Archives of Neurology

doi: 10.1001/archneurol.2007.15pmid: N/A

On behalf of the Editors and Editorial Board of the Archives, I want to express our most sincere thanks to our reviewers for your commitment to provide scientifically excellent reviews of the papers sent to us. These reviews serve a vital function making sure that only the best clinical and basic research, reviews, and comments are finally published. The peer review process is an arduous one and there is no substitute. Thank you very much for your support of our efforts and the Archives. We are most grateful. A-c Johan A. Aarli, MD, Harold P. Adams, MD, Mark Agostini, MD, J. Eric Ahlskog, PhD, MD, Paul S. Aisen, MD, Mark J. Alberts, MD, Andrei V. Alexandrov, MD, RVT, Greg Allen, PhD, Anthony A. Amato, MD, Jack P. Antel, MD, Samson B. Antel, PhD, Douglas L. Arnold, MD, Arthur K. Asbury, MD Alberto Ascherio, MD, DrPH, Tetsuo Ashizawa, MD, Valerie Askanas, MD, PhD, Rohit Bakshi, MD, Robert W. Baloh, MD, Amit Bar-Or, MD, FRCPC, MSc, J. Richard Baringer, MD, Frederik Barkhof, MD, PhD, Henry J. Barnett, MD, Richard J. Barohn, MD, Jean-Claude Baron, MD, FRCP, FMedSci, Mark S. Baron, MD, George Bartzokis, MD, Randall Bateman, MD, Uwe Beffert, PhD, Rodney D. Bell, MD, William L. Bell, MD, Ralph H. B. Benedict, PhD, Joseph R. Berger, MD, Samuel F. Berkovic, MD, FRACP, Gary L. Bernardini, MD, PhD, James L. Bernat, MD, Erin D. Bigler, PhD, Jose Biller, MD, Valerie Biousse, MD, Thomas D. Bird, MD, Thomas P. Bleck, MD, Kaj Blennow, MD, PhD, Bradley F. Boeve, MD, Nicolaas I. Bohnen, MD, PhD, Teodoro Bottiglieri, PhD, Blaise F. Bourgeois, MD, Adam L. Boxer, MD, PhD, John C. Breitner, MD, MPH, Alexis Brice, MD, Adam M. Brickman, PhD, Staley A. Brod, MD, David Brody, MD, PhD, George Buchanan, MD, Nigel J. Cairns, PhD, Peter A. Calabresi, MD, Donald B. Calne, DM, FRSC, Richard M. Camicioli, MD, Fredric Cantor, MD, Gregory D. Cascino, MD, Honglei Chen, MD, PhD, Robert E. Chen, MBBCir, Marc I. Chimowitz, MB, ChB, Shilpa Chitnis, MD, PhD, Ji Y. Chong, MD, Tiffany W. Chow, MD, Helena C. Chui, MD, Christopher M. Clark, MD, David B. Clifford, MD, Jeffrey A. Cohen, MD, Andrew J. Cole, MD, FRCPC, Cristoforo Comi, MD, John R. Corboy, MD, David R. Cornblath, MD, Maria M. Corrada, ScD, Paula Coutinho, MD, PhD, Paul Crane, MD, MPH, Anne H. Cross, MD, C. Munro Cullum, PhD, Jeffrey L. Cummings, MD D-G Marinos C. Dalakas, MD, Richard M. Dasheiff, MD, Larry E. Davis, MD, Lisa M. DeAngelis, MD, Charles DeCarli, MD, Antonio V. Delgado-Escueta, MD, Robert J. DeLorenzo, MD, PhD, MPH, Orrin Devinsky, MD, Richard B. Dewey, MD, Ramon Diaz-Arrastia, MD, PhD, Dennis W. Dickson, MD, Salvatore DiMauro, MD, Michael N. Diringer, MD, Geoffrey A. Donnan, MBBS, MD, Ray E. Dorsey, MD, MBA, Michelle Dougherty, MD, Michael M. Dowling, MD, PhD, Ranjan Duara, MD, Douglas A. Dulli, MD, MS, Peter J. Dyck, MD, Todd N. Eagar, PhD, Mitchell S. Elkind, MD, MS, Jerome Engel, MD, PhD, Alberto J. Espay, MD, MSc, Denis A. Evans, MD, Stewart A. Factor, DO, Anne M. Fagan, PhD, Martin R. Farlow, MD, Thomas E. Feasby, MD, Cesare Fieschi, MD, Massimo Filippi, MD, Gerda G. Fillenbaum, PhD, John K. Fink, MD, Matthew E. Fink, MD, Elizabeth Fisher, PhD, Marc Fisher, MD, Mark Fisher, MD, Marvin A. Fishman, MD, Annette L. Fitzpatrick, PhD, Blair Ford, MD, Barbara M. Foster, PhD, Norman L. Foster, MD, Robert J. Fox, MD, Margaret Frazer, MD, Elliot Frohman, MD, PhD, Matthew Frosch, MD, PhD, Douglas R. Galasko, MD, Steven L. Galetta, MD, James E. Galvin, MD, MPH, Yuehua Gao, MD, PhD, Donald H. Gilden, MD, Peter J. Goadsby, MD, PhD, Christopher G. Goetz, MD, Lawrence I. Golbe, MD, Ralf Gold, MD, Matthew S. Goldberg, PhD, Joshua N. Goldstein, MD, PhD, Christopher M. Gomez, MD, PhD, Francisco Gonzalez-Scarano, MD, Douglas S. Goodin, MD, Philip B. Gorelick, MD, MPH, Neill R. Graff-Radford, MD, Steven A. Greenberg, MD, Steven M. Greenberg, MD, PhD, Paul E. Greene, MD, David M. Greer, MD, MA, Daryl R. Gress, MD, Murray Grossman, MD, James C. Grotta, MD, Katrina A. Gwinn-Hardy, MD H-K Werner Hacke, MD, PhD, David A. Hafler, MD, Angelika F. Hahn, MD, FRCPC, Hen Hallevi, MD, Glenda M. Halliday, PhD, Robert W. Hamill, MD, John Hammerstad, MD, Lawrence A. Hansen, MD, John Hardy, PhD, Robert G. Hart, MD, Hans-Peter Hartung, MD, Kimmo J. Hatanpaa, MD, PhD, Wolf-Dieter Heiss, MD, Bernhard Hemmer, MD, Andrea Hester, PhD, Argye E. Hillis, MD, Michio Hirano, MD, R. Edward Hogan, MD, Ahmet Hoke, MD, PhD, Robert G. Holloway, MD, MPH, David M. Holtzman, MD, Maria K. Houtchens, MD, Virginia J. Howard, MSPH, Song-Chou Hsieh, MD, PhD, Wei Hu, MD, PhD, Edward Huey, MD, Aatif M. Husain, MD, Linda S. Hynan, PhD, Susan T. Iannaccone, MD, Michael C. Irizarry, MD, MPH, Clifford R. Jack, MD, William J. Jagust, MD, Joseph Jankovic, MD, Mark D. Johnson, MD, Keith A. Josephs, MST, MD, Burk Jubelt, MD, John Kamholz, MD, PhD, Carlos S. Kase, MD, Claudia H. Kawas, MD, Jeffrey A. Kaye, MD, Christopher Kennard, PhD, Karl D. Kieburtz, MD, MPH, Bernd C. Kieseier, MD, Richard D. King, MD, PhD, John T. Kissel, MD, Miia Kivipelto, MD, PhD, Christine Klein, MD, Thomas Klockgether, MD, William E. Klunk, MD, PhD, David S. Knopman, MD, Prakash Kotagal, MD, Neil W. Kowall, MD, Walter A. Kukull, PhD, Ruben I. Kuzniecky, MD L-O Laura H. Lacritz, PhD, Anthony E. Lang, MD, Annette Langer-Gould, MS, MD, Norman Latov, MD, PhD, Alan J. Lerner, MD, Ronald P. Lesser, MD, Richard J. Leventer, MBBS, BMedSci, PhD, FRACP, James B. Leverenz, MD, Allan I. Levey, MD, PhD, Harvey S. Levin, PhD, Steven R. Levine, MD, David S. Liebeskind, MD, John W. Lindsey, MD, Richard B. Lipton, MD, Catherine Lomen-Hoerth, MD, PhD, W. T. Longstreth, MD, MPH, Iscia Lopes Cendes, MD, PhD, Oscar L. Lopez, MD, Elan D. Louis, MD, MSc, Po H. Lu, PsyD, Claudia F. Lucchinetti, MD, Jose A. Luchsinger, MD, MPH, Brian N. Maddux, MD, PhD, Margery H. Mark, MD, William R. Markesbery, MD, Frederick J. Marshall, MD, Randolph S. Marshall, MS, MD, Colin L. Masters, MD, Richard P. Mayeux, MD, MS, Elizabeth A. McCusker, MD, Guy M. McKhann, MD, Aaron McMurtray, MD, Marek-Marsel Mesulam, MD, Robert S. Miletich, MD, PhD, Bruce L. Miller, MD, Kerry R. Mills, PhD, Nancy Minshew, MD, J. P. Mohr, MD, Richard C. Mohs, PhD, Nancy L. Monson, PhD, Lewis B. Morgenstern, MD, Martha C. Morris, ScD, Richard T. Moxley, MD, Theodore L. Munsat, MD, Joseph A. Murray, MD, Richard H. Myers, PhD, Robert T. Naismith, MD, Ponnada Narayana, PhD, Sharon P. Nations, MD, Nancy J. Newman, MD, John M. Newsom-Davis, MD, John G. Nutt, MD, William L. Nyhan, MD, PhD, Jose A. Obeso, MD, John T. O'Brien, DM, FRCPsych, Sid E. O'Bryant, PhD, Paul W. O'Connor, MD, MSc, Michael S. Okun, MD, William G. Ondo, MD, Padraig E. O'Suilleabhain, MD P-S Gary D. Paige, MD, PhD, Ann Pakalnis, MD, Juan M. Pascual, MD, PhD, Giulio M. Pasinetti, MD, PhD, Haydeh Payami, PhD, Elaine R. Peskind, MD, Ronald C. Petersen, MD, PhD, Amie Peterson, MD, J. T. Phillips, MD, PhD, Jonathan H. Pincus, MD, David Pitt, MD, Sean J. Pittock, MD, Daniel Z. Press, MD, Michael Privitera, MD, Stefan-M. Pulst, MD, Alejandro A. Rabinstein, MD, Isabelle Rapin, MD, Stanley I. Rapoport, MD, Murray A. Raskind, MD, John R. Rinker, MD, Moses Rodriguez, MD, Catherine M. Roe, PhD, Ekaterina Rogaeva, PhD, Gustavo C. Roman, MD, Karen L. Roos, MD, Allan H. Ropper, MD, Howard Rosen, MD, Guy A. Rouleau, MD, PhD, Lewis P. Rowland, MD, Walter Royal, MD, Marwan N. Sabbagh, MD, Ralph L. Sacco, MD, MS, Ned Sacktor, MD, Jean A. Saint-Cyr, PhD, Mary Sano, PhD, Clifford B. Saper, MD, PhD, Justin A. Sattin, MD, Jeffrey L. Saver, MD, Nikolaos Scarmeas, MD, Anthony H. Schapira, MD, DSc, FRCP, FMedSci, Gerard D. Schellenberg, PhD, Mya C. Schiess, MD, Lon S. Schneider, MD, Ludger Schols, MD, Steven R. Schwid, MD, Alan Z. Segal, MD, Michael E. Selzer, MD, PhD, Jorge Sequeiros, MD, PhD, Kapil D. Sethi, MD, Caroline Sewry, PhD, David Shprecher, MD, Michael E. Shy, MD, Stephen D. Silberstein, MD, Mike Singer, MD, PhD, Aneesh B. Singhal, MD, Christopher Skidmore, MD, Jeremy D. Slater, MD, Kristel Sleegers, MD, PhD, Gary W. Small, MD, Eric E. Smith, MD, MPH, FRCPC, Elson L. So, MD, Bing-Wen Soong, MD, PhD, Sandro Sorbi, MD, Susan S. Spencer, MD, Lawrence Steinman, MD, Yaakov Stern, PhD, Lael Stone, MD, Warren J. Strittmatter, MD, Arie Struyk, MD, PhD, S. H. Subramony, MD, Lewis R. Sudarsky, MD, Austin J. Sumner, MD, Thomas P. Sutula, MD, PhD T-V Keith E. Tansey, MD, PhD, Daniel Tarsy, MD, William H. Theodore, MD, A. J. Thompson, FRCP, Edward J. Thompson, MD, Ron Tintner, MD, Eduardo Tolosa, MD, PhD, Doris A. Trauner, MD, Georgios Tsivgoulis, MD, Shoji Tsuji, MD, PhD, Gloria L. Vega, PhD, Steven A. Vernino, MD, PhD, Paul M. Vespa, MD, Harry V. Vinters, MD, FRCPC, Timothy L. Vollmer, MD, Valerie Voon, MD, Rhonda Voskuhl, MD, Tiffini Voss, MD W-Z Steven J. Warach, MD, PhD, Stephen C. Waring, DVM, PhD, Cornelius Weiller, MD, Myron F. Weiner, MD, William J. Weiner, MD, Brian G. Weinshenker, MD, Barbara F. Westmoreland, MD, Vanessa Wheeler, PhD, Charles L. White, MD, Eelco F. M. Wijdicks, MD, Kirk C. Wilhelmsen, MD, PhD, Nicholas Willcox, MD, PhD, Jeff D. Williamson, MD, MHS, Golder N. Wilson, MD, PhD, Robert S. Wilson, PhD, Dean M. Wingerchuk, MD, Thomas M. Wisniewski, MD, Robert J. Wityk, MD, Gil I. Wolfe, MD, David A. Wolk, MD, Benjamin Wolozin, MD, PhD, Kyle B. Womack, MD, Gregory A. Worrell, MD, PhD, Jerome Yesavage, MD, Steven G. Younkin, MD, PhD, Gang Yu, PhD, W. K. Alfred Yung, MD, Peter P. Zandi, PhD, Justin A. Zivin, MD, PhD, Douglas W. Zochodne, MD, FRCPC

doi: 10.1001/archneurol.2007.28pmid: N/A

Aging Face of the Fragile X Gene Amiri and colleaguesArticle review the 2 opposing faces of the fragile X mental retardation 1 (FMR1) gene: a neurodegenerative syndrome (fragile X–associated tremor/ataxia syndrome) in older adults, caused by excess gene activity and production of a toxic RNA, and a childhood-onset disorder (fragile X syndrome), caused by absence of gene activity. Neuroprotection in Multiple Sclerosis: Modeling Axonal Degeneration in the Anterior Visual System A major objective in multiple sclerosis therapeutics is to develop strategic targeting of specific injury pathways to provide neuroprotection and potentially even restoration. Frohman et alArticle in this review underscore the potential utility of the anterior visual system for the purpose of modeling neuroprotection in response to novel therapies. Undernutrition and Outcome in Acute Ischemic Stroke Acute ischemic stroke patients with baseline malnutrition are undernourished during hospitalization. Yoo and colleaguesArticle show that nutritional support, particularly in patients with baseline undernutrition, improves clinical outcome. Article Genomewide Association of Alzheimer Disease A genomewide association analysis of Alzheimer disease (AD) presented by Li et alArticle identified the APOE linkage disequilibrium region as the strongest genetic risk factor for AD. This could be a consequence of the co-evolution of more than 1 susceptibility allele, such as APOC1, in this region. They also provide new evidence for additional candidate genetic risk factors for AD that can be tested in further studies. Increased Risk for Alzheimer Disease in Type 2 Diabetes With APOE ε4 Irie and colleaguesArticle found that having both diabetes and the APOE ε4 allele increases the risk of dementia, especially for Alzheimer disease. Noninvasive Ventilation in Myasthenic Crisis Bilevel positive airway pressure (BiPAP) noninvasive ventilation is an effective treatment in patients in myasthenic crisis as reported by Seneviratne and colleaguesArticle. They show that a BiPAP trial before the development of hypercapnia can prevent intubation and prolonged ventilation, thus reducing pulmonary complications and length of intensive care unit and hospital stay. Validating CNS Penetration-Effectiveness Rank for Antiretroviral Agents Into Brain Letendre and colleaguesArticle show that poorer penetration of antiretroviral (ARV) drugs into brain appears to allow continued human immunodeficiency virus (HIV) replication in the central nervous system as indicated by higher cerebrospinal HIV viral load (Figure). It is important, they point out, that ARV treatment strategies that account for brain penetration should be considered in consensus treatment guidelines and validated in clinical studies. Figure. View LargeDownload Proportion of subjects with detectable cerebrospinal fluid (CSF) viral load decreases with central nervous system Penetration-Effectiveness (CPE) rank. The proportions (black circles) and 95% confidence interval (vertical bars) were calculated from observations at each CPE rank level (1 subject with a CPE rank of 0 and 2 with a CPE rank of 4 were grouped with the adjacent groups). The solid curve represents predicted proportions of CSF viral suppression from the univariate logistic regression. Mesial Frontal Epilepsy and Body Turning Leung et alArticle show that ictal body turning along the horizontal body axis is a feature of mesial frontal epilepsy and distinguishes it from lateral frontal and orbitofrontal seizures. Neuromyelitis Optica and Non–Organ-Specific Autoimmunity Pittock and colleaguesArticle in an elegant study show that neuromyelitis optica (NMO)-IgG–seropositive NMO spectrum disorders occurring with Sjögren syndrome/systemic lupus erythematosus (SS/SLE) or non–organ-specific autoantibodies is an indication of coexisting NMO rather than a vasculopathic or other complication of SS/SLE. Cognitive Functions in Neuromyelitis Optica This study by Blanc et alArticle confirmed recent findings of brain involvement in neuromyelitis optica (NMO). They report that cognitive performance was significantly lower in NMO and multiple sclerosis groups compared with healthy subjects in a battery of neuropsychological tests. Magnetic Resonance Imaging White Matter Hyperintensities and Brain Volume in Mild Cognitive Impairment and Dementia White matter hyperintensities are associated with the risk of progressing from normal to mild cognitive impairment. In persons whose cognitive abilities are already impaired, brain parenchymal fraction predicts the conversion to dementia as reported by Smith et alArticle. Reduced Purkinje Cell Number and Tremor Axelrad et alArticle demonstrated a reduction in Purkinje cell number in the brains of patients with essential tremor who do not have Lewy bodies. Their data further support the view that the cerebellum is anatomically, as well as functionally, abnormal in these essential tremor patients. Education and Reported Age at Onset for Alzheimer Disease Roe and colleaguesArticle found that the reported age at onset of dementia symptoms is earlier for participants with more education. Participants with fewer years of education show greater clinical severity of Alzheimer disease at first assessment. Symptoms of Alzheimer disease are recognized later among those with less education. Brain Volume Decline in Aging Fotenos et alArticle found that privileged, nondemented older adults harbor more preclinical brain atrophy, consistent with their having greater reserve against the expression of Alzheimer disease.

Badjatia, Neeraj;Elkind, Mitchell S. V.

doi: 10.1001/archneurol.2007.5pmid: 18195135

The physiological and hormonal responses to the stress of an acute brain injury, like other critical illnesses, result in a redistribution of fat, protein, and glycogen stores. There is also evidence that brain injury may lead to more severe metabolic derangements compared with those associated with critical illness affecting other organs.1 This hypermetabolic response can lead to a undernourished state and impair the normal reparative processes essential for recovery if the patient does not receive adequate nutritional supplementation. Clinically, undernourishment is a common problem in ischemic stroke patients, with up to 16% of patients demonstrating signs and symptoms related to undernourishment on presentation.2 Results from the Feed or Ordinary Diet (FOOD) Trial Collaboration, a large multicenter study of approximately 3000 ischemic stroke patients, indicate that a undernourished state at the time of stroke presentation is an independent predictor of poor functional outcome and mortality at 6 months after stroke.3 Even more worrying is the fact that the incidence of undernourishment may increase to 25% during the first week of hospitalization after an ischemic stroke.3 This has been attributed to dysphagia, age, poor baseline nutritional status, and immobilization in patients with impaired functional capacity.4 Nonetheless, large observational studies and randomized trials assessing the effect of early nutritional support on long-term morbidity and mortality have produced mixed results, indicating little benefit in morbidity and no clear decrease in mortality.5,6 In dysphagic stroke patients in one of the FOOD trials, for example, early enteral tube feeding was associated with a nonsignificant trend toward a reduction in mortality and no beneficial effect on functional outcomes when compared with a delay of feeding for 7 days.6 Does this minimize the importance of early feeding after stroke? Prior to answering this question, one must first better understand the changes in the metabolic and nutritional profile during the short-term period after stroke. In this issue of the Archives, Yoo et al7 describe the relationship between undernourishment after stroke and clinical outcomes at 3 months. They prospectively assessed nutritional status in 131 acute stroke patients and found undernutrition to be present at admission in 12% of the patients. Undernourishment was assessed by a series of laboratory values and clinical assessments that, taken individually, are nonspecific and influenced by many other factors.8 Additional measurement of nitrogen balance and indirect calorimetry as well as a detailed evaluation of the caloric intake during the first week of hospitalization would have provided a more comprehensive and specific assessment of nutritional status. It is also important to note that a large proportion of screened patients were not included in the study owing to unavailability of nutritional assessments. This absence of nutritional data in many patients points not only to the limitations of the observational study design but also to the current lack of importance given to the utility of nutritional support after stroke. Despite these shortcomings, the results from this study have important clinical implications. Similar to results previously reported, the incidence of undernourishment 1 week after stroke increased from 12% to 20% and undernourishment at 1 week was significantly associated with baseline undernutrition. Baseline undernutrition was seen more often in patients who developed in-hospital complications, predominantly those related to pneumonia. It is not clear whether this was due to attempts at early oral nutritional support in dysphagic patients. Yoo and colleagues decided to use a responder analysis model to determine the effect on outcomes. This model has recently been validated in ischemic stroke studies and allows for an adjustment of outcomes based on injury severity.9 Using this outcomes model, they found that only the National Institutes of Health Stroke Scale score and undernourished status at 1 week independently predicted poor outcome at 3 months. Taken together, these striking findings suggest that more attention to the nutritional status of stroke patients, including interventions to improve caloric balance, is warranted. The undernourished state may represent another modifiable physiological risk factor, like hyperglycemia and fever, that when actively treated leads to improved outcomes. It is important to realize that the need for nutritional intervention in this setting should be based on an understanding of how the metabolic response to physiological stress acts to inhibit normal adaptation to a fasting state. In a nonstressed fasting state, glycogen stores are used first to sustain a constant blood glucose concentration. When fasting persists, blood glucose and insulin levels decline, allowing for increased use of fat reserves in an effort to reduce the need for protein catabolism to maintain the energy-requiring functions of the body. By contrast, the surge of catecholamines after an acute brain injury leads to hyperglycemia and hyperinsulinemia, which impairs ketogenesis and promotes protein catabolism. The resultant catabolic state can have significant detrimental effects on systemic organ function. It is likely that not all patients need aggressive nutritional support. Individual patient selection and appropriate timing and route of delivery are probably crucial issues. These are ideally done with a combination of laboratory assessments, including urine nitrogen balance assessments and indirect calorimetry. Failure to account for these variables may explain some of the absence of an effect of nutritional support in earlier studies. The severity of illness, degree of physiological stress, and baseline nutritional status before stroke often determine a patient's need for and response to nutritional therapy. This article is the latest in a series of studies representing current thinking about the potential value of nutritional support for stroke patients in the acute care setting. Providing adequate caloric intake early in the course after ischemic stroke may now be seen as a therapeutic intervention used to minimize disease severity, reduce complications, and favorably affect patient outcomes. In the end, factors related to overall amount, content, route, and timing may determine whether nutritional support improves outcomes or is ineffective. Correspondence: Dr Elkind, Department of Neurology, Columbia University College of Physicians and Surgeons, 710 W 168th St, Box 182, New York, NY 10032 ([email protected]). Author Contributions:Study concept and design: Badjatia and Elkind. Drafting of the manuscript: Badjatia. Critical revision of the manuscript for important intellectual content: Elkind. Administrative, technical, and material support: Badjatia. Study supervision: Elkind. Financial Disclosure: None reported. References 1. Clifton GLRobertson CSGrossman RGHodge SFoltz RGarza C The metabolic response to severe head injury. J Neurosurg 1984;60 (4) 687- 696PubMedGoogle ScholarCrossref 2. Dávalos ARicart WGonzalez-Huix F et al. Effect of malnutrition after acute stroke on clinical outcome. Stroke 1996;27 (6) 1028- 1032PubMedGoogle ScholarCrossref 3. FOOD Trial Collaboration, Poor nutritional status on admission predicts poor outcomes after stroke: observational data from the FOOD trial. Stroke 2003;34 (6) 1450- 1456PubMedGoogle ScholarCrossref 4. Finestone HMGreene-Finestone LSWilson ESTeasell RW Prolonged length of stay and reduced functional improvement rate in malnourished stroke rehabilitation patients. Arch Phys Med Rehabil 1996;77 (4) 340- 345PubMedGoogle ScholarCrossref 5. Dennis MSLewis SCWarlow CFOOD Trial Collaboration, Routine oral nutritional supplementation for stroke patients in hospital (FOOD): a multicentre randomised controlled trial. Lancet 2005;365 (9461) 755- 763PubMedGoogle ScholarCrossref 6. Dennis MSLewis SCWarlow CFOOD Trial Collaboration, Effect of timing and method of enteral tube feeding for dysphagic stroke patients (FOOD): a multicentre randomised controlled trial. Lancet 2005;365 (9461) 764- 772PubMedGoogle ScholarCrossref 7. Yoo S-HKim JSKwon SUYun S-CKoh J-YKang D-W Undernutrition as a predictor of poor clinical outcomes in acute ischemic stroke patients. Arch Neurol 2008;65 (1) 39- 43PubMedGoogle ScholarCrossref 8. Seres DS Surrogate nutrition markers, malnutrition, and adequacy of nutrition support. Nutr Clin Pract 2005;20 (3) 308- 313PubMedGoogle ScholarCrossref 9. Adams HP JrLeclerc JRBluhmki EClarke WHansen MDHacke W Measuring outcomes as a function of baseline severity of ischemic stroke. Cerebrovasc Dis 2004;18 (2) 124- 129PubMedGoogle ScholarCrossref

doi: 10.1001/archneurol.2007.6pmid: N/A

Retiring editorial board members Mahlon R. DeLong, MD, W.P. Timmie Professor of Neurology, Department of Neurology, Emory University Medical Center, Atlanta, Georgia, and Bruce R. Ransom, MD, PhD, Warren and Jermaine Magnuson Professor and Chair, Department of Neurology, University of Washington, Seattle, have served with great distinction from 1997 to 2007 as members of the editorial board. They have provided wisdom, scholarship, and collegiality for the past decade and the Archives has benefited greatly by their active participation. We thank them most enthusiastically for their contributions and efforts in ensuring that the Archives publishes the finest papers in clinical neurology and neuroscience. New editorial appointments We are pleased to announce the appointment of two new members to our editorial board. They are Helena C. Chui, MD, and Mya C. Schiess, MD. Helena C. Chui, MD, brings to our editorial board a great perspective and scholarship on neurodegenerative diseases, especially Alzheimer disease, vascular dementia, and the frontotemporal dementias and has published extensively in these areas. Dr Chui is the Raymond and Betty McCarron Endowed Chair of Neurology and is professor and chair of the Department of Neurology at the University of Southern California Keck School of Medicine, Los Angeles. She is also director of the National Institutes of Health–funded Alzheimer Disease Research Center at the University of Southern California. Mya C. Schiess, MD, provides our editorial board with extensive experience in movement disorders. She has published important articles during the past decade on Parkinson disease and the dyskinesias. She is professor and vice chair of the Department of Neurology at the University of Texas Houston Medical Center. In addition, she is director of the University of Texas–Houston Movement Disorders Clinic and fellowship program and director of the neurology residency program. Thank you, Drs DeLong and Ransom, for your distinguished service to the Archives and welcome Drs Chui and Schiess. Correspondence: Dr Rosenberg, Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 ([email protected]). Financial Disclosure: None reported.

Amiri, Khaled;Hagerman, Randi J.;Hagerman, Paul J.

doi: 10.1001/archneurol.2007.30pmid: 18195136

Fragile X–associated tremor/ataxia syndrome (FXTAS) is a late-adult–onset neurodegenerative disorder affecting primarily male (and occasionally female) carriers of a premutation expansion (55-200 CGG repeats) of the fragile X mental retardation 1 gene (FMR1). FXTAS is principally characterized as a movement disorder with progressive intention tremor and gait ataxia, with more variable associated features of parkinsonism, dysautonomia, peripheral neuropathy, and dementia. The pathogenic basis of FXTAS is overexpression of the “toxic” expanded CGG repeat FMR1 RNA, which leads to neural cell dysregulation, formation of intranuclear inclusions in neurons and astrocytes, and disruption of the nuclear lamin architecture. By contrast, larger CGG repeat expansions (> 200 CGG repeats, full mutation) generally result in FMR1 silencing and absence of FMR1 RNA and protein (FMRP). The lack of FMRP is the pathogenic basis of the developmental disorder fragile X syndrome, the leading heritable form of mental impairment. Thus, the same gene presents 2 opposing faces: a neurodegenerative syndrome (FXTAS) in older adults, caused by excess gene activity and production of a toxic RNA, and a childhood-onset disorder (fragile X syndrome), caused by absence of gene activity. This review will focus on FXTAS, the aging face of the fragile X gene. FXTAS is a late-onset neurodegenerative disorder with core features of intention tremor and gait ataxia with associated neurological and nonneurological features.1-3 FXTAS affects carriers of premutation expansions (55-200 CGG repeats)4 of the fragile X mental retardation 1 gene (FMR1) (Online Mendelian Inheritance in Man [OMIM] *309550). Larger expansions (> 200 CGG repeats, full mutation) of the same gene give rise to the neurodevelopmental disorder fragile X syndrome, the leading inherited form of mental impairment. Fragile X syndrome results from the transcriptional silencing of FMR1, with consequent deficiency/absence of the FMR1 protein (FMRP). Fragile X syndrome has been recognized for more than a quarter of a century, and the causative gene (FMR1) was identified 17 years ago.5 However, FXTAS was not recognized until nearly 10 years after the discovery of FMR1.1 There were 2 basic reasons for the delayed recognition of FXTAS. First, geneticists who were studying fragile X syndrome were focused on a developmental disorder (ie, a childhood condition) affecting cognition. Because the gene was unknown before 1991, it was nearly impossible to establish any association with late-onset problems in adults (carriers) who had been essentially normal in childhood. Furthermore, the grandfathers of children with fragile X syndrome rarely came to the pediatric clinics, so their own age-associated symptoms were generally not recognized as being linked to their carrier status. With the discovery of FMR1 in 1991, there arose a different problem: the pathogenic mechanism of fragile X syndrome was gene silencing (ie, absence of the FMR1 protein FMRP) due to hypermethylation of the FMR1 promoter, and this only occurred for alleles with more than 200 CGG repeats. Therefore, clinical abnormalities were not expected among carriers of premutation alleles. The second reason for the delay in recognition was that adult neurologists, geriatricians, and psychiatrists who were treating the carriers (unidentified as such) were generally unaware of fragile X syndrome, a childhood-onset disorder. Thus, cases now known to be FXTAS were generally regarded as being any one of a number of sporadic neurological disorders in older adults, with no obvious genetic basis.6 The first clue to any form of clinical involvement in carriers came about through discussions with mothers and grandmothers of the fragile X syndrome probands, who themselves were premutation carriers and who often described their own problems with premature ovarian failure (POF) (cessation of menses before age 40 years).7 Premature ovarian failure is now known to occur in approximately 20% of female premutation carriers, and the prevalence of POF is correlated with the number of repeats within the premutation range.8 Recognition of a premutation-associated syndrome (POF) set the stage for the later recognition of the neurodegenerative disorder in the carrier grandfathers, in this instance through the expressed concerns of mothers of the children with fragile X syndrome regarding their own fathers.1 Clinical phenotype and spectrum of involvement in fxtas FXTAS represents the most severe form of clinical involvement associated with premutation FMR1 alleles; its core features are intention tremor and/or ataxia, with lower extremity neuropathy, autonomic dysfunction, and gradual cognitive decline beginning with memory and executive function deficits.1,3,9 Psychiatric features, including anxiety, disinhibition, depression, and apathy, are also common problems.10 In an initial longitudinal study of 55 male premutation carriers, the major motor signs of FXTAS had a median onset of approximately 60 years of age.11 Although intention tremor preceded the onset of gait ataxia in the majority of cases, either tremor or ataxia could be the presenting feature. A typical presentation is a progressive intention tremor that interferes with handwriting, followed by interference with other activities of daily living (use of eating utensils, pouring liquids, dressing) and progressive problems with balance. From the onset of the initial motor sign, median delay of onset of ataxia was 2 years; onset of falls, 6 years; dependence on a walking aid, 15 years; and death, 21 years. Preliminary data on life expectancy are variable, ranging from 5 to 25 years. The age at onset of FXTAS correlates with the CGG expansion within the premutation range; the higher the repeat, the earlier the tremor or ataxia.12 Associated features include a neuropathy, usually in a stocking distribution3,13; psychiatric problems, including reclusive behavior, anxiety, mood instability, depression, and apathy10; and autonomic dysfunction, including orthostatic hypotension, impotence, and eventually urine and stool incontinence.3 Relatively mild parkinsonism (bradykinesis, masked facies, and resting tremor) is common, with approximately 30% demonstrating a resting tremor in addition to the intention tremor.3 A head-bobbing tremor and slurring of speech may also been seen in occasional cases of FXTAS. As more cases are described, it has become evident that presenting features may include not only intention tremor and ataxia, which would direct these individuals to movement disorders clinics, but also neuropathy or cognitive problems, including dementia, which might result in initial visits to neuropathy, pain management, or psychiatric clinics.14,15 We recently performed a survey of 56 patients with FXTAS who were given 98 prior diagnoses by adult-practice physicians (primary care, 26%; general neurologists, about 70%; movement disorders specialists, 4%).6 None of those diagnoses recognized an association with the fragile X gene (parkinsonism, 24%; tremor, 20%; ataxia, 17%; dementia, 13%; cerebrovascular disease, 10%; miscellaneous, 16%). Women also present with FXTAS, although the movement disorder is less common in female carriers compared with male carriers presumably because of the protective effect of the second X chromosome.4,16-18 As discussed later, the penetrance of FXTAS is incomplete, suggesting that second-gene and/or environmental factors may influence penetrance. In 1 intriguing case report,19 a female premutation carrier experienced a dramatic worsening of clinical and magnetic resonance imaging (MRI) features of FXTAS while receiving cancer chemotherapy (carboplatin/docetaxel), with substantial improvement of FXTAS symptoms following cessation of chemotherapy. The MRI features of FXTAS include global brain atrophy; white matter disease in the subcortical, middle cerebellar peduncle (MCP), and periventricular regions; and dilated ventricles.2,3,20 A bilateral increased signal intensity in the MCPs on T2-weighted MRI (MCP sign) is a relatively distinct, although not unique, radiological feature of FXTAS found in approximately 60% of male carriers with neurological involvement; it is currently used as a supporting diagnostic feature (Table). In a study of 36 male premutation carriers, the CGG repeat within the premutation range correlated with reductions in both IQ and cerebellar volume, increased ventricular volume, and volume of whole-brain white matter disease.20 At the time individuals present with motor symptoms, they usually already have mild cognitive features, including memory problems and executive function deficits. These problems progress over time and, in about 50% of cases, lead to a frontal subcortical dementia with relative preservation of verbal abilities, at least initially, but with gradual development of behavioral dysinhibition.10,21,22 The memory decline may reflect early, or more extensive, involvement of the hippocampus, since expression of FMR1 messenger RNA (mRNA) is highest in the hippocampus, and the numbers of intranuclear inclusions, which are found in all postmortem premutation cases analyzed to date (see later), are highest in hippocampal neurons and astrocytes.23-25 The psychiatric problems that frequently occur in carriers during adulthood and before the onset of FXTAS may also relate to the effects of elevated mRNA levels in the hippocampus, an important component of the limbic system. In our studies of adult carriers, we found a significant positive association between the psychiatric problems in men, including obsessive-compulsive behavior on Symptom Checklist–90 (a psychiatric questionnaire), and the level of FMR1 mRNA.26 This was most pronounced in men who did not have FXTAS; it was also seen in female carriers in whom the majority of cells had the premutation allele as the active allele. These findings suggest that RNA toxicity in the limbic system may be responsible for the psychiatric problems seen in some carriers. The premutation is also the most common known cause of POF in women in the general population, with approximately 2% to 14% of women with POF demonstrating the premutation.8 In women with the premutation, approximately 20% will develop ovarian failure before age 40 years and an additional 20%, before age 45 years.8 Even female carriers who are cycling have elevations of their follicle-stimulating hormone compared with controls.27 It has been hypothesized that the ovarian dysfunction in female carriers may also be related to RNA toxicity in the ovum,8,28 although a direct mechanistic link has yet to be established. Epidemiology Studies of the penetrance of FXTAS among adult premutation carriers, ascertained through families with known probands with fragile X syndrome, revealed that approximately 40% of male (premutation) carriers older than 50 years presented with both intention tremor and gait ataxia.15,18 The penetrance of the movement disorder increased with age, with more than one-half of male carriers older than 70 years displaying features of the disorder.18 Estimates of the number of males in the general population who carry a premutation allele (1 in 25929 and 1 in 81330) suggest that an upper bound in excess of 1 in 2000 males in the general population would have a lifetime risk of developing FXTAS. However, this upper-bound estimate is biased by the ascertainment of FXTAS cases within known fragile X syndrome families, where transmission of full-mutation alleles (fragile X syndrome probands) is highly biased toward larger CGG repeats in the premutation range. The magnitude of this bias can be gauged from epidemiological studies demonstrating that the penetrance among carriers of larger premutation alleles is greater than among carriers of smaller premutation alleles.31 In particular, 86% of persons with FXTAS, ascertained either through a family history of fragile X syndrome or from populations with movement disorders, but without known family history of fragile X syndrome, had alleles with 70 or more repeats.31 This result differs significantly (P < .001) from the general population where only about 22% of premutation alleles are 70 or more repeats. A simple correction for this size bias would reduce the expectation for lifetime risk among males in the general population to about 1 in 3000 to 6000. This number is much lower than Parkinson disease or essential tremor and similar in prevalence to inherited ataxia, progressive supranuclear palsy, multiple system atrophy, and amyotrophic lateral sclerosis.32 Another approach to assess the prevalence of cases of FXTAS is to screen movement disorders populations based on phenotypic overlap between FXTAS and other disorders with parkinsonism, tremor, and/or gait ataxia. Of the roughly 15 studies reported to date, no increase in premutation alleles was found in parkinsonism populations, and only about 2% to 4% of cerebellar ataxia cases were found to be carriers of premutation alleles.31,33 However, as noted earlier, in a survey of patients with FXTAS, only 4% were seen in movement disorders clinics (the source for essentially all of the high-risk screens).6 Thus, there remains a large disconnect between the populations being screened and the physicians actually seeing the patients with FXTAS. Clearly, better prevalence estimates are needed based on larger-scale screens of US populations. Neuropathology The principal feature of the neuropathology of FXTAS is the presence of ubiquitin-positive intranuclear inclusions in neurons and astrocytes (but not oligodendroglia) in broad distribution throughout the brain (Figure 1).23,34 The inclusions are solitary and spherical and appear as nonmembrane-bound collections of granulofilamentous material by electron microscopy.34 Inclusion counts are highest in the hippocampus, having been observed in as many as approximately 40% of hippocampal neurons in some cases, with smaller numbers (approximately 5%-10%) present in cortical neurons. Inclusions are only rarely detected in Purkinje cells despite substantial cerebellar Purkinje cell dropout.34 The observation of inclusions in neuronal nuclei within the hypoglossal cranial nerve nucleus may be a neuropathological correlate to the difficulties with swallowing experienced by individuals with late-stage FXTAS. Inclusions have not been identified in motor neurons of the spinal cord, although they are present in spinal autonomic neurons in the same region and astrocytic nuclei of the spinal cord.34 Finally, the fraction of inclusion-bearing neurons and astrocytes is highly correlated with the number of CGG repeats in the FMR1 gene,23 further establishing the relationship between the length of the premutation expansion and disease formation. Associated neuropathological changes include patches of subcortical white matter pallor and spongiosis, with axonal spheroids present to varying degrees in white matter, accompanied by loss of axons and myelin. The regions of patchy pallor correspond to areas of increased signal intensity on T2-weighted MRI in the same individuals. The MCP sign seen on MRI is generally more prominent than the mild degree of spongiosis of the MCPs at autopsy. Deep cerebellar white matter in the region of the dentate nucleus also shows some abnormalities, with spongiosis and axonal and myelin loss. The more severe FXTAS cases also possess markedly enlarged astrocytes containing cytoplasmic material that appears to have been phagocytosed.23 The diagnostic criteria for FXTAS outlined in the Table, originally published in Jacquemont et al,3 have been modified to include the presence of inclusions when brain tissue is available.4 More recently, inclusions have also been observed in other tissues, including both the anterior and posterior pituitary,35 and in the Leydig and myotubular cells of the testes of 2 males with FXTAS.28 Because the Leydig cells produce testosterone, we routinely measure testosterone levels in patients with FXTAS. Testosterone levels are often deficient, and replacement therapy has been helpful anecdotally in several patients.28 Molecular pathogenesis There are several lines of evidence that support an RNA “toxic” gain-of-function model for FXTAS (Figure 2).4,36 First, the disorder appears to be confined to carriers of active premutation alleles of FMR1; that is, FXTAS has not been reported among older adults with fragile X syndrome, for whom the gene is generally silent.4 The absence of FXTAS among older individuals with fragile X syndrome also argues against deficiency of the FMR1 protein (FMRP) as part of the pathogenic mechanism, since such individuals generally have little or no FMRP as a consequence of gene silencing. Moreover, absence of FXTAS in those with full-mutation alleles also argues against DNA level effects (eg, protein-DNA interactions), since full-mutation alleles are generally many times larger than alleles in the premutation range. Therefore, FMR1 must be transcriptionally active to give rise to FXTAS. Thus, the pathogenesis of FXTAS (RNA toxicity) is completely distinct from the pathogenesis of fragile X syndrome (protein deficiency). Second, FMR1 expression is abnormal in at least 3 respects for alleles in the premutation range: (1) FMR1 mRNA levels are elevated by as much as 8-fold for premutation alleles over the levels found for normal alleles; (2) the mRNA itself is altered because of the presence of the expanded CGG repeat in the 5′ noncoding region of the message; and (3) the start site for transcription is altered (shifted upstream) by the presence of the expanded repeat, such that the 5′ end of the message is extended by about 50 nucleotides. Third, both mouse and Drosophila(fly) models that harbor the CGG repeat expansions in the premutation range (approximately 90-100 CGG repeats) manifest features of the neuropathology of FXTAS.37,38 Furthermore, the knock-in mice with an expanded (approximately 100 CGG repeat) FMR1 showed cognitive and behavioral impairment as well as ubiquitin-positive intranuclear inclusions.37,39 In the case of the fly model, neuropathic features are present even when the expanded CGG repeat is transcribed upstream of an unrelated reporter gene.38 Therefore, the expanded repeat, as RNA, is capable of inducing several features of the human disease. Fourth, in direct support of an RNA-based pathogenesis for FXTAS, the FMR1 mRNA is detected within the inclusions of patients with FXTAS.24 This observation provides a clear parallel with the intranuclear foci of the myotonic dystrophies DM1 (DMPK, OMIM #160900) and DM2 (ZNF9, OMIM #602668), which contain the expanded CUG repeat (DMPK) or CCUG repeat (ZNF9) RNAs, respectively.40-42 In this regard, the myotonic dystrophy model represents a useful framework for understanding the RNA gain-of-function pathogenesis of FXTAS, namely, that a normal interaction between 1 or more nuclear proteins and the repeat element, rendered abnormal by the expanded, and for FXTAS, overexpressed, repeat-containing RNA, is the inciting event for disease pathogenesis. For myotonic dystrophy, the RNA binding protein, muscleblind-like 1 (MBNL1), is sequestered by the large mRNA C(C)UG expansions; this sequestration is responsible, in part, for the altered splicing events associated with disease formation.42 Initial immunocytochemical studies of FXTAS inclusions demonstrated the presence of both ubiquitin and the small heat shock protein αB-crystallin, which is also found in the Rosenthal fibers of Alexander disease.43 The inclusions were found to be negative for either α-synuclein or tau isoforms. Recently, we have been able to isolate microgram quantities of purified inclusions using a novel automated particle-sorting protocol with immunofluorescence-tagged inclusions. Mass spectrometric analysis of the protein complement of the inclusions has revealed the presence of more than 30 proteins.44 Several of these proteins are of potential interest to the pathogenesis of FXTAS, including 2 RNA binding proteins, heterogeneous nuclear ribonuclear protein A2 (hnRNP A2) and MBNL1, and the nuclear intermediate filament protein lamin A/C (A and C isoforms). MBNL1 is also associated with the pathogenesis of myotonic dystrophy, although the functional significance of MBNL1 in FXTAS inclusions is not known. Expression of the expanded CGG repeat RNA in cultured neural cells results in the accumulation of lamin A/C within the intranuclear inclusions. This finding is in accord with the observation that lamin A/C is present within the neural cell intranuclear inclusions of patients with FXTAS. Furthermore, the expanded CGG repeat RNA leads to substantial disruption of the normal ringlike arrangement of lamin A/C at the nuclear periphery (Figure 3).45 This second aspect of the altered distribution of lamin A/C, with associated changes in nuclear morphology, is far more widespread than the formation of inclusions per se.45 These observations, and the finding that lamin A/C is present in both the inclusions of patients with FXTAS and the inclusions in cell culture, suggest that lamin A/C dysregulation may be a component of the pathogenesis of FXTAS. In this regard, a significant clinical feature of FXTAS is a peripheral (axonal) neuropathy13 that is similar to a form of type 2 Charcot-Marie-Tooth disease that is caused by mutations in the LMNA gene. On the basis of our current and previous findings, we hypothesize that FXTAS may represent a functional laminopathy; that is, abnormal lamin A/C function, induced by the expanded CGG repeat RNA, leads to many of the downstream effects involving both the central nervous and peripheral nervous systems. Treatment options There is no single therapeutic agent that is effective for all of the neurological features of FXTAS; current treatment approaches for symptomatic relief in FXTAS have focused on the use of existing agents that have shown some degree of efficacy in other movement disorders. A recent survey of medication use in 56 patients with FXTAS indicated that 40% were taking some form of medication for tremor/ataxia, parkinsonism, or cognitive decline, and most of these patients reported some improvement with various treatments.46 Although the numbers of patients treated are quite small, with results accordingly regarded as anecdotal, some improvement in the core movement disorder was reported with use of primidone (3 of 6 patients), β-blockers (3 of 8 patients), memantine (1 of 1 patient), or benzodiapines (2 of 8 patients). Parkinsonism improved while taking carbidopa/levodopa in 2 of 9 patients. Family members reported slowing of cognitive decline in 2 of 6 patients with FXTAS taking venlafaxine hydrochloride and 3 of 9 patients taking acetylcholinesterase inhibitors. Reduced anxiety was also reported in 2 of 6 patients with FXTAS taking venlafaxine and 5 of 8 patients taking benzodiazepines. An additional caveat with this initial survey was the questionnaire study design itself, which may have underestimated reported effectiveness in part because of the small sample sizes, cognitive impairment of the respondents, and lack of insight into some of the symptoms of the disease.46 Another anecdotal report noted that gabapentin appeared to be helpful for neuropathic pain in some patients with FXTAS.47 Both anxiety and depressive disorder in FXTAS may respond to antidepressant medications, such as selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors. The association of FXTAS with dementia indicates that benzodiazepines (associated risks to cognitive function) and tricyclic antidepressants (anticholinergic, possibly exacerbating cognitive impairment in some patients with FXTAS)48-52 should be used only with caution and careful follow-up. Clearly, what is needed at this point are large controlled trials with agents that have been reported to be of some benefit in the anecdotal reports. Hypertension, often observed in patients with FXTAS,47 should be treated aggressively to avoid the added deleterious effects of hypertensive vascular disease on the white matter disease associated with FXTAS. Furthermore, since the pathogenic trigger is known (FMR1 RNA), it is hoped that targeted intervention involving knock down of the RNA itself may become a viable approach to therapeutic intervention in the near future. Correspondence: Paul J. Hagerman, MD, PhD, Department of Biochemistry and Molecular Medicine, 4303 Tupper Hall, University of California, Davis, School of Medicine, 1 Shields Ave, Davis, CA 95616 ([email protected]). Accepted for Publication: January 8, 2007. Author Contributions:Study concept and design: R. J. Hagerman and P. J. Hagerman. Acquisition of data: Amiri, R. J. Hagerman, and P. J. Hagerman. Analysis and interpretation of data: Amiri, R. J. Hagerman, and P. J. Hagerman. Drafting of the manuscript: Amiri, R. J. Hagerman, and P. J. Hagerman. Critical revision of the manuscript for important intellectual content: R. J. Hagerman and P. J. Hagerman. Obtained funding: R. J. Hagerman and P. J. Hagerman. Administrative, technical, and material support: R. J. Hagerman and P. J. Hagerman. Study supervision: R. J. Hagerman and P. J. Hagerman. Financial Disclosure: None reported. Funding/Support: This work was supported by National Institutes of Health grants NS43532 and AG24488 (Dr P. J. Hagerman) and HD36071 (Dr R. J. Hagerman) and the National Fragile X Foundation (Drs P. J. Hagerman and R. J. Hagerman). Additional Contributions: Claudia Greco, MD, provided an unpublished image. We thank the families whose cooperation and support have made our research possible. References 1. Hagerman RJLeehey MHeinrichs W et al. 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Frohman, Elliot M.;Costello, Fiona;Stüve, Olaf;Calabresi, Peter;Miller, David H.;Hickman, Simon J.;Sergott, Robert;Conger, Amy;Salter, Amber;Krumwiede, Kimberly H.;Frohman, Teresa C.;Balcer, Laura;Zivadinov, Robert

Yoo, Sung-Hee;Kim, Jong S.;Kwon, Sun U.;Yun, Sung-Cheol;Koh, Jae-Young;Kang, Dong-Wha

doi: 10.1001/archneurol.2007.12pmid: 18195138

Abstract Objective To determine whether changes in nutritional status in the first week after acute ischemic stroke and undernutrition predicts poor clinical outcomes. Design Prospective observational study. Setting Tertiary university hospital. Patients We included 131 acute ischemic stroke patients who underwent nutritional assessments within 24 hours and at 1 week after symptom onset. Main Outcome Measures Undernutrition was diagnosed when 1 or more of the following 5 parameters were present: (1) weight loss 10% or more during the past 3 months or 6% or more during the week after admission, (2) a weight index less than 80%, (3) a serum albumin level less than 3.0 g/dL, (4) a transferrin level less than 150 mg/dL, or (5) a prealbumin level less than 10 mg/dL. We assessed poststroke complications and 3-month outcome using modified Rankin Scale responder analysis. Results Of 131 patients included in this study, undernutrition was observed in 16 (12.2%) patients at admission and in 26 (19.8%) at 1 week. Multiple logistic regression analysis showed that baseline undernutrition independently predicted 1-week undernutrition (odds ratio [OR], 14.85; 95% confidence interval [CI], 3.52-62.76; P < .001) and poststroke complications (OR, 6.72; 95% CI, 1.09-41.56; P = .04), and that 1-week undernutrition (OR, 4.49; 95% CI, 1.07-18.94; P = .04) and 1-week National Institutes of Health Stroke Scale score (OR, 1.76; 95% CI, 1.31-2.37; P < .001) independently predicted poor 3-month outcomes. Conclusions These findings suggest that acute ischemic stroke patients with baseline undernutrition are being undernourished during hospitalization. Strategic nutritional support, particularly in patients with baseline undernutrition, may improve clinical outcomes. Although undernutrition is common in medical,1 geriatric,2 and stroke3-12 patients, its treatment has received little attention. Because undernutrition may influence clinical outcomes, it is important to assess nutritional status and treat undernutrition particularly during acute stage of stroke. In investigating the association between undernutrition and clinical outcomes in stroke patients, several studies have shown that undernutrition contributes to clinical outcomes,5,7-9 whereas others have not.6,10 These inconsistent results may be because of the following reasons: Nutritional parameters and the definitions of undernutrition differ among studies. Many studies have evaluated undernutrition using a combination of hematologic and anthropometric parameters,4,5,8,9,11 while others have used subjective assessments, such as clinician's decision7 or patient-generated global assessment.6,10 The time point of nutritional assessment has also varied among studies, including within 24 hours,4-6 48 hours,8,10,11 or 7 days7 after stroke onset. Serial nutritional assessments have been performed rarely.5Moreover, many of these studies have evaluated ischemic and hemorrhagic stroke patients together,3,5-8,10-12 despite undernutrition being more prevalent in hemorrhagic than in ischemic stroke.4 There are also differences in clinical outcome measures, which have included the Barthel index,5 the modified Rankin Scale (mRS),6 hospital stay,3,8,10 poststroke complications,7 and mortality,8,9 and in the confounding variables considered in the data analysis. With these considerations in mind, we sought to determine whether undernutrition independently predicts poststroke complications and long-term poor clinical outcomes in acute ischemic stroke patients by serial measurements of more objective nutritional parameters and by adjusting for all potential confounding factors. Methods Patients This was a prospective study performed between December 8, 2004, and December 12, 2005, at the Asan Medical Center, Seoul, Korea. Patients were included if they had an acute ischemic stroke confirmed by diffusion-weighted imaging performed within 24 hours of symptom onset and if they had serial nutritional assessments within 24 hours and 1 week after onset. We excluded patients who were treated with intravenous or intra-arterial thrombolysis or who might need angioplasty, stenting, or an operation such as craniectomy within 1 week after stroke onset, because these invasive treatments may strongly influence subsequent nutritional status and clinical outcomes. This study was approved by the institutional review boards of the Asan Medical Center, and written informed consent was obtained from each patient, family, or legal guardian. Data collection Demographics, risk factors for vascular disease, comorbid disease (such as cancer, recent surgery, or recent infection), premorbid mRS score, stroke severity, stroke subtype according to the Trial of ORG 10172 in Acute Stroke Treatment classification,13 nutritional status, diet methods (regular, dysphagic, or enteral feed) and amount (sufficient vs insufficient), and clinical outcomes were assessed. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) within 24 hours and at 1 week after onset or at the time of discharge. Swallowing function at admission was evaluated at bed side by a physician and, if necessary, by video fluoroscopic swallow study. Patients were given a regular oral diet, dysphagic diet, or enteral feed via Levin tube according to the results of a swallowing function test and were supplied with daily calories as total energy expenditure based on the Harris-Benedict equation and activity factor.14 Patients were considered to have been given enteral feed if they were fed via Levin tube for more than half of the first week. Patients were encouraged to intake total calories and were considered as having consumed a sufficient diet when they were fed more than 80% of total desired calories. Nutritional assessment Nutritional status was evaluated at admission and at 1 week or discharge using the following 5 nutritional parameters: (1) weight loss,15 (2) weight index,16 measured as actual body weight in relation to reference weight, (3) serum albumin level,14,15 (4) serum transferrin level,14,15 and (5) serum prealbumin level.14 These parameters were selected because they reflected global assessment (weight loss), somatic protein compartment (weight index), and visceral protein compartment (albumin, transferrin, and prealbumin levels). Previous weight loss was assessed by a face-to-face interview with the patients or their significant others at admission. Body weight was measured using a portable in-bed scale for immobile patients and a fatness measuring system for ambulatory patients at admission. Undernutrition was diagnosed when 1 or more of 5 parameters showed moderate or severe undernutrition: (1) weight loss of 10% or more of body weight for the past 3 months or 6% or more during the first week after admission, (2) weight index less than 80%, (3) serum albumin level of less than 3.0 g/dL (to convert to grams per liter, multiply by 10), (4) serum transferrin level of less than 150 mg/dL, or (5) serum prealbumin level of less than 10 mg/dL (to convert to milligrams per liter, multiply by 10).14 Nutritional changes from baseline to 1 week were categorized as no change (from healthy to healthy, or from undernutrition to undernutrition), improved (from undernutrition to healthy), or worsened (from healthy to undernutrition). Clinical outcomes The presence of poststroke complications was assessed immediately after admission and up to discharge or transfer to a rehabilitation unit and included pneumonia, myocardial infarction, urinary tract infection, extracranial hemorrhage, deep vein thrombosis, and pressure sore. Pneumonia was diagnosed as probable by the presence of (1) high fever (> 38.0°C), (2) 1 or more clinical symptoms or signs (purulent sputum or rale), and (3) abnormal laboratory findings (leukocytosis or increased erythrocyte sedimentation rate or C-reactive protein level) and as definite when these 3 criteria were accompanied by lung infiltrates on chest radiography. Myocardial infarction was diagnosed when 2 of the following 3 criteria were met: chest pain continuing for more than 30 minutes, increased cardiac enzyme (creatine kinase MB, troponin T, or troponin I) levels, and diagnostic electrocardiographic changes. Urinary tract infection was diagnosed when clinical symptoms, such as high fever and pyuria, were present or when bacteria (> 105 colony-forming units/mL) were grown from urine culture. Extracranial hemorrhage, such as gastrointestinal bleeding or gross hematuria, was defined as clinically significant hemorrhage that needed close observation, transfusion, or operation. Deep vein thrombosis was diagnosed by swelling or pain in the calf, with or without abnormal image (ultrasound scan or venography) findings. A pressure sore was defined as an abrasion or necrosis of the skin and tissue due to sustained pressure, friction, or moisture. Long-term clinical outcome was assessed by mRS score at 3 months, with outcome categorized as good or poor according to responder analysis, which judges outcome based on baseline NIHSS score.17 Good outcome was defined as an mRS score of 0 if baseline NIHSS score was less than 8, an mRS score of 0 to 1 if baseline NIHSS score was 8 to 14, and an mRS score of 0 to 2 if baseline NIHSS score was 15 or higher. Serial NIHSS scores, poststroke complications, and long-term clinical outcome were assessed by one investigator blinded to baseline characteristics and nutritional status. Data analysis The McNemar test was used to compare baseline and 1-week undernutrition. To identify the factors associated with baseline and 1-week undernutrition, poststroke complication, and 3-month outcome, the Fisher exact test, t test, and the Mann-Whitney test were used where appropriate. Multiple logistic regression analysis was used to determine independent predictors of 1-week undernutrition, poststroke complication, and poor 3-month outcome. Variables were selected for entry into the model based on the results of univariate analyses (P < .05). Because we tried to identify predictors of clinical outcomes, the precedent variables to poststroke complications and 3-month outcome were entered into the models. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The Hosmer-Lemeshow goodness-of-fit test was used to assess how well the model accounted for outcomes. SPSS, version 12.0 (SPSS Inc, Chicago, Illinois), for Windows was used for statistical analyses. Two-tailed P < .05 was considered to indicate a significant difference. Results A total of 264 patients were screened for this study, but 133 were excluded: 40 for thrombolysis, 9 for angioplasty or other operation, 75 for unavailable nutritional assessment, and 9 for refusal of consent or withdrawal. There were no differences in demographic characteristics, risk factors, or stroke subtypes between included and excluded participants, except that baseline NIHSS scores were higher in excluded (median, 7; range, 0-30) than in included (median, 4; range, 0-23; P < .001) patients. Of the 131 patients included in this study, 84 (64.1%) were men. Patients had a mean (SD) age of 64.8 (10.3) years and a median (range) baseline NIHSS score of 4 (0-23). Stroke intensity was mild (baseline NIHSS score, 0-7) in 109 patients (83.2%), moderate (baseline NIHSS score, 8-14) in 15 (11.5%), and severe (baseline NIHSS score, ≥ 15) in 7 (5.3%). Premorbid mRS score was 0 in all patients. Undernutrition was observed in 16 (12.2%) patients at admission and in 26 (19.8%) at 1 week, showing a significant increase during the first week (P = .03 by McNemar test) (Table 1). Nutritional status according to each parameter also deteriorated during hospitalization, with the most profound being serum albumin concentration (P < .001 by McNemar test). During the first week, there were no nutritional changes in 113 (86.3%) patients, improved nutrition in 4 (3.1%), and worsened nutrition in 14 (10.7%). Factors associated with undernutrition at baseline and 1 week Age (P = .001), cardioembolic stroke (P = .001), and higher baseline NIHSS score (P = .04) were associated with the presence of baseline undernutrition. The baseline characteristics associated with 1-week undernutrition included age (P = .01), absence of hypercholesterolemia (P = .04), baseline undernutrition (P < .001), and enteral feed (P = .049). Multiple logistic regression analysis showed that only baseline undernutrition (OR, 14.85; 95% CI, 3.52-62.76; P < .001) independently predicted subsequent undernutrition. Predictors of poststroke complications Poststroke complications were observed in 11 of 131 (8.3%) patients, with aspiration pneumonia in 5, extracranial hemorrhage in 3, myocardial infarction in 2, and bed sores in 1. Univariate analysis showed that old age (P = .001), cardioembolic stroke (P = .003), higher baseline NIHSS score (P < .001), baseline undernutrition (P < .001), and enteral feed (P < .001) were associated with more frequent poststroke complications (Table 2). Multiple logistic regression analysis showed that baseline NIHSS score (OR, 1.21; 95% CI, 1.01-1.45; P = .04) and baseline undernutrition (OR, 6.72; 95% CI, 1.09-41.56; P = .04) were independent predictors of poststroke complications during hospitalization (Table 3). Predictors of poor outcome at 3 months During the 3-month follow-up period, recurrent stroke occurred in 2 (1.5%) patients and death occurred in 4 (3.1%) patients, 2 due to respiratory failure, 1 due to cancer, and 1 unknown cause. Baseline and 1-week undernutrition were not associated with recurrent stroke or death. Poor outcome, as defined by 3-month mRS responder analysis, was observed in 87 (66.4%) patients and was significantly associated with female sex (P = .01), 1-week undernutrition (P = .01), insufficient diet for the first week (P = .02), and higher baseline (P < .001) and 1-week (P < .001) NIHSS scores by univariate analysis (Table 2). Multiple logistic regression analysis revealed that 1-week undernutrition (OR, 4.49; 95% CI, 1.07-18.94; P = .04) and 1-week NIHSS score (OR, 1.76; 95% CI, 1.31-2.37; P < .001) predicted poor 3-month outcome (Table 3). When we defined poor outcome as an mRS score of 2 to 6 (n = 47 [35.9%]) or of 3 to 6 (n = 24 [18.3%]), 1-week undernutrition was associated with poor outcomes (mRS score, 2-6, P = .01; mRS score, 3-6, P = .006). However, multivariate analyses showed that only 1-week NIHSS score (OR, 2.19; 95% CI, 1.57-3.06) remained an independent predictor of poor outcome (mRS score, 2-6) and that age (OR, 1.16; 95% CI, 1.05-1.27) and 1-week NIHSS score (OR, 2.48; 95% CI, 1.59-3.87) remained independent predictors of poor outcome (mRS score, 3-6). Comment This study shows that undernutrition was an independent predictor of poststroke complications and poor clinical outcome in acute ischemic stroke patients. This study has several methodological advantages over previous ones. Serial nutritional assessments using more objective nutritional parameters were performed in the acute stage of stroke. Only acute ischemic stroke patients were included. All potential confounding variables, such as vascular risk factors, comorbid diseases, stroke severity, stroke subtypes, and diet methods and amount, were considered in the analysis to demonstrate the independent contribution of undernutrition to poor clinical outcomes. Baseline undernutrition was an independent predictor of subsequent undernutrition in our sample. We also observed significant associations between baseline undernutrition and poststroke complications during hospitalization and between 1-week undernutrition and poor 3-month clinical outcomes. These results suggest that patients undernourished at admission do not recover well with general hospital diets and are more likely to have poststroke complications and that undernourished patients during hospitalization are more likely to develop poor functional outcomes. However, baseline undernutrition was not directly associated with long-term outcome, a finding similar to previous work.6 For an explanation of this lack of correlation, we speculate that long-term outcome may be more affected by progress during hospitalization than by baseline characteristics. We also consider that these results emphasize the significance of nutritional support during hospitalization. The frequency of undernutrition in our study was 12.2% at admission (< 24 hours after onset) and 19.8% at 1 week, which was relatively lower than in previous studies.4,5,8,9,11 The difference in the frequency may be related to different definitions of undernutrition. We defined only moderate to severe undernutrition of each parameter as undernutrition, whereas other studies have included mild undernutrition in the definition.4,5,8,9 In addition, we included patients who had relatively mild strokes while excluding patients receiving thrombolysis or emergency interventional treatments. Because stroke severity was significantly associated with undernutrition, excluding severe stroke patients may have resulted in a lower prevalence of undernutrition. We also excluded hemorrhagic stroke patients in whom undernutrition has been shown to be more prevalent than in ischemic stroke patients.4 The parameters for nutritional assessment also differ among studies. As a visceral protein compartment, serum albumin level has been used for nutritional assessment and is known to be a good predictor of clinical outcome.8,9 However, serum albumin level is of limited utility in detecting acute nutritional changes owing to its long half-life (18 days).15 We therefore also measured transferrin and prealbumin levels, which have shorter half-lives, 8 and 2 days, respectively. In this study, undernutrition was more likely detected in the transferrin parameter than in the albumin parameter at admission, but temporal changes during 1 week were more pronounced in the albumin parameter. The mechanism of these findings is unclear, and the advantages of transferrin and prealbumin over albumin levels in detecting undernutrition were not demonstrated in this study. Moreover, whereas other studies have used anthropometric parameters, such as caliper skin fold measures at multiple body sites, for nutritional assessment, we did not use these parameters, as they have been shown to be unsuitable for stroke patients with tetraparesis or spasticity as a sequelae of stroke, especially in assessing acute nutritional change.15,18 We used mRS responder analysis, which is influenced by initial stroke severity, to assess long-term clinical outcome. Because most of our patients had had mild or moderate strokes, we thought that responder analysis might be more appropriate than conventional mRS categorical analysis. Our study has several limitations. First, it was conducted in a single tertiary hospital in an Asian country, thus limiting generalization of our results to other communities or countries where dietary patterns are likely different. Second, not all acute ischemic stroke patients were included, which resulted in including patients with relatively milder stroke in this study. The low incidence of poststroke complications may have resulted in wide CI of ORs. The incidence of recurrent stroke or death was too low to find an association with undernutrition. Third, undernutrition was not an independent predictor of poor outcome when we defined poor outcome as an mRS score of 2 to 6 or 3 to 6. Thus, further studies with a larger sample size should be conducted to confirm our findings. In conclusion, this study shows that acute ischemic stroke patients with baseline undernutrition are being undernourished during hospitalization and that undernutrition independently predicts poor clinical outcomes in these patients. Strategic nutritional support, particularly in patients with baseline undernutrition, may improve clinical outcomes after acute ischemic stroke. Correspondence: Dong-Wha Kang, MD, PhD, Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-2 dong, Songpa-gu, Seoul 138-736, Korea ([email protected]). Accepted for Publication: January 31, 2007. Author Contributions:Study concept and design: Yoo and Kang. Acquisition of data: Yoo and Kang. Analysis and interpretation of data: Yoo, Kim, Kwon, Yun, Koh, and Kang. Drafting of the manuscript: Yoo and Kang. Critical revision of the manuscript for important intellectual content: Kim, Kwon, Yun, Koh, and Kang. Statistical analysis: Yun. Obtained funding: Kang. Administrative, technical, and material support: Kim, Kwon, Koh, and Kang. Study supervision: Kang. Financial Disclosure: None reported. Funding/Support: This study was supported by grant 03-PJ1-PG1-CH06–0001 from the Korean Ministry of Health and Welfare, grant A060171 from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea, and grant M103KV010010 06K2201 01010 from the Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology of Korea. References 1. Bistrian BRBlackburn GLVitale JCochran DNaylor J Prevalence of malnutrition in general medical patients. JAMA 1976;235 (15) 1567- 1570PubMedGoogle ScholarCrossref 2. Potter JKlipstein KReilly JJRoberts M The nutritional status and clinical course of acute admissions to a geriatric unit. Age Ageing 1995;24 (2) 131- 136PubMedGoogle ScholarCrossref 3. Axelsson KAsplund KNorberg AAlafuzoff I Nutritional status in patients with acute stroke. Acta Med Scand 1988;224 (3) 217- 224PubMedGoogle ScholarCrossref 4. Choi-Kwon SYang YHKim EKJeon MYKim JS Nutritional status in acute stroke: undernutrition versus overnutrition in different stroke subtypes. Acta Neurol Scand 1998;98 (3) 187- 192PubMedGoogle ScholarCrossref 5. Dávalos ARicart WGonzalez-Huix F et al. Effect of malnutrition after acute stroke on clinical outcome. Stroke 1996;27 (6) 1028- 1032PubMedGoogle ScholarCrossref 6. Davis JPWong AASchluter PJHenderson RDO'Sullivan JDRead SJ Impact of premorbid undernutrition on outcome in stroke patients. Stroke 2004;35 (8) 1930- 1934PubMedGoogle ScholarCrossref 7. FOOD Trial Collaboration, Poor nutritional status on admission predicts poor outcomes after stroke: observational data from the FOOD trial. Stroke 2003;34 (6) 1450- 1456PubMedGoogle ScholarCrossref 8. Gariballa SEParker SGTaub NCastleden CM Influence of nutritional status on clinical outcome after acute stroke. Am J Clin Nutr 1998;68 (2) 275- 281PubMedGoogle Scholar 9. Gariballa SEParker SGTaub NCastleden M Nutritional status of hospitalized acute stroke patients. Br J Nutr 1998;79 (6) 481- 487PubMedGoogle ScholarCrossref 10. Martineau JBauer JDIsenring ECohen S Malnutrition determined by the patient-generated subjective global assessment is associated with poor outcomes in acute stroke patients. Clin Nutr 2005;24 (6) 1073- 1077PubMedGoogle ScholarCrossref 11. Unosson MEk ACBjurulf Pvon Schenck HLarsson J Feeding dependence and nutritional status after acute stroke. Stroke 1994;25 (2) 366- 371PubMedGoogle ScholarCrossref 12. Westergren AKarlsson SAndersson POhlsson OHallberg IR Eating difficulties, need for assisted eating, nutritional status and pressure ulcers in patients admitted for stroke rehabilitation. J Clin Nurs 2001;10 (2) 257- 269PubMedGoogle ScholarCrossref 13. Adams HP JrBendixen BHKappelle LJ et al. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial, TOAST, Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24 (1) 35- 41PubMedGoogle ScholarCrossref 14. Curtas SChapman GMeguid MM Evaluation of nutritional status. Nurs Clin North Am 1989;24 (2) 301- 313PubMedGoogle Scholar 15. Lipkin EWBell S Assessment of nutritional status: the clinician's perspective. Clin Lab Med 1993;13 (2) 329- 352PubMedGoogle Scholar 16. Warnold ILundholm K Clinical significance of preoperative nutritional status in 215 noncancer patients. Ann Surg 1984;199 (3) 299- 305PubMedGoogle ScholarCrossref 17. Adams HP JrLeclerc JRBluhmki EClarke WHansen MDHacke W Measuring outcomes as a function of baseline severity of ischemic stroke. Cerebrovasc Dis 2004;18 (2) 124- 129PubMedGoogle ScholarCrossref 18. 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Li, Hao;Wetten, Sally;Li, Li;Jean, Pamela L. St.;Upmanyu, Ruchi;Surh, Linda;Hosford, David;Barnes, Michael R.;Briley, James David;Borrie, Michael;Coletta, Natalie;Delisle, Richard;Dhalla, Daniella;Ehm, Margaret G.;Feldman, Howard H.;Fornazzari, Luis;

Seneviratne, Janaka;Mandrekar, Jay;Wijdicks, Eelco F. M.;Rabinstein, Alejandro A.

doi: 10.1001/archneurol.2007.1pmid: 18195139

Abstract Background Myasthenic crisis (MC) is often associated with prolonged intubation and with respiratory complications. Objectives To assess predictors of ventilation duration and to compare the effectiveness of endotracheal intubation and mechanical ventilation (ET-MV) with bilevel positive airway pressure (BiPAP) noninvasive ventilation in MC. Design Retrospective cohort study. Setting Academic research. Patients We reviewed consecutive episodes of MC treated at the Mayo Clinic, Rochester, Minnesota. Main Outcome Measures Collected information included patients' demographic data, immunotherapy, medical complications, mechanical ventilation duration, and hospital lengths of stay, as well as baseline and preventilation measurements of forced vital capacity, maximal inspiratory and expiratory pressures, and arterial blood gases. Results We identified 60 episodes of MC in 52 patients. BiPAP was the initial method of ventilatory support in 24 episodes and ET-MV was performed in 36 episodes. There were no differences in patient demographics or in baseline respiratory variables and arterial gases between the groups of episodes initially treated using BiPAP vs ET-MV. In 14 episodes treated using BiPAP, intubation was avoided. The mean duration of BiPAP in these patients was 4.3 days. The only predictor of BiPAP failure (ie, requirement for intubation) was a PCO2 level exceeding 45 mm Hg on BiPAP initiation (P = .04). The mean ventilation duration was 10.4 days. Longer ventilation duration was associated with intubation (P = .02), atelectasis (P < .005), and lower maximal expiratory pressure on arrival (P = .02). The intensive care unit and hospital lengths of stay statistically significantly increased with ventilation duration (P < .001 for both). The only variable associated with decreased ventilation duration was initial BiPAP treatment (P < .007). Conclusions BiPAP is effective for the treatment of acute respiratory failure in patients with myasthenia gravis. A BiPAP trial before the development of hypercapnia can prevent intubation and prolonged ventilation, reducing pulmonary complications and lengths of intensive care unit and hospital stay. Myasthenic crisis (MC) is defined by the appearance of acute neuromuscular respiratory failure requiring mechanical ventilation.1-3 Traditionally, patients with MC are managed using endotracheal intubation and mechanical ventilation (ET-MV), which explains why class V in the Myasthenia Gravis Foundation of America4 clinical classification is defined by intubation. Improvements in respiratory care were primarily responsible for the dramatic reduction in mortality among patients with MC that occurred in the 1970s.5 Despite the introduction of effective immunotherapies (plasma exchange and intravenous immunoglobulin),6,7 prolonged care in the intensive care unit (ICU) is still necessary for many patients.8-10 The development of pulmonary complications (atelectasis and pneumonia) after ET-MV is probably the most frequent cause for lengthier ICU stays.8,10 Therefore, averting ET-MV could have a strong beneficial effect on duration of hospitalization and on cost of care. Bilevel positive airway pressure (BiPAP) noninvasive ventilation may offer a viable alternative to ET-MV, as suggested by previous findings.11 Noninvasive ventilation seems desirable in patients with MC because prolonged ET-MV is associated with higher risk of ventilator-associated pneumonia and other systemic complications.10 BiPAP has been successfully used to treat acute respiratory failure from cardiopulmonary illnesses12-14 and chronic neuromuscular disorders with ventilatory compromise.15-17 Through a face mask, BiPAP machines deliver adjustable degrees of continuous positive pressure, which is highest during inspiration and lower during expiration. Each cycle is triggered by the patient's breathing effort. Inspiratory positive pressure helps overcome upper airway resistance and reduces the work of breathing. End-expiratory positive pressure prevents airway collapse at the conclusion of each breathing cycle, diminishing the risk of atelectasis. This type of ventilatory support fits well the needs of fatigued patients with MC, who remain capable of initiating breaths but cannot move sufficient air volumes to prevent the progression of microatelectasis and to maintain normal gas exchange and who develop problems from upper airway collapse. We reviewed our experience treating patients with MC to assess the efficacy of noninvasive ventilation using BiPAP in these patients. We sought to identify predictors of noninvasive ventilation outcome and to evaluate which factors predict ventilation duration in MC. Methods The study was approved by our institutional review board. We retrospectively identified all patients with MC admitted to the Mayo Clinic ICU and neurology ICU between January 1987 and December 2006. Myasthenic crisis was defined as acute exacerbation of muscle weakness leading to neuromuscular respiratory failure requiring invasive (ET-MV) or noninvasive (BiPAP) ventilatory support. Postthymectomy patients (n = 10), patients with Lambert-Eaton syndrome (n = 1), and patients with congenital myasthenia (n = 6) were excluded from the study. One patient with MC who was initially seen in respiratory distress due to a pneumothorax was excluded. Patients with MC who were intubated for respiratory failure because of cardiac failure and underlying respiratory disease were also excluded. All patients had severe generalized and bulbar weakness. A clinical diagnosis of MC was confirmed in all patients by 1 or more of the following investigations: repetitive nerve stimulation, acetylcholine receptor antibody positivity, or single-fiber electromyographic testing. The general criteria to consider ventilation were forced vital capacity less than 15 to 20 mL/kg of body weight, maximal inspiratory pressure (MIP) less than −40 cm of water, maximal expiratory pressure (MEP) less than 40 cm of water, or evidence of respiratory muscle fatigue, hypercapnia, or hypoxia. However, these criteria were used as guidelines, and the timing of initiation of ventilation and the decision to intubate depended on the clinical assessment and practice preference of the emergency department staff or intensivist in the ICU. We collected patients' demographic and clinical information, including age, sex, weight, previous crisis, history of thymoma, treatment on admission, time from diagnosis to present crisis, acetylcholine receptor antibody positivity, trigger factors (eg, infection, surgery, or change of medications), and other medical history (lung disease, smoking history, diabetes mellitus, cancer, or cardiac failure). The presence of lung disease was determined by the documented diagnosis of asthma, restrictive lung disease, obstructive sleep apnea, or chronic obstructive pulmonary disease. Arterial blood gases and bedside pulmonary function test results (forced vital capacity [FVC] in milliliters per kilogram of body weight, MIP, and MEP) were recorded when available on admission, before BiPAP or intubation, and on extubation or discontinuation of BiPAP. Bedside pulmonary function tests were performed using a scubalike device that reduced air leakage. Arterial-alveolar gradients were calculated using the alveolar air equation. Duration of BiPAP or intubation (total ventilation duration) was recorded. If a patient required reintubation or BiPAP during the same ICU admission, this period was included in the total ventilation duration. The medical treatment initiated (plasmapheresis, intravenous immunoglobulin, or intravenous corticosteroids) in the ICU was recorded. Weaning of ventilated patients was not attempted until adequate medical treatment had been initiated. The use of a T-piece or BiPAP support after extubation was recorded. In patients who failed extubation, we collected the time of reintubation, cause of reintubation (fatigue, atelectasis, or lobar collapse), and complications from extubation failure. When applicable, the timing of tracheostomy was noted. All medical complications during the ICU stay were recorded, with the major categories being atelectasis, pneumonia, bronchitis, cardiac arrest, and sepsis. Chest radiographs were reviewed for the presence of atelectasis and consolidation. Atelectasis was defined by unequivocal radiological evidence of segmental or lobar collapse. The diagnosis of pneumonia required the presence of fever, new infiltrate on chest radiographs, and positive culture of respiratory secretions. The ICU length of stay and the total hospital length of stay were tabulated. Functional status and disposition at discharge (home, rehabilitation facility, or nursing home) were also collected. We analyzed predictors of outcome in patients treated using noninvasive ventilation. Failure of noninvasive ventilation was determined by a requirement for intubation after BiPAP trial. Predictors of longer duration of mechanical ventilation were evaluated in our entire population. Ventilation duration was computed by adding the duration of BiPAP use and the duration of invasive ventilation (synchronized intermittent mandatory ventilation or pressure support of ≥7 mm Hg). Descriptive summaries were given as medians and ranges for continuous variables and as frequencies and percentages for categorical variables. Baseline demographic and physiological variables among the 3 groups (BiPAP success, BiPAP failure, and ET-MV) were compared using Kruskal-Wallis test or χ2 test based on whether the variable was continuous or categorical. Similarly, comparisons of clinical end points between groups receiving initial BiPAP vs initial ET-MV were made using the Wilcoxon rank sum test or χ2 test (or Fisher exact test) as appropriate. Nonparametric tests were used because of small sample sizes and nongaussian distribution of the data. Univariate logistic regression analysis was used to assess the association between the several potential predictors and ventilation duration as binary outcome variables. Associations were reported in terms of odds ratios and 95% confidence intervals. All tests were 2-sided, and P < .05 was considered statistically significant. Results We identified 60 episodes of MC in 52 patients treated using BiPAP or ET-MV. BiPAP was tried initially in 24 episodes (40%) and ET-MV was performed without preceding BiPAP trial in 36 episodes (60%). Ten episodes initially treated using BiPAP subsequently required ET-MV during the same admission (ie, BiPAP failure). Therefore, 46 of 60 patients (77%) in our population were intubated for the treatment of their MC. The mean patient age was 62.6 years (age range, 17-90 years), and 52% (32) were women. The median disease duration from diagnosis to presentation with MC was 4 years (range, 1 month to 43 years). Thymoma was documented in 19 patients (42%), previous crisis in 17 patients (43%), and lung disease in 12 patients (22%). Acetylcholine receptor antibodies were present in 42 patients (91%). Anti-MuSK (muscle-specific receptor tyrosine kinase) antibody was not present in any of the patients. The most common triggers were medication changes in 21 episodes (32% [most frequently the addition of medications unrelated to the therapy of MC or a reduction in the dosages of pyridostigmine bromide or immune medications]), infection in 20 episodes (35%), and surgery in 8 episodes (12%). Bulbar weakness was uniformly present in all episodes. Immunotherapy was administered in all cases, including plasma exchange in 40 episodes (67%), high-dose intravenous corticosteroids in 13 episodes (22%), and intravenous immunoglobulin in 6 episodes (10%). We compared baseline demographic and physiological variables (measured at the time of presentation in the emergency department) of patients treated initially using BiPAP with those of patients managed using ET-MV without preceding BiPAP trial. There were no statistically significant differences between these 2 groups. No baseline differences were observed when cases of BiPAP success and BiPAP failure were analyzed separately or were compared with cases treated directly using ET-MV, as summarized in Table 1. We then focused the analysis on 24 patients initially treated using BiPAP. The median age was 61 years (age range, 17-90 years). The median disease duration was 4 years (range, 0.08-15 years), 11 patients (46%) had experienced a previous crisis, and 8 patients (33%) had a history of thymoma. All patients had acetylcholine receptor antibodies. Bulbar weakness was uniformly present. Fourteen patients (58%) were successfully treated using BiPAP only (ie, did not require endotracheal intubation). The mean maximal inspiratory/expiratory BiPAP pressures were 14/6 mm Hg (range, 10-18/96-100 mm Hg). The mean (SD) duration of BiPAP use in these successful cases was 4.3 (2.9) days. The FVC, MIP, MEP, and PO2 level on admission or on BiPAP initiation failed to predict outcome of noninvasive ventilation, although pulmonary function tests on BiPAP initiation were not performed in 9 patients (38%). Trigger factors, type of immunotherapy administered, and history of crisis or preexisting lung disease also failed to predict outcome of BiPAP treatment. The only predictor of BiPAP failure was a PCO2 level exceeding 45 mm Hg on BiPAP initiation (P = .04). The mean (SD) ventilation duration in the entire population was 10.4 (11.1) days. Ventilation duration was 5.6 days (range, 1.5-21.0 days) in patients initially treated using BiPAP vs 13.6 days (range, 3-60 days) in patients initially treated using ET-MV. When assessing ventilation duration as a continuous variable, longer ventilation duration was associated with ET-MV use (P = .02), lower MEP on arrival (P = .02), and the development of atelectasis (P < .005). The only variable associated with decreased ventilation duration was BiPAP treatment (P < .007). Ventilation duration longer than 7 days (which was the median ventilation duration for the entire population) was associated with ET-MV use, atelectasis, lower MEP on arrival, treatment with intravenous corticosteroids, and a history of crisis and thymoma. Conversely, the only variable associated with lower likelihood of ventilation duration longer than 7 days was BiPAP use (Table 2). The median ICU length of stay for the entire study population was 10.5 days (range, 1-60 days), and the median hospital length of stay was 17 days (range, 1-123 days). The intensive care unit and hospital lengths of stay statistically significantly increased with ventilation duration (P < .001 for both). Initial BiPAP use statistically significantly shortened these stays by one-third (median, 7 days). Rates of pulmonary complications, atelectasis, and pneumonia did not differ between the patients initially treated using BiPAP vs ET-MV. However, the difference was statistically significant when patients successfully treated using BiPAP vs patients treated using ET-MV (ie, BiPAP failure plus initial ET-MV) were compared (3[21%] vs 25[54%], P =.04). Table 3 summarizes the differences in pulmonary complications and lengths of stay between patients initially treated using BiPAP vs ET-MV. Two patients died of complications from their MC, resulting in a mortality rate of 3.3%. Both deaths occurred in patients initially treated using ET-MV. Comment In this analysis of 60 episodes of MC, initial treatment using BiPAP was associated with shorter ventilation duration and ICU stay compared with patients managed using the conventional strategy of ET-MV. This benefit may have been because of the decreased rates of pulmonary complications among patients successfully treated using BiPAP. When instituted early, BiPAP avoided the use of ET-MV, but the presence of hypercapnia at the time of BiPAP initiation predicted failure of noninvasive ventilation and subsequent ET-MV. Fatigue of the diaphragm and accessory breathing muscles resulting in insufficient air exchange constitutes the most common indication for mechanical ventilation in MC. In addition, upper airway collapse from weakness of oropharyngeal and laryngeal muscles and the inability to clear secretions may precipitate respiratory failure or may contribute to its development.3,18 BiPAP may effectively support the weak respiratory muscles, enhance alveolar recruitment, prevent atelectasis from alveolar collapse, and help overcome the increased upper airway resistance. The concern that accumulation or aspiration of respiratory secretions could limit the usefulness of BiPAP in patients with MC is not substantiated by the results of this study, as patients treated in a timely manner using BiPAP had low rates of pneumonia. To assess the validity of our findings, we compared our groups of patients initially treated using BiPAP vs ET-MV. There were no differences in serologic status, comorbid conditions, demographic variables, duration of myasthenia, history of thymoma or crisis, or distribution of precipitants for the crisis. Furthermore, arterial blood gases and respiratory function test results were comparable on arrival to the emergency department, indicating that the patients had similar degrees of respiratory compromise. Patients were also similarly treated using immunotherapy during their hospitalization. Hence, baseline differences did not seem to have accounted for the better results observed in patients initially treated using BiPAP. The baseline characteristics of our patient population (ie, age, disease duration, and triggering factors) were comparable with those of previously reported large case series.8,10 As in other series, our patients were treated using immunotherapy (plasma exchange or intravenous immunoglobulin [and sometimes intravenous corticosteroids]). Our overall rates of pulmonary complications and ICU lengths of stay were in the lower ranges of those previously reported,8,10 mostly because of the lower incidence of pulmonary complications and the shorter ICU lengths of stay in patients successfully treated using BiPAP. Therefore, the population of patients with MC presented herein is comparable to other large published series, except for the use of noninvasive ventilation. Bedside variables of respiratory function, pulmonary function test results (FVC, MIP, and MEP), and arterial blood gases had limited predictive value in our study, with few exceptions. Results of tests of pulmonary function measured on arrival to the emergency department and before BiPAP initiation failed to predict the outcome of noninvasive ventilation. The small size of the population under study for this part of the analysis and the lack of measurement of pulmonary function immediately before BiPAP initiation in approximately one-third of patients treated using noninvasive ventilation may have limited our ability to assess the predictive value of these tests. Nonetheless, hypercapnia (PCO2 level, >45 mm Hg) on arterial blood gas measurement was associated with BiPAP failure. Conversely, arterial blood gas measures on arrival and at the time of BiPAP initiation or ET-MV did not predict ventilation duration, but patients with initial lower MEP were at risk for requiring prolonged ventilation. Lower MEP on arrival, the development of atelectasis, and initial ET-MV were the variables most consistently associated with prolonged ventilation. Initial BiPAP was the only factor associated with lower risk of long ventilatory requirement. This association may have resulted from the lower rate of pulmonary complications in patients successfully treated using BiPAP only. However, patients in whom BiPAP failed had high rates of pulmonary complications (present in 8 of 10 patients) that often resulted in prolonged ventilation (5 of 10 patients needed ventilation for >10 days). Hence, initial treatment using BiPAP may decrease the risk of prolonged ventilatory requirement, but early institution of noninvasive ventilation, before the development of hypercapnia, is crucial to achieve this goal. The main limitation of our study is that the criteria for initiating ventilation and choosing the initial mode of ventilation (noninvasive or invasive) were not uniform. These decisions were made by the treating physicians based on some general guidelines (see the “Methods” section) but were often mostly based on personal preferences. This practice variation explains why patients with similar disease severity were sometimes initially treated using BiPAP and at other times using ET-MV. The lack of statistically significant differences in the initial measures of respiratory muscle strength (FVC, MIP, and MEP) and gas exchange (arterial blood gases) between the 2 treatment groups supports the validity of the comparison, although the small size of the subpopulations compromises the power of the analysis. Hence, our findings should be best interpreted as raising a hypothesis that needs to be tested in a randomized controlled study. The results of this study indicate that noninvasive ventilation using BiPAP should be considered in selected patients with MC who have respiratory compromise (those without hypercapnia and with the ability to synchronize with the machine) as the initial method of ventilatory support. We believe that a randomized trial comparing BiPAP vs ET-MV in patients with MC should be undertaken. Correspondence: Alejandro A. Rabinstein, MD, Department of Neurology, Mayo Clinic, 200 First St SW, Mayo W8, Rochester, MN 55905 ([email protected]). Accepted for Publication: August 14, 2007. Author Contributions:Study concept and design: Seneviratne and Rabinstein. Acquisition of data: Seneviratne. Analysis and interpretation of data: Seneviratne, Mandrekar, Wijdicks, and Rabinstein. Drafting of the manuscript: Seneviratne and Rabinstein. Critical revision of the manuscript for important intellectual content: Seneviratne, Mandrekar, Wijdicks, and Rabinstein. Statistical analysis: Seneviratne and Mandrekar. Study supervision: Wijdicks and Rabinstein. Financial Disclosure: None reported. References 1. Lacomis D Myasthenic crisis. Neurocrit Care 2005;3 (3) 189- 194PubMedGoogle ScholarCrossref 2. Bedlack RSSD On the concept of myasthenic crisis. J Clin Neuromusc Dis 2002;4 (1) 40- 42Google ScholarCrossref 3. Keesey JC “Crisis” in myasthenia gravis: an historical perspective. 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Letendre, Scott;Marquie-Beck, Jennifer;Capparelli, Edmund;Best, Brookie;Clifford, David;Collier, Ann C.;Gelman, Benjamin B.;McArthur, Justin C.;McCutchan, J. Allen;Morgello, Susan;Simpson, David;Grant, Igor;Ellis, Ronald J.