemical correction is possible with neurosurgical or endovascular gene therapy approaches for MPS-I. Intraventricular or endovascular delivery of rAAV5-IDUA was effective in reversing brain pathology, but in the latter method, effects were limited to the ipsilateral hemisphere. |
| doi_str_mv | 10.1227/NEU.0000000000000157 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4116107</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><oup_id>10.1227/NEU.0000000000000157</oup_id><sourcerecordid>1490734107</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5257-4e92d4258726542f9c0ab45e9f001c194365d8fb8ca59d61f93cc8c9c2f0a4cd3</originalsourceid><addsrcrecordid>eNqNkUFu1DAYhS0EokPhBghZYsMmre3YcbJBGg1DO9IINi2wszy2Q1wydmrHU3VT9Q6chItwCE6Cq5SqdANe2NLv7z39Tw-AlxgdYEL44Yfl6QG6fzDjj8AMM0ILiih6DGYI07oom-rLHngW41lGKsrrp2CPUMQ5q8sZuFr47SCDjd5B38Kl034no0q9DFA6DVduDHJn8m2n4ZFxBp50JsjhEn62Ywfn2jhfzGP0ysrRaPjJhhR_XX__-aNYFyudgndWy2hg6wM8TqE3Ab6z0eTRc_CklX00L27ffXD6fnmyOC7WH49Wi_m6UIwwXlDTEE0JqzmpGCVto5DcUGaaNmdSuKFlxXTdbmolWaMr3DalUrVqFGmRpEqX--Dt5DukzdZodRNI9mIIdivDpfDSir9_nO3EV78TFOMKI54N3twaBH-eTBzF1kZl-l4641MUmDaZohP6-gF65lNwOZ4gJeM5BidlpuhEqeBjDKa9WwYjcVOwyAWLhwVn2av7Qe5EfxrNQD0BF74fTYjf-nRhguiM7MfuX96Hk9Sn4f-2-Q3hW8L2</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2357425723</pqid></control><display><type>article</type><title>Comparison of Endovascular and Intraventricular Gene Therapy With Adeno-Associated Virus–α-L-Iduronidase for Hurler Disease</title><source>MEDLINE</source><source>Journals@Ovid Complete</source><creator>Janson, Christopher G. ; Romanova, Liudmila G. ; Leone, Paola ; Nan, Zhenhong ; Belur, Lalitha ; McIvor, R. Scott ; Low, Walter C.</creator><creatorcontrib>Janson, Christopher G. ; Romanova, Liudmila G. ; Leone, Paola ; Nan, Zhenhong ; Belur, Lalitha ; McIvor, R. Scott ; Low, Walter C.</creatorcontrib><description>Abstract
BACKGROUND:
Hurler disease (mucopolysaccharidosis type I [MPS-I]) is an inherited metabolic disorder characterized by deficiency of the lysosomal enzyme α-L-iduronidase (IDUA). Currently, the only therapies for MPS-I, enzyme replacement and hematopoietic stem cell transplantation, are generally ineffective for central nervous system manifestations.
OBJECTIVE:
To test whether brain-targeted gene therapy with recombinant adeno-associated virus (rAAV5)-IDUA vectors in an MPS-I transgenic mouse model would reverse the pathological hallmarks.
METHODS:
Gene therapy approaches were compared using intraventricular or endovascular delivery with a marker (rAAV5-green fluorescent protein) or therapeutic (rAAV5-IDUA) vector. To improve the efficiency of brain delivery, we tested different applications of hyperosmolar mannitol to disrupt the blood-brain barrier or ependymal-brain interface.
RESULTS:
Intraventricular delivery of 1 × 1011 viral particles of rAAV5-IDUA with systemic 5 g/kg mannitol co-administration resulted in IDUA expression throughout the brain, with global enzyme activity >200% of the baseline level in age-matched, wild-type mice. Endovascular delivery of 1 × 1012 viral particles of rAAV5-IDUA to the carotid artery with 29.1% mannitol blood-brain barrier disruption resulted in mainly ipsilateral brain IDUA expression and ipsilateral brain enzyme activity 42% of that in wild-type mice. Quantitative assays for glycosaminoglycans showed a significant decrease in both hemispheres after intraventricular delivery and in the ipsilateral hemisphere after endovascular delivery compared with untreated MPS-I mice. Immunohistochemistry for ganglioside GM3, another disease marker, showed reversal of neuronal inclusions in areas with IDUA co-expression in both delivery methods.
CONCLUSION:
Physiologically relevant biochemical correction is possible with neurosurgical or endovascular gene therapy approaches for MPS-I. Intraventricular or endovascular delivery of rAAV5-IDUA was effective in reversing brain pathology, but in the latter method, effects were limited to the ipsilateral hemisphere.</description><identifier>ISSN: 0148-396X</identifier><identifier>EISSN: 1524-4040</identifier><identifier>DOI: 10.1227/NEU.0000000000000157</identifier><identifier>PMID: 24077583</identifier><language>eng</language><publisher>United States: Oxford University Press</publisher><subject>Animals ; Blood-brain barrier ; Dependovirus - genetics ; Disease Models, Animal ; Enzymes ; Gene therapy ; Genetic Therapy - methods ; Genetic Vectors ; Humans ; Iduronidase - administration & dosage ; Iduronidase - genetics ; Injections, Intra-Arterial ; Injections, Intraventricular ; Mice ; Mice, Transgenic ; Mucopolysaccharidosis I - pathology ; Neurosurgery ; Rodents</subject><ispartof>Neurosurgery, 2014-01, Vol.74 (1), p.99-111</ispartof><rights>Copyright © 2013 by the Congress of Neurological Surgeons 2013</rights><rights>Copyright © by the Congress of Neurological Surgeons</rights><rights>Copyright © 2013 by the Congress of Neurological Surgeons</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5257-4e92d4258726542f9c0ab45e9f001c194365d8fb8ca59d61f93cc8c9c2f0a4cd3</citedby><cites>FETCH-LOGICAL-c5257-4e92d4258726542f9c0ab45e9f001c194365d8fb8ca59d61f93cc8c9c2f0a4cd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24077583$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Janson, Christopher G.</creatorcontrib><creatorcontrib>Romanova, Liudmila G.</creatorcontrib><creatorcontrib>Leone, Paola</creatorcontrib><creatorcontrib>Nan, Zhenhong</creatorcontrib><creatorcontrib>Belur, Lalitha</creatorcontrib><creatorcontrib>McIvor, R. Scott</creatorcontrib><creatorcontrib>Low, Walter C.</creatorcontrib><title>Comparison of Endovascular and Intraventricular Gene Therapy With Adeno-Associated Virus–α-L-Iduronidase for Hurler Disease</title><title>Neurosurgery</title><addtitle>Neurosurgery</addtitle><description>Abstract
BACKGROUND:
Hurler disease (mucopolysaccharidosis type I [MPS-I]) is an inherited metabolic disorder characterized by deficiency of the lysosomal enzyme α-L-iduronidase (IDUA). Currently, the only therapies for MPS-I, enzyme replacement and hematopoietic stem cell transplantation, are generally ineffective for central nervous system manifestations.
OBJECTIVE:
To test whether brain-targeted gene therapy with recombinant adeno-associated virus (rAAV5)-IDUA vectors in an MPS-I transgenic mouse model would reverse the pathological hallmarks.
METHODS:
Gene therapy approaches were compared using intraventricular or endovascular delivery with a marker (rAAV5-green fluorescent protein) or therapeutic (rAAV5-IDUA) vector. To improve the efficiency of brain delivery, we tested different applications of hyperosmolar mannitol to disrupt the blood-brain barrier or ependymal-brain interface.
RESULTS:
Intraventricular delivery of 1 × 1011 viral particles of rAAV5-IDUA with systemic 5 g/kg mannitol co-administration resulted in IDUA expression throughout the brain, with global enzyme activity >200% of the baseline level in age-matched, wild-type mice. Endovascular delivery of 1 × 1012 viral particles of rAAV5-IDUA to the carotid artery with 29.1% mannitol blood-brain barrier disruption resulted in mainly ipsilateral brain IDUA expression and ipsilateral brain enzyme activity 42% of that in wild-type mice. Quantitative assays for glycosaminoglycans showed a significant decrease in both hemispheres after intraventricular delivery and in the ipsilateral hemisphere after endovascular delivery compared with untreated MPS-I mice. Immunohistochemistry for ganglioside GM3, another disease marker, showed reversal of neuronal inclusions in areas with IDUA co-expression in both delivery methods.
CONCLUSION:
Physiologically relevant biochemical correction is possible with neurosurgical or endovascular gene therapy approaches for MPS-I. Intraventricular or endovascular delivery of rAAV5-IDUA was effective in reversing brain pathology, but in the latter method, effects were limited to the ipsilateral hemisphere.</description><subject>Animals</subject><subject>Blood-brain barrier</subject><subject>Dependovirus - genetics</subject><subject>Disease Models, Animal</subject><subject>Enzymes</subject><subject>Gene therapy</subject><subject>Genetic Therapy - methods</subject><subject>Genetic Vectors</subject><subject>Humans</subject><subject>Iduronidase - administration & dosage</subject><subject>Iduronidase - genetics</subject><subject>Injections, Intra-Arterial</subject><subject>Injections, Intraventricular</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Mucopolysaccharidosis I - pathology</subject><subject>Neurosurgery</subject><subject>Rodents</subject><issn>0148-396X</issn><issn>1524-4040</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNqNkUFu1DAYhS0EokPhBghZYsMmre3YcbJBGg1DO9IINi2wszy2Q1wydmrHU3VT9Q6chItwCE6Cq5SqdANe2NLv7z39Tw-AlxgdYEL44Yfl6QG6fzDjj8AMM0ILiih6DGYI07oom-rLHngW41lGKsrrp2CPUMQ5q8sZuFr47SCDjd5B38Kl034no0q9DFA6DVduDHJn8m2n4ZFxBp50JsjhEn62Ywfn2jhfzGP0ysrRaPjJhhR_XX__-aNYFyudgndWy2hg6wM8TqE3Ab6z0eTRc_CklX00L27ffXD6fnmyOC7WH49Wi_m6UIwwXlDTEE0JqzmpGCVto5DcUGaaNmdSuKFlxXTdbmolWaMr3DalUrVqFGmRpEqX--Dt5DukzdZodRNI9mIIdivDpfDSir9_nO3EV78TFOMKI54N3twaBH-eTBzF1kZl-l4641MUmDaZohP6-gF65lNwOZ4gJeM5BidlpuhEqeBjDKa9WwYjcVOwyAWLhwVn2av7Qe5EfxrNQD0BF74fTYjf-nRhguiM7MfuX96Hk9Sn4f-2-Q3hW8L2</recordid><startdate>20140101</startdate><enddate>20140101</enddate><creator>Janson, Christopher G.</creator><creator>Romanova, Liudmila G.</creator><creator>Leone, Paola</creator><creator>Nan, Zhenhong</creator><creator>Belur, Lalitha</creator><creator>McIvor, R. Scott</creator><creator>Low, Walter C.</creator><general>Oxford University Press</general><general>Copyright by the Congress of Neurological Surgeons</general><general>Wolters Kluwer Health, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20140101</creationdate><title>Comparison of Endovascular and Intraventricular Gene Therapy With Adeno-Associated Virus–α-L-Iduronidase for Hurler Disease</title><author>Janson, Christopher G. ; Romanova, Liudmila G. ; Leone, Paola ; Nan, Zhenhong ; Belur, Lalitha ; McIvor, R. Scott ; Low, Walter C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5257-4e92d4258726542f9c0ab45e9f001c194365d8fb8ca59d61f93cc8c9c2f0a4cd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Blood-brain barrier</topic><topic>Dependovirus - genetics</topic><topic>Disease Models, Animal</topic><topic>Enzymes</topic><topic>Gene therapy</topic><topic>Genetic Therapy - methods</topic><topic>Genetic Vectors</topic><topic>Humans</topic><topic>Iduronidase - administration & dosage</topic><topic>Iduronidase - genetics</topic><topic>Injections, Intra-Arterial</topic><topic>Injections, Intraventricular</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Mucopolysaccharidosis I - pathology</topic><topic>Neurosurgery</topic><topic>Rodents</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Janson, Christopher G.</creatorcontrib><creatorcontrib>Romanova, Liudmila G.</creatorcontrib><creatorcontrib>Leone, Paola</creatorcontrib><creatorcontrib>Nan, Zhenhong</creatorcontrib><creatorcontrib>Belur, Lalitha</creatorcontrib><creatorcontrib>McIvor, R. Scott</creatorcontrib><creatorcontrib>Low, Walter C.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Neurosurgery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Janson, Christopher G.</au><au>Romanova, Liudmila G.</au><au>Leone, Paola</au><au>Nan, Zhenhong</au><au>Belur, Lalitha</au><au>McIvor, R. Scott</au><au>Low, Walter C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Comparison of Endovascular and Intraventricular Gene Therapy With Adeno-Associated Virus–α-L-Iduronidase for Hurler Disease</atitle><jtitle>Neurosurgery</jtitle><addtitle>Neurosurgery</addtitle><date>2014-01-01</date><risdate>2014</risdate><volume>74</volume><issue>1</issue><spage>99</spage><epage>111</epage><pages>99-111</pages><issn>0148-396X</issn><eissn>1524-4040</eissn><abstract>Abstract
BACKGROUND:
Hurler disease (mucopolysaccharidosis type I [MPS-I]) is an inherited metabolic disorder characterized by deficiency of the lysosomal enzyme α-L-iduronidase (IDUA). Currently, the only therapies for MPS-I, enzyme replacement and hematopoietic stem cell transplantation, are generally ineffective for central nervous system manifestations.
OBJECTIVE:
To test whether brain-targeted gene therapy with recombinant adeno-associated virus (rAAV5)-IDUA vectors in an MPS-I transgenic mouse model would reverse the pathological hallmarks.
METHODS:
Gene therapy approaches were compared using intraventricular or endovascular delivery with a marker (rAAV5-green fluorescent protein) or therapeutic (rAAV5-IDUA) vector. To improve the efficiency of brain delivery, we tested different applications of hyperosmolar mannitol to disrupt the blood-brain barrier or ependymal-brain interface.
RESULTS:
Intraventricular delivery of 1 × 1011 viral particles of rAAV5-IDUA with systemic 5 g/kg mannitol co-administration resulted in IDUA expression throughout the brain, with global enzyme activity >200% of the baseline level in age-matched, wild-type mice. Endovascular delivery of 1 × 1012 viral particles of rAAV5-IDUA to the carotid artery with 29.1% mannitol blood-brain barrier disruption resulted in mainly ipsilateral brain IDUA expression and ipsilateral brain enzyme activity 42% of that in wild-type mice. Quantitative assays for glycosaminoglycans showed a significant decrease in both hemispheres after intraventricular delivery and in the ipsilateral hemisphere after endovascular delivery compared with untreated MPS-I mice. Immunohistochemistry for ganglioside GM3, another disease marker, showed reversal of neuronal inclusions in areas with IDUA co-expression in both delivery methods.
CONCLUSION:
Physiologically relevant biochemical correction is possible with neurosurgical or endovascular gene therapy approaches for MPS-I. Intraventricular or endovascular delivery of rAAV5-IDUA was effective in reversing brain pathology, but in the latter method, effects were limited to the ipsilateral hemisphere.</abstract><cop>United States</cop><pub>Oxford University Press</pub><pmid>24077583</pmid><doi>10.1227/NEU.0000000000000157</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0148-396X |
| ispartof | Neurosurgery, 2014-01, Vol.74 (1), p.99-111 |
| issn | 0148-396X 1524-4040 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4116107 |
| source | MEDLINE; Journals@Ovid Complete |
| subjects | Animals Blood-brain barrier Dependovirus - genetics Disease Models, Animal Enzymes Gene therapy Genetic Therapy - methods Genetic Vectors Humans Iduronidase - administration & dosage Iduronidase - genetics Injections, Intra-Arterial Injections, Intraventricular Mice Mice, Transgenic Mucopolysaccharidosis I - pathology Neurosurgery Rodents |
| title | Comparison of Endovascular and Intraventricular Gene Therapy With Adeno-Associated Virus–α-L-Iduronidase for Hurler Disease |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-22T04%3A47%3A17IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Comparison%20of%20Endovascular%20and%20Intraventricular%20Gene%20Therapy%20With%20Adeno-Associated%20Virus%E2%80%93%CE%B1-L-Iduronidase%20for%20Hurler%20Disease&rft.jtitle=Neurosurgery&rft.au=Janson,%20Christopher%20G.&rft.date=2014-01-01&rft.volume=74&rft.issue=1&rft.spage=99&rft.epage=111&rft.pages=99-111&rft.issn=0148-396X&rft.eissn=1524-4040&rft_id=info:doi/10.1227/NEU.0000000000000157&rft_dat=%3Cproquest_pubme%3E1490734107%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2357425723&rft_id=info:pmid/24077583&rft_oup_id=10.1227/NEU.0000000000000157&rfr_iscdi=true |