Opinion Editorial
The time is now for the public, the US Congress, and the scientific community to achieve this highest level of scientific comARTICLE INFORMATION Author Affiliations: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas (Rosenberg); Editor, JAMA Neurology (Rosenberg); Alzheimer’s Disease Research Center, Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota (Petersen).
mitment to understand and treat this disease. The call to arms against Alzheimer disease is urgent and requires action.
interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Consortium. Initial sequencing and analysis of the human genome. Nature. 2001;409(6822):860-921.
REFERENCES
7. Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science. 2001;291 (5507):1304-1351.
1. US Burden of Disease Collaborators. The state of US health, 1990-2010: burden of diseases, injuries, and risk factors. JAMA. 2013;310(6):591-608.
8. Katzman R. The prevalence and malignancy of Alzheimer disease: a major killer. Arch Neurol. 1976; 33(4):217-218.
Corresponding Author: Roger N. Rosenberg, MD, Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 (roger [email protected]).
2. Reiman EM, Langbaum JB, Fleisher AS, et al. Alzheimer’s Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. J Alzheimers Dis. 2011;26(suppl 3):321329.
9. US Department of Health & Human Services. National Alzheimer’s Project Act website. http://aspe.hhs.gov/daltcp/napa/. Published 2015.
Published Online: April 6, 2015. doi:10.1001/jamaneurol.2015.67.
3. Bateman RJ, Xiong C, Benzinger TL, et al; Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367(9): 795-804.
Conflict of Interest Disclosures: Dr Petersen serves as chair of the data monitoring committees at Pfizer Inc and Janssen Alzheimer Immunotherapy and is a consultant for Roche Inc, Merck, and Genentech. No other disclosures were reported. Funding/Support: Dr Rosenberg received grant P30AG12300 20 as principal investigator of the National Institutes of Health, National Institute on Aging Alzheimer’s Disease Center at the University of Texas Southwestern Medical Center, Dallas. Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and
4. Carrillo MC, Brashear HR, Logovinsky V, et al. Can we prevent Alzheimer’s disease? secondary “prevention” trials in Alzheimer’s disease. Alzheimers Dement. 2013;9(2):123-131.e1. 5. Lambracht-Washington D, Rosenberg RN. Advances in the development of vaccines for Alzheimer’s disease. Discov Med. 2013;15(84):319326.
10. Bargmann CI, Newsome WT. The Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative and neurology. JAMA Neurol. 2014;71(6):675-676. 11. Collins FS. Exceptional opportunities in medical science: a view from the National Institutes of Health. JAMA. 2015;313(2):131-132. 12. Fox NC, Petersen RC. The G8 Dementia Research Summit: a starter for eight? Lancet. 2013; 382(9909):1968-1969. 13. Hurd MD, Martorell P, Delavande A, Mullen KJ, Langa KM. Monetary costs of dementia in the United States. N Engl J Med. 2013;368(14):1326-1334.
6. Lander ES, Linton LM, Birren B, et al; International Human Genome Sequencing
Cognition and Quality-of-Life Outcomes in the Targeted Temperature Management Trial for Cardiac Arrest Venkatesh Aiyagari, MBBS, DM; Michael N. Diringer, MD
The last decade has witnessed significant advances in the management of patients with cardiac arrest (CA), resulting in improvement in survival and functional outcome. An analysis of data from the Cardiac Arrest Registry to Enhance Survival, a proRelated article page 634 spective registry of patients with out-of-hospital CA, found that risk-adjusted rates of survival to hospital discharge in the United States increased from 5.7% in 2005-2006 to 8.3% in 2012, with a concomitant improvement in neurologic outcomes among survivors. 1 Denmark, the United Kingdom, and Japan have also reported similar trends. 2-4 Improved survival has been attributed to implementation of the 2005 American Heart Association guidelines for cardiopulmonary resuscitation, increase in bystander cardiopulmonary resuscitation rates, and the use of automated external defibrillators.4-6 More recently, the focus has shifted from improving survival to minimizing the neurologic consequences of CA, and temperature management has emerged as a major component of post-CA care. In 2002, two randomized clinical trials7,8 628
reported that mild hypothermia in comatose patients after CA with ventricular fibrillation improved survival and resulted in a favorable neurologic outcome compared with no temperature management. These studies drove wide institution of hypothermia protocols for treating CA. To further define the appropriate temperature target, the investigators of the Targeted Temperature Management (TTM) trial randomly assigned 939 unconscious CA survivors to temperature management with a target of 33°C or 36°C.9 At 6 months, no significant difference in mortality or neurologic function evaluated with the Cerebral Performance Category or the modified Rankin scale was found. However, these scales are coarse and not designed to detect mild cognitive impairment; thus, the results of the preplanned detailed tests of cognitive outcome in the survivors were eagerly awaited.10 In this issue of JAMA Neurology, Cronberg et al11 report cognitive and health-related quality-of-life assessments performed on survivors 6 months after enrollment in the TTM trial. The assessments included the Mini-Mental State Examination (MMSE) and the Informant Questionnaire of Cognitive Decline in the Elderly (IQCODE) to evaluate cognition, the
JAMA Neurology June 2015 Volume 72, Number 6 (Reprinted)
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Medical Outcomes Study 36-Item Short-Form Health Survey, version 2, to measure health-related quality of life, and Two Simple Questions to assess daily function and mental recovery. Remarkably, more than 90% of the survivors participated in the follow-up examination at 6 months, of which more than 90% were face-to-face. The IQCODE and MMSE completion rate was similarly high. These rates are noteworthy, and the investigators need to be commended for their rigor and persistence while conducting this study. The major findings of the study are as follows. More than 90% of the survivors returned home, and approximately 18% needed help with daily activities; however, less than 50% returned to their previous state of employment. Although approximately two-thirds of all survivors had a normal MMSE score and reported having made a complete mental recovery, relatives or close acquaintances reported cognitive decline in more than half the survivors. There was no statistically significant difference in 3 of the 4 test scores between patients treated with temperature management at 33°C or 36°C. The only exception was in the IQCODE among survivors, favoring the group treated at 33°C (P = .04). However, as the authors point out, this needs to be interpreted with caution because of the unadjusted P value for multiple comparisons, insufficient power to detect minor differences in the IQCODE, and group imbalances. None of the individual measures used in this study is particularly good at assessing cognitive outcome. The Cerebral Performance Category has been historically used in most studies reporting postresuscitation outcome; however, it has several limitations.12 The ICQODE has not been validated in this population, and the MMSE is insensitive for the detection of mild cognitive impairment. However, the investigators took the unique approach of combining the tests to highlight differences between what is reported by patients and observers. As we move forward and focus on cognitive outcome, we must identify, refine, and validate more sensitive measures and apply them in a standardized format. Currently, we know little about long-term cognitive outcomes and changes over time in patients after CA, and a longitudinal study of a cohort such as this would advance the field of resuscitation research. The description and rationale of an additional preplanned substudy of cognitive outcome of the survivors of the TTM trial have been published. Participants are to be tested for difficulties with memory (Rivermead Behavioral Memory Test), attention (Symbol Digit Modalities Test), executive function (Frontal Assessment Battery), and anxiety and depresARTICLE INFORMATION Author Affiliations: Departments of Neurological Surgery and Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas (Aiyagari); Departments of Neurology, Neurosurgery, Anesthesiology, and Occupational Therapy, Washington University School of Medicine, St Louis, Missouri (Diringer). Corresponding Author: Venkatesh Aiyagari, MBBS, DM, Departments of Neurological Surgery and Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Mail Code 8855, Dallas, TX 75390-8855 ([email protected]). jamaneurology.com
sion (Hospital Anxiety and Depression Rating Scale). In addition, the patients’ degree of participation in society (MayoPortland Adaptability Inventory 4) and the caregivers’ situation (Zarit Burden Interview) are also to be tested, and the 2 temperature targeted intervention groups are to be compared with a matched control group of patients with myocardial infarction and emergency percutaneous coronary revascularization.13 The results of this substudy should shed further light on outcomes after CA survival and may help design a comprehensive battery of tests that could be used in future studies. Of note, the TTM trial was not powered to detect differences in the cognitive and quality-of-life outcomes presented in this study, but the authors present the results of post hoc power calculations in the supplemental material. The group treated at 33°C had a slightly lower proportion of patients with a bystander-witnessed arrest and a shockable rhythm and a slightly higher proportion of patients with shock, seizures, and absence of pupillary and corneal reflexes.14 It would be interesting to see the effect of these variables and others, such as age, duration of coma, length of stay in the intensive care unit, and the use of sedative drugs on cognitive dysfunction. This study does not support the superiority of one target temperature for 6-month cognitive and quality-of-life outcomes. In a study of 45 patients enrolled in the Hypothermia after Cardiac Arrest Trial who underwent neuropsychological testing at 3 months, 67% of patients with hypothermia and 44% of patients with normothermia were cognitively intact or had minor deficits; however, the difference was not statistically significant.15 Thus, although temperature management after CA significantly improves survival, a lower temperature target does not seem to translate to better cognitive outcomes. Whether there are certain subgroups that may benefit from the lower temperature target remains to be seen. For neurologists who are often called on to render an opinion on the prognosis of unconscious patients after CA, an important take-home message from this study is that although cognitive changes are common, the overall long-term outcome of patients with a CA who survive to hospital discharge is quite good. Most of these patients are discharged home and report no problems with self-care, and a significant number are gainfully employed. Similar findings have also been reported in a study of 927 CA survivors in Victoria, Australia, and reinforce the view that patients who survive a CA and are unconscious should be managed with intensive support measures, including TTM, and premature prognostication should be avoided.16
Published Online: April 6, 2015. doi:10.1001/jamaneurol.2015.0164. Conflict of Interest Disclosures: None reported. REFERENCES 1. Chan PS, McNally B, Tang F, Kellermann A; CARES Surveillance Group. Recent trends in survival from out-of-hospital cardiac arrest in the United States. Circulation. 2014;130(21):1876-1882. 2. Fothergill RT, Watson LR, Chamberlain D, Virdi GK, Moore FP, Whitbread M. Increases in survival from out-of-hospital cardiac arrest: a five year study. Resuscitation. 2013;84(8):1089-1092.
3. Kitamura T, Iwami T, Kawamura T, et al; Japanese Circulation Society Resuscitation Science Study Group. Nationwide improvements in survival from out-of-hospital cardiac arrest in Japan. Circulation. 2012;126(24):2834-2843. 4. Wissenberg M, Lippert FK, Folke F, et al. Association of national initiatives to improve cardiac arrest management with rates of bystander intervention and patient survival after out-of-hospital cardiac arrest. JAMA. 2013;310(13): 1377-1384. 5. Aufderheide TP, Yannopoulos D, Lick CJ, et al. Implementing the 2005 American Heart Association Guidelines improves outcomes after
(Reprinted) JAMA Neurology June 2015 Volume 72, Number 6
Copyright 2015 American Medical Association. All rights reserved.
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629
Opinion Editorial
out-of-hospital cardiac arrest. Heart Rhythm. 2010; 7(10):1357-1362. 6. Weisfeldt ML, Everson-Stewart S, Sitlani C, et al; Resuscitation Outcomes Consortium Investigators. Ventricular tachyarrhythmias after cardiac arrest in public versus at home. N Engl J Med. 2011;364(4): 313-321. 7. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557-563. 8. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549-556. 9. Nielsen N, Wetterslev J, Cronberg T, et al; TTM Trial Investigators. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197-2206.
10. Oh S, Park EJ, Choi SC. Targeted temperature management after cardiac arrest. N Engl J Med. 2014;370(14):1357.
management; rationale and description of a sub-study in the Target Temperature Management trial. BMC Cardiovasc Disord. 2013;13:85.
11. Cronberg T, Lilja G, Horn J, et al. Neurologic function and health-related quality of life in patients following targeted temperature management at 33°C vs 36°C after out-of-hospital cardiac arrest: a randomized clinical trial [published online April 6, 2015]. JAMA Neurol. doi:10.1001 /jamaneurol.2015.0169.
14. Polderman KH, Varon J. We should not abandon therapeutic cooling after cardiac arrest. Crit Care. 2014;18(2):130.
12. Becker LB, Aufderheide TP, Geocadin RG, et al; American Heart Association Emergency Cardiovascular Care Committee; Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation. Primary outcomes for resuscitation science studies: a consensus statement from the American Heart Association. Circulation. 2011;124 (19):2158-2177.
15. Tiainen M, Poutiainen E, Kovala T, Takkunen O, Häppölä O, Roine RO. Cognitive and neurophysiological outcome of cardiac arrest survivors treated with therapeutic hypothermia. Stroke. 2007;38(8):2303-2308. 16. Smith K, Andrew E, Lijovic M, Nehme Z, Bernard S. Quality of life and functional outcomes 12 months after out-of-hospital cardiac arrest. Circulation. 2015;131(2):174-181.
13. Lilja G, Nielsen N, Friberg H, et al. Cognitive function after cardiac arrest and temperature
Unraveling the Enigma of Seronegative Myasthenia Gravis Steven Vernino, MD, PhD
Myasthenia gravis (MG) is the prototypic autoimmune neurological disorder. Weakness and muscle fatigue in MG result from an autoimmune attack on the neuromuscular junction, which causes a failure of neuromuscular transmission. 1 Related article page 642 The autoimmune nature of the disease was initially proposed in 1960, and in the 1970s, serum antibodies against the acetylcholine receptor (AChR) were identified in patients with MG.2 Subsequently, many convincing experiments demonstrated that these AChR antibodies produce direct effects on the neuromuscular junction. A radioimmunoprecipitation assay (RIA) using solubilized human AChR complexed to 125I-labeled α-bungarotoxin has been considered the most sensitive method for detection of AChR antibodies in human serum and has remained largely unchanged for the past 40 years. Using this assay, AChR antibodies are found in about 80% of patients with MG.1 A small number of these patients may eventually be diagnosed as having a disorder other than autoimmune myasthenia (including Lambert-Eaton syndrome or congenital myasthenic syndromes). However, ever since the development of the antibody assay, seronegative patients have been a cause of clinical consternation. In the initial 1976 article describing the RIA assay for AChR antibodies,2 the authors prophetically commented, “The absence of significant antibody titers in some myasthenia gravis patients is unexplained. It is possible that myasthenia gravis represents not one but two or several disorders with similar clinical and neurophysiologic appearances. One ‘variety’ of myasthenia gravis, apparently the most common one, could be characterized by antireceptor antibody. Alternatively, … sensitivity [of the RIA] may not be sufficient to reliably detect very low titers of antireceptor antibody.”2 In the past decade, new data demonstrated that both of these hypotheses were correct. 630
Myasthenic patients lacking AChR antibodies fall into 3 general clinical categories: seronegative generalized MG, seronegative ocular myasthenia, and seronegative childhoodonset myasthenia. Nearly 90% of patients with generalized MG have detectable AChR antibodies by RIA. Among the others, roughly 40% have antibodies against muscle-specific kinase (MUSK) and another small group have antibodies against the agrin receptor low-density lipoprotein receptor–related protein 4. Musclespecific kinase and low-density lipoprotein receptor–related protein 4 are proteins that help organize the neuromuscular junction and are critical for clustering the AChR at the junctional folds. Patients with MUSK antibodies often have a characteristic form of MG, which has several important differences compared with MG with AChR antibodies. These patients have early and prominent weakness of bulbar, neck, and respiratory muscles. They also do not respond well to acetylcholinesterase inhibitors such as pyridostigmine.3 The recognition and characterization of MUSK antibody myasthenia has helped explain many of the formerly seronegative cases of generalized MG. However, cases of double-seronegative severe generalized MG still exist and remain perplexing. We may yet discover antibodies against other important antigens at the neuromuscular junction in this minority of patients with generalized MG. Among patients with milder forms of MG, specifically those with symptoms limited to ptosis and intermittent diplopia, up to 50% lack AChR antibodies by standard RIA, and MUSK antibodies are rarely found in cases of ocular MG. Seronegativity in ocularMGisparticularlychallengingbecausethedifferentialdiagnosis of double vision and ptosis is fairly broad, and electrophysiological studies, such as repetitive stimulation and single-fiber electromyography, may be normal in these patients. Similarly, test results from up to 50% of children with MG (prepubertal onset) are negative for both MUSK and AChR antibodies.4 When antibody
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The time is now for the public, the US Congress, and the scientific community to achieve this highest level of scientific comARTICLE INFORMATION Author Affiliations: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas (Rosenberg); Editor, JAMA Neurology (Rosenberg); Alzheimer’s Disease Research Center, Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota (Petersen).
mitment to understand and treat this disease. The call to arms against Alzheimer disease is urgent and requires action.
interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Consortium. Initial sequencing and analysis of the human genome. Nature. 2001;409(6822):860-921.
REFERENCES
7. Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science. 2001;291 (5507):1304-1351.
1. US Burden of Disease Collaborators. The state of US health, 1990-2010: burden of diseases, injuries, and risk factors. JAMA. 2013;310(6):591-608.
8. Katzman R. The prevalence and malignancy of Alzheimer disease: a major killer. Arch Neurol. 1976; 33(4):217-218.
Corresponding Author: Roger N. Rosenberg, MD, Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 (roger [email protected]).
2. Reiman EM, Langbaum JB, Fleisher AS, et al. Alzheimer’s Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. J Alzheimers Dis. 2011;26(suppl 3):321329.
9. US Department of Health & Human Services. National Alzheimer’s Project Act website. http://aspe.hhs.gov/daltcp/napa/. Published 2015.
Published Online: April 6, 2015. doi:10.1001/jamaneurol.2015.67.
3. Bateman RJ, Xiong C, Benzinger TL, et al; Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367(9): 795-804.
Conflict of Interest Disclosures: Dr Petersen serves as chair of the data monitoring committees at Pfizer Inc and Janssen Alzheimer Immunotherapy and is a consultant for Roche Inc, Merck, and Genentech. No other disclosures were reported. Funding/Support: Dr Rosenberg received grant P30AG12300 20 as principal investigator of the National Institutes of Health, National Institute on Aging Alzheimer’s Disease Center at the University of Texas Southwestern Medical Center, Dallas. Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and
4. Carrillo MC, Brashear HR, Logovinsky V, et al. Can we prevent Alzheimer’s disease? secondary “prevention” trials in Alzheimer’s disease. Alzheimers Dement. 2013;9(2):123-131.e1. 5. Lambracht-Washington D, Rosenberg RN. Advances in the development of vaccines for Alzheimer’s disease. Discov Med. 2013;15(84):319326.
10. Bargmann CI, Newsome WT. The Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative and neurology. JAMA Neurol. 2014;71(6):675-676. 11. Collins FS. Exceptional opportunities in medical science: a view from the National Institutes of Health. JAMA. 2015;313(2):131-132. 12. Fox NC, Petersen RC. The G8 Dementia Research Summit: a starter for eight? Lancet. 2013; 382(9909):1968-1969. 13. Hurd MD, Martorell P, Delavande A, Mullen KJ, Langa KM. Monetary costs of dementia in the United States. N Engl J Med. 2013;368(14):1326-1334.
6. Lander ES, Linton LM, Birren B, et al; International Human Genome Sequencing
Cognition and Quality-of-Life Outcomes in the Targeted Temperature Management Trial for Cardiac Arrest Venkatesh Aiyagari, MBBS, DM; Michael N. Diringer, MD
The last decade has witnessed significant advances in the management of patients with cardiac arrest (CA), resulting in improvement in survival and functional outcome. An analysis of data from the Cardiac Arrest Registry to Enhance Survival, a proRelated article page 634 spective registry of patients with out-of-hospital CA, found that risk-adjusted rates of survival to hospital discharge in the United States increased from 5.7% in 2005-2006 to 8.3% in 2012, with a concomitant improvement in neurologic outcomes among survivors. 1 Denmark, the United Kingdom, and Japan have also reported similar trends. 2-4 Improved survival has been attributed to implementation of the 2005 American Heart Association guidelines for cardiopulmonary resuscitation, increase in bystander cardiopulmonary resuscitation rates, and the use of automated external defibrillators.4-6 More recently, the focus has shifted from improving survival to minimizing the neurologic consequences of CA, and temperature management has emerged as a major component of post-CA care. In 2002, two randomized clinical trials7,8 628
reported that mild hypothermia in comatose patients after CA with ventricular fibrillation improved survival and resulted in a favorable neurologic outcome compared with no temperature management. These studies drove wide institution of hypothermia protocols for treating CA. To further define the appropriate temperature target, the investigators of the Targeted Temperature Management (TTM) trial randomly assigned 939 unconscious CA survivors to temperature management with a target of 33°C or 36°C.9 At 6 months, no significant difference in mortality or neurologic function evaluated with the Cerebral Performance Category or the modified Rankin scale was found. However, these scales are coarse and not designed to detect mild cognitive impairment; thus, the results of the preplanned detailed tests of cognitive outcome in the survivors were eagerly awaited.10 In this issue of JAMA Neurology, Cronberg et al11 report cognitive and health-related quality-of-life assessments performed on survivors 6 months after enrollment in the TTM trial. The assessments included the Mini-Mental State Examination (MMSE) and the Informant Questionnaire of Cognitive Decline in the Elderly (IQCODE) to evaluate cognition, the
JAMA Neurology June 2015 Volume 72, Number 6 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
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Editorial Opinion
Medical Outcomes Study 36-Item Short-Form Health Survey, version 2, to measure health-related quality of life, and Two Simple Questions to assess daily function and mental recovery. Remarkably, more than 90% of the survivors participated in the follow-up examination at 6 months, of which more than 90% were face-to-face. The IQCODE and MMSE completion rate was similarly high. These rates are noteworthy, and the investigators need to be commended for their rigor and persistence while conducting this study. The major findings of the study are as follows. More than 90% of the survivors returned home, and approximately 18% needed help with daily activities; however, less than 50% returned to their previous state of employment. Although approximately two-thirds of all survivors had a normal MMSE score and reported having made a complete mental recovery, relatives or close acquaintances reported cognitive decline in more than half the survivors. There was no statistically significant difference in 3 of the 4 test scores between patients treated with temperature management at 33°C or 36°C. The only exception was in the IQCODE among survivors, favoring the group treated at 33°C (P = .04). However, as the authors point out, this needs to be interpreted with caution because of the unadjusted P value for multiple comparisons, insufficient power to detect minor differences in the IQCODE, and group imbalances. None of the individual measures used in this study is particularly good at assessing cognitive outcome. The Cerebral Performance Category has been historically used in most studies reporting postresuscitation outcome; however, it has several limitations.12 The ICQODE has not been validated in this population, and the MMSE is insensitive for the detection of mild cognitive impairment. However, the investigators took the unique approach of combining the tests to highlight differences between what is reported by patients and observers. As we move forward and focus on cognitive outcome, we must identify, refine, and validate more sensitive measures and apply them in a standardized format. Currently, we know little about long-term cognitive outcomes and changes over time in patients after CA, and a longitudinal study of a cohort such as this would advance the field of resuscitation research. The description and rationale of an additional preplanned substudy of cognitive outcome of the survivors of the TTM trial have been published. Participants are to be tested for difficulties with memory (Rivermead Behavioral Memory Test), attention (Symbol Digit Modalities Test), executive function (Frontal Assessment Battery), and anxiety and depresARTICLE INFORMATION Author Affiliations: Departments of Neurological Surgery and Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas (Aiyagari); Departments of Neurology, Neurosurgery, Anesthesiology, and Occupational Therapy, Washington University School of Medicine, St Louis, Missouri (Diringer). Corresponding Author: Venkatesh Aiyagari, MBBS, DM, Departments of Neurological Surgery and Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Mail Code 8855, Dallas, TX 75390-8855 ([email protected]). jamaneurology.com
sion (Hospital Anxiety and Depression Rating Scale). In addition, the patients’ degree of participation in society (MayoPortland Adaptability Inventory 4) and the caregivers’ situation (Zarit Burden Interview) are also to be tested, and the 2 temperature targeted intervention groups are to be compared with a matched control group of patients with myocardial infarction and emergency percutaneous coronary revascularization.13 The results of this substudy should shed further light on outcomes after CA survival and may help design a comprehensive battery of tests that could be used in future studies. Of note, the TTM trial was not powered to detect differences in the cognitive and quality-of-life outcomes presented in this study, but the authors present the results of post hoc power calculations in the supplemental material. The group treated at 33°C had a slightly lower proportion of patients with a bystander-witnessed arrest and a shockable rhythm and a slightly higher proportion of patients with shock, seizures, and absence of pupillary and corneal reflexes.14 It would be interesting to see the effect of these variables and others, such as age, duration of coma, length of stay in the intensive care unit, and the use of sedative drugs on cognitive dysfunction. This study does not support the superiority of one target temperature for 6-month cognitive and quality-of-life outcomes. In a study of 45 patients enrolled in the Hypothermia after Cardiac Arrest Trial who underwent neuropsychological testing at 3 months, 67% of patients with hypothermia and 44% of patients with normothermia were cognitively intact or had minor deficits; however, the difference was not statistically significant.15 Thus, although temperature management after CA significantly improves survival, a lower temperature target does not seem to translate to better cognitive outcomes. Whether there are certain subgroups that may benefit from the lower temperature target remains to be seen. For neurologists who are often called on to render an opinion on the prognosis of unconscious patients after CA, an important take-home message from this study is that although cognitive changes are common, the overall long-term outcome of patients with a CA who survive to hospital discharge is quite good. Most of these patients are discharged home and report no problems with self-care, and a significant number are gainfully employed. Similar findings have also been reported in a study of 927 CA survivors in Victoria, Australia, and reinforce the view that patients who survive a CA and are unconscious should be managed with intensive support measures, including TTM, and premature prognostication should be avoided.16
Published Online: April 6, 2015. doi:10.1001/jamaneurol.2015.0164. Conflict of Interest Disclosures: None reported. REFERENCES 1. Chan PS, McNally B, Tang F, Kellermann A; CARES Surveillance Group. Recent trends in survival from out-of-hospital cardiac arrest in the United States. Circulation. 2014;130(21):1876-1882. 2. Fothergill RT, Watson LR, Chamberlain D, Virdi GK, Moore FP, Whitbread M. Increases in survival from out-of-hospital cardiac arrest: a five year study. Resuscitation. 2013;84(8):1089-1092.
3. Kitamura T, Iwami T, Kawamura T, et al; Japanese Circulation Society Resuscitation Science Study Group. Nationwide improvements in survival from out-of-hospital cardiac arrest in Japan. Circulation. 2012;126(24):2834-2843. 4. Wissenberg M, Lippert FK, Folke F, et al. Association of national initiatives to improve cardiac arrest management with rates of bystander intervention and patient survival after out-of-hospital cardiac arrest. JAMA. 2013;310(13): 1377-1384. 5. Aufderheide TP, Yannopoulos D, Lick CJ, et al. Implementing the 2005 American Heart Association Guidelines improves outcomes after
(Reprinted) JAMA Neurology June 2015 Volume 72, Number 6
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 06/16/2015
629
Opinion Editorial
out-of-hospital cardiac arrest. Heart Rhythm. 2010; 7(10):1357-1362. 6. Weisfeldt ML, Everson-Stewart S, Sitlani C, et al; Resuscitation Outcomes Consortium Investigators. Ventricular tachyarrhythmias after cardiac arrest in public versus at home. N Engl J Med. 2011;364(4): 313-321. 7. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557-563. 8. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549-556. 9. Nielsen N, Wetterslev J, Cronberg T, et al; TTM Trial Investigators. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197-2206.
10. Oh S, Park EJ, Choi SC. Targeted temperature management after cardiac arrest. N Engl J Med. 2014;370(14):1357.
management; rationale and description of a sub-study in the Target Temperature Management trial. BMC Cardiovasc Disord. 2013;13:85.
11. Cronberg T, Lilja G, Horn J, et al. Neurologic function and health-related quality of life in patients following targeted temperature management at 33°C vs 36°C after out-of-hospital cardiac arrest: a randomized clinical trial [published online April 6, 2015]. JAMA Neurol. doi:10.1001 /jamaneurol.2015.0169.
14. Polderman KH, Varon J. We should not abandon therapeutic cooling after cardiac arrest. Crit Care. 2014;18(2):130.
12. Becker LB, Aufderheide TP, Geocadin RG, et al; American Heart Association Emergency Cardiovascular Care Committee; Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation. Primary outcomes for resuscitation science studies: a consensus statement from the American Heart Association. Circulation. 2011;124 (19):2158-2177.
15. Tiainen M, Poutiainen E, Kovala T, Takkunen O, Häppölä O, Roine RO. Cognitive and neurophysiological outcome of cardiac arrest survivors treated with therapeutic hypothermia. Stroke. 2007;38(8):2303-2308. 16. Smith K, Andrew E, Lijovic M, Nehme Z, Bernard S. Quality of life and functional outcomes 12 months after out-of-hospital cardiac arrest. Circulation. 2015;131(2):174-181.
13. Lilja G, Nielsen N, Friberg H, et al. Cognitive function after cardiac arrest and temperature
Unraveling the Enigma of Seronegative Myasthenia Gravis Steven Vernino, MD, PhD
Myasthenia gravis (MG) is the prototypic autoimmune neurological disorder. Weakness and muscle fatigue in MG result from an autoimmune attack on the neuromuscular junction, which causes a failure of neuromuscular transmission. 1 Related article page 642 The autoimmune nature of the disease was initially proposed in 1960, and in the 1970s, serum antibodies against the acetylcholine receptor (AChR) were identified in patients with MG.2 Subsequently, many convincing experiments demonstrated that these AChR antibodies produce direct effects on the neuromuscular junction. A radioimmunoprecipitation assay (RIA) using solubilized human AChR complexed to 125I-labeled α-bungarotoxin has been considered the most sensitive method for detection of AChR antibodies in human serum and has remained largely unchanged for the past 40 years. Using this assay, AChR antibodies are found in about 80% of patients with MG.1 A small number of these patients may eventually be diagnosed as having a disorder other than autoimmune myasthenia (including Lambert-Eaton syndrome or congenital myasthenic syndromes). However, ever since the development of the antibody assay, seronegative patients have been a cause of clinical consternation. In the initial 1976 article describing the RIA assay for AChR antibodies,2 the authors prophetically commented, “The absence of significant antibody titers in some myasthenia gravis patients is unexplained. It is possible that myasthenia gravis represents not one but two or several disorders with similar clinical and neurophysiologic appearances. One ‘variety’ of myasthenia gravis, apparently the most common one, could be characterized by antireceptor antibody. Alternatively, … sensitivity [of the RIA] may not be sufficient to reliably detect very low titers of antireceptor antibody.”2 In the past decade, new data demonstrated that both of these hypotheses were correct. 630
Myasthenic patients lacking AChR antibodies fall into 3 general clinical categories: seronegative generalized MG, seronegative ocular myasthenia, and seronegative childhoodonset myasthenia. Nearly 90% of patients with generalized MG have detectable AChR antibodies by RIA. Among the others, roughly 40% have antibodies against muscle-specific kinase (MUSK) and another small group have antibodies against the agrin receptor low-density lipoprotein receptor–related protein 4. Musclespecific kinase and low-density lipoprotein receptor–related protein 4 are proteins that help organize the neuromuscular junction and are critical for clustering the AChR at the junctional folds. Patients with MUSK antibodies often have a characteristic form of MG, which has several important differences compared with MG with AChR antibodies. These patients have early and prominent weakness of bulbar, neck, and respiratory muscles. They also do not respond well to acetylcholinesterase inhibitors such as pyridostigmine.3 The recognition and characterization of MUSK antibody myasthenia has helped explain many of the formerly seronegative cases of generalized MG. However, cases of double-seronegative severe generalized MG still exist and remain perplexing. We may yet discover antibodies against other important antigens at the neuromuscular junction in this minority of patients with generalized MG. Among patients with milder forms of MG, specifically those with symptoms limited to ptosis and intermittent diplopia, up to 50% lack AChR antibodies by standard RIA, and MUSK antibodies are rarely found in cases of ocular MG. Seronegativity in ocularMGisparticularlychallengingbecausethedifferentialdiagnosis of double vision and ptosis is fairly broad, and electrophysiological studies, such as repetitive stimulation and single-fiber electromyography, may be normal in these patients. Similarly, test results from up to 50% of children with MG (prepubertal onset) are negative for both MUSK and AChR antibodies.4 When antibody
JAMA Neurology June 2015 Volume 72, Number 6 (Reprinted)
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