Letters
tion to evidence of bAVM obliteration. Of the 50 first, second, or third occurrences of secondary outcomes following intervention, 19 occurred in patients who never had evidence of obliteration, 26 before obliteration occurred, and 5 after obliteration. Because the majority of these outcomes occurred before or after obliteration, and the risk of incurring a secondary outcome while attempting to achieve bAVM obliteration with intervention outweighed the risk of conservative management over 12 years, the benefits of intervention remain to be proven. Third, the authors of both letters suggest that the interventions in this population-based study were substandard bec ause bAVM obliteration was infrequent. A metaregression analysis2 found that a median of 96% of bAVMs were obliterated after microsurgery in published case series (which may have been subject to selection, publication, and partial verification biases), while in our cohort, 29 of 31 (94%) undergoing microsurgical excision and follow-up imaging achieved obliteration. Proportions of bAVMs obliterated after stereotactic radiosurgery and embolization in our cohort exceeded the medians reported in the metaregression analysis. Weiner and colleagues compare our cohort’s 1-year complication rate with the meta-regression analysis,2 but studies in the latter did not record cerebral infarcts or focal neurological deficits, lacked independent prospective assessment, and may have been influenced by publication bias. However, A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA)3 identified outcomes in a similar way as our cohort and its findings agreed with ours. Zaidi and colleagues suggest that endovascular therapy alone is currently not considered to be a curative procedure, yet bAVM obliteration occurred in 45% of people selected for embolization alone in our cohort, similar to recent case series. Given the range of treatments used for unruptured bAVMs in our study and in ARUBA,3 international consensus on the use of microsurgery seems to be less than suggested in the letters. In addition, the hierarchy of evidence1 dictates that clinical practice should be guided by a study’s risk of bias. In this case, the findings of a randomized trial (level 2)3 and a nonrandomized controlled cohort study (level 3) concur and are more reliable than case series without a comparison group or independent outcome assessment, potentially subject to selection and publication biases (level 4). Rustam Al-Shahi Salman, PhD Carl E. Counsell, MD Philip M. White, FRCR Author Affiliations: Division of Clinical Neurosciences, University of Edinburgh, Edinburgh, Scotland (Al-Shahi Salman); Division of Applied Health Sciences, University of Aberdeen, Aberdeen, Scotland (Counsell); Institute for Ageing and Health, Newcastle University, Newcastle-upon-Tyne, England (White). Corresponding Author: Rustam Al-Shahi Salman, PhD, Division of Clinical Neurosciences, University of Edinburgh, Bramwell Dott Building, Western General Hospital, Edinburgh EH4 2XU, Scotland ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Al-Shahi Salman reported receipt of grants from the Medical Research Council, the Stroke Association, and the Chief Scientist Office of the Scottish Government.
Dr White reported receipt of grants and personal fees from Covidien, Codman, and Microvention Terumo during the conduct of the study. No other disclosures were reported. 1. University of Oxford Centre for Evidence-Based Medicine. OCEBM levels of evidence. http://www.cebm.net/ocebm-levels-of-evidence/. Accessed June 2, 2014. 2. van Beijnum J, van der Worp HB, Buis DR, et al. Treatment of brain arteriovenous malformations: a systematic review and meta-analysis. JAMA. 2011;306(18):2011-2019. 3. Mohr JP, Parides MK, Stapf C, et al; International ARUBA Investigators. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet. 2014;383(9917):614-621.
Idiopathic Intracranial Hypertension To the Editor The Idiopathic Intracranial Hypertension Treatment Trial1 evaluated the use of acetazolamide vs placebo in conjunction with a weight-reducing, low sodium diet in adults with idiopathic intracranial hypertension (IIH). Although the authors stated “there are no properly designed clinical trials,” the widespread use of acetazolamide has been questioned since the results of the first randomized controlled trial2 that did not demonstrate benefit of acetazolamide in IIH, although it was underpowered. The trial demonstrated a small difference in the primary outcome measure, the perimetric mean deviation (PMD), in the acetazolamide vs placebo cohorts (0.71 dB [95% CI, 0-1.43 dB]; P = .05). The sample size was not powered to detect this small a difference, almost half that originally predicted (1.3 dB) and defined a priori as the minimal clinically meaningful difference. Consequently, the results must be seen as hypothesis generating only. There was no significant difference in lumbar puncture pressure, headache disability, or visual acuity between the 2 groups. However, adverse events (nausea, paresthesia, and diarrhea) and drug discontinuation were significantly higher in the acetazolamide group. The latter may reflect the high doses given in the study (>40% were taking 4 g of acetazolamide). A prospective cohort study3 established that weight loss is an effective disease-modifying therapy in IIH, with patients who followed a 3-month low-calorie diet having significantly reduced intracranial pressure compared with pressure measured in the 3 months before the diet, as well as improved symptoms and reduced papilledema. In the current trial,1 the acetazolamide group lost significantly more weight than the placebo group (−4.05 kg [95% CI, −6.27 to −1.83 kg]; P < .001). We believe that this potentially relates to the anorexigenic adverse event profile of acetazolamide. Thus weight loss may be the reason for the small improvement in the acetazolamide cohort despite the findings from their mediation model analysis, which we believe may have been misinterpreted.4 When the analysis was adjusted for weight change, differences between treatment groups were nonsignificant (0.03 dB [95% CI, −0.10 to 0.16 dB]; P = .64). Consequently, we are unable to understand why weight was not considered a mediating factor. It is difficult to interpret what new information the Idiopathic Intracranial Hypertension Treatment Trial provides
jama.com
JAMA September 10, 2014 Volume 312, Number 10
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/24/2015
1059
Letters
and what is clinically useful. The use of acetazolamide in IIH with mild visual loss is again questioned given the minimal efficacy and high adverse event profile. We believe that weight loss remains an important disease-modifying therapy in IIH.3 Alex J. Sinclair, MBChB, PhD Rebecca Woolley, BScHons Susan P. Mollan, MBChB, FRCOphth Author Affiliations: Department of Neurotrauma and Neurodegeneration, University of Birmingham, Birmingham, England (Sinclair); Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, England (Woolley); Birmingham Neuro-Ophthalmology Unit, University Hospitals Birmingham NHS Trust, Birmingham, England (Mollan). Corresponding Author: Alex J. Sinclair, MBChB, PhD, Department of Neurotrauma and Neurodegeneration, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, Birmingham B15 2TT, England ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Wall M, McDermott MP, Kieburtz KD, et al; NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee. Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial. JAMA. 2014; 311(16):1641-1651. 2. Ball AK, Howman A, Wheatley K, et al. A randomised controlled trial of treatment for idiopathic intracranial hypertension. J Neurol. 2011;258(5):874-881. 3. Sinclair AJ, Burdon MA, Nightingale PG, et al. Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension: prospective cohort study. BMJ. 2010;341:c2701. 4. Baron RM, Kenny DA. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol. 1986;51(6):1173-1182.
In Reply We stand by our statement that there were no properly designed and executed clinical trials to guide therapy in IIH prior to ours. The results of the study by Ball et al1 were inconclusive with respect to efficacy due to the small sample size and consequent low power. The authors stated in their report that “This pilot study was not powered to detect a treatment effect.” 1 Also, 12 of 25 patients in the acetazolamide group stopped taking medication, a discontinuation rate of nearly 50%. Dosing schedules for acetazolamide were at the discretion of the supervising clinician and did not get above 1500 mg/d. Twenty percent of the patients in the control group were eventually given acetazolamide. Therefore, this trial should not be used to guide therapy in IIH. Dr Sinclair and colleagues point out the modest effect of acetazolamide on PMD observed in our trial. We addressed this issue in the article. We do not consider these results as hypothesis generating because the trial had adequate power and actually detected effects of acetazolamide. The acetazolamide group had significantly better general and visual qualityof-life measures than the placebo group. Acetazolamide reduced cerebrospinal fluid pressure and improved papilledema grades. Also, in cases with high-grade papilledema, the effect size of acetazolamide was 2.27 dB (P = .001), suggesting a meaningful benefit of acetazolamide 1060
in this subgroup. With regard to acetazolamide adverse events, patients were told to increase study drug dosage until adverse events interfered with their activities of daily living, and then to decrease the dosage, resulting generally in successful management. That is one reason why significantly better quality-of-life scores were observed in acetazolamide-treated patients. Sinclair and colleagues misinterpreted the mediation analysis, which showed that the effect of acetazolamide on visual field function was independent of its effect on weight loss. The effect of acetazolamide on PMD does not relate to the anorexigenic adverse event profile of acetazolamide. The coefficient of 0.03 (P = .64) represents the indirect effect of treatment (ie, that mediated through an effect on weight), not the effect of treatment on PMD adjusted for change in weight. The direct effect of acetazolamide on PMD (0.72 dB) remained virtually unchanged and significant (P = .04); this effect would have been greatly reduced if weight loss were a significant mediator. Even though diet also may improve visual outcome, this has never been established in a randomized clinical trial and cannot be discerned from our study. In our study, acetazolamide significantly improved visual field function, lessened papilledema grade, improved general and visual quality-of-life measures, and lowered cerebrospinal fluid pressure. Adverse events associated with acetazolamide were relatively mild and generally well tolerated with no permanent morbidity. We stand by our conclusion that acetazolamide is an effective treatment for IIH in patients with mild visual loss. Michael Wall, MD Michael McDermott, PhD Mark Kupersmith, MD Author Affiliations: Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City (Wall); University of Rochester School of Medicine and Dentistry, Rochester, New York (McDermott); Roosevelt Hospital, New York, New York (Kupersmith). Corresponding Author: Michael Wall, MD, Department of Neurology, University of Iowa Hospitals and Clinics, 200 Hawkins Dr, Iowa City, IA 52242 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr McDermott reported receiving personal fees from Teva Pharmaceutical Industries, Impax Pharmaceuticals, Biotie Therapies Corporation, Bioness Inc, Isis Pharmaceuticals, Biogen Idec Inc, Novartis Pharmaceuticals Corporation, and Asubio Pharmaceuticals; and grants from Rhythm Pharmaceuticals and the SMA Foundation. No other disclosures are reported. 1. Ball AK, Howman A, Wheatley K, et al. A randomised controlled trial of treatment for idiopathic intracranial hypertension. J Neurol. 2011;258(5):874-881.
Diagnosis of Herpes Simplex Virus in Patients With Erythema Multiforme To the Editor In their JAMA Clinical Challenge, Drs Ladizinski and Lee 1 presented a patient with herpes simplex virus (HSV)-induced erythema multiforme and suggested viral cultures or polymerase chain reaction (PCR) analysis of the oral vesicles to diagnose herpes. I would suggest a Tzanck smear first.
JAMA September 10, 2014 Volume 312, Number 10
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/24/2015
jama.com
tion to evidence of bAVM obliteration. Of the 50 first, second, or third occurrences of secondary outcomes following intervention, 19 occurred in patients who never had evidence of obliteration, 26 before obliteration occurred, and 5 after obliteration. Because the majority of these outcomes occurred before or after obliteration, and the risk of incurring a secondary outcome while attempting to achieve bAVM obliteration with intervention outweighed the risk of conservative management over 12 years, the benefits of intervention remain to be proven. Third, the authors of both letters suggest that the interventions in this population-based study were substandard bec ause bAVM obliteration was infrequent. A metaregression analysis2 found that a median of 96% of bAVMs were obliterated after microsurgery in published case series (which may have been subject to selection, publication, and partial verification biases), while in our cohort, 29 of 31 (94%) undergoing microsurgical excision and follow-up imaging achieved obliteration. Proportions of bAVMs obliterated after stereotactic radiosurgery and embolization in our cohort exceeded the medians reported in the metaregression analysis. Weiner and colleagues compare our cohort’s 1-year complication rate with the meta-regression analysis,2 but studies in the latter did not record cerebral infarcts or focal neurological deficits, lacked independent prospective assessment, and may have been influenced by publication bias. However, A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA)3 identified outcomes in a similar way as our cohort and its findings agreed with ours. Zaidi and colleagues suggest that endovascular therapy alone is currently not considered to be a curative procedure, yet bAVM obliteration occurred in 45% of people selected for embolization alone in our cohort, similar to recent case series. Given the range of treatments used for unruptured bAVMs in our study and in ARUBA,3 international consensus on the use of microsurgery seems to be less than suggested in the letters. In addition, the hierarchy of evidence1 dictates that clinical practice should be guided by a study’s risk of bias. In this case, the findings of a randomized trial (level 2)3 and a nonrandomized controlled cohort study (level 3) concur and are more reliable than case series without a comparison group or independent outcome assessment, potentially subject to selection and publication biases (level 4). Rustam Al-Shahi Salman, PhD Carl E. Counsell, MD Philip M. White, FRCR Author Affiliations: Division of Clinical Neurosciences, University of Edinburgh, Edinburgh, Scotland (Al-Shahi Salman); Division of Applied Health Sciences, University of Aberdeen, Aberdeen, Scotland (Counsell); Institute for Ageing and Health, Newcastle University, Newcastle-upon-Tyne, England (White). Corresponding Author: Rustam Al-Shahi Salman, PhD, Division of Clinical Neurosciences, University of Edinburgh, Bramwell Dott Building, Western General Hospital, Edinburgh EH4 2XU, Scotland ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Al-Shahi Salman reported receipt of grants from the Medical Research Council, the Stroke Association, and the Chief Scientist Office of the Scottish Government.
Dr White reported receipt of grants and personal fees from Covidien, Codman, and Microvention Terumo during the conduct of the study. No other disclosures were reported. 1. University of Oxford Centre for Evidence-Based Medicine. OCEBM levels of evidence. http://www.cebm.net/ocebm-levels-of-evidence/. Accessed June 2, 2014. 2. van Beijnum J, van der Worp HB, Buis DR, et al. Treatment of brain arteriovenous malformations: a systematic review and meta-analysis. JAMA. 2011;306(18):2011-2019. 3. Mohr JP, Parides MK, Stapf C, et al; International ARUBA Investigators. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet. 2014;383(9917):614-621.
Idiopathic Intracranial Hypertension To the Editor The Idiopathic Intracranial Hypertension Treatment Trial1 evaluated the use of acetazolamide vs placebo in conjunction with a weight-reducing, low sodium diet in adults with idiopathic intracranial hypertension (IIH). Although the authors stated “there are no properly designed clinical trials,” the widespread use of acetazolamide has been questioned since the results of the first randomized controlled trial2 that did not demonstrate benefit of acetazolamide in IIH, although it was underpowered. The trial demonstrated a small difference in the primary outcome measure, the perimetric mean deviation (PMD), in the acetazolamide vs placebo cohorts (0.71 dB [95% CI, 0-1.43 dB]; P = .05). The sample size was not powered to detect this small a difference, almost half that originally predicted (1.3 dB) and defined a priori as the minimal clinically meaningful difference. Consequently, the results must be seen as hypothesis generating only. There was no significant difference in lumbar puncture pressure, headache disability, or visual acuity between the 2 groups. However, adverse events (nausea, paresthesia, and diarrhea) and drug discontinuation were significantly higher in the acetazolamide group. The latter may reflect the high doses given in the study (>40% were taking 4 g of acetazolamide). A prospective cohort study3 established that weight loss is an effective disease-modifying therapy in IIH, with patients who followed a 3-month low-calorie diet having significantly reduced intracranial pressure compared with pressure measured in the 3 months before the diet, as well as improved symptoms and reduced papilledema. In the current trial,1 the acetazolamide group lost significantly more weight than the placebo group (−4.05 kg [95% CI, −6.27 to −1.83 kg]; P < .001). We believe that this potentially relates to the anorexigenic adverse event profile of acetazolamide. Thus weight loss may be the reason for the small improvement in the acetazolamide cohort despite the findings from their mediation model analysis, which we believe may have been misinterpreted.4 When the analysis was adjusted for weight change, differences between treatment groups were nonsignificant (0.03 dB [95% CI, −0.10 to 0.16 dB]; P = .64). Consequently, we are unable to understand why weight was not considered a mediating factor. It is difficult to interpret what new information the Idiopathic Intracranial Hypertension Treatment Trial provides
jama.com
JAMA September 10, 2014 Volume 312, Number 10
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/24/2015
1059
Letters
and what is clinically useful. The use of acetazolamide in IIH with mild visual loss is again questioned given the minimal efficacy and high adverse event profile. We believe that weight loss remains an important disease-modifying therapy in IIH.3 Alex J. Sinclair, MBChB, PhD Rebecca Woolley, BScHons Susan P. Mollan, MBChB, FRCOphth Author Affiliations: Department of Neurotrauma and Neurodegeneration, University of Birmingham, Birmingham, England (Sinclair); Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, England (Woolley); Birmingham Neuro-Ophthalmology Unit, University Hospitals Birmingham NHS Trust, Birmingham, England (Mollan). Corresponding Author: Alex J. Sinclair, MBChB, PhD, Department of Neurotrauma and Neurodegeneration, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, Birmingham B15 2TT, England ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Wall M, McDermott MP, Kieburtz KD, et al; NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee. Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial. JAMA. 2014; 311(16):1641-1651. 2. Ball AK, Howman A, Wheatley K, et al. A randomised controlled trial of treatment for idiopathic intracranial hypertension. J Neurol. 2011;258(5):874-881. 3. Sinclair AJ, Burdon MA, Nightingale PG, et al. Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension: prospective cohort study. BMJ. 2010;341:c2701. 4. Baron RM, Kenny DA. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol. 1986;51(6):1173-1182.
In Reply We stand by our statement that there were no properly designed and executed clinical trials to guide therapy in IIH prior to ours. The results of the study by Ball et al1 were inconclusive with respect to efficacy due to the small sample size and consequent low power. The authors stated in their report that “This pilot study was not powered to detect a treatment effect.” 1 Also, 12 of 25 patients in the acetazolamide group stopped taking medication, a discontinuation rate of nearly 50%. Dosing schedules for acetazolamide were at the discretion of the supervising clinician and did not get above 1500 mg/d. Twenty percent of the patients in the control group were eventually given acetazolamide. Therefore, this trial should not be used to guide therapy in IIH. Dr Sinclair and colleagues point out the modest effect of acetazolamide on PMD observed in our trial. We addressed this issue in the article. We do not consider these results as hypothesis generating because the trial had adequate power and actually detected effects of acetazolamide. The acetazolamide group had significantly better general and visual qualityof-life measures than the placebo group. Acetazolamide reduced cerebrospinal fluid pressure and improved papilledema grades. Also, in cases with high-grade papilledema, the effect size of acetazolamide was 2.27 dB (P = .001), suggesting a meaningful benefit of acetazolamide 1060
in this subgroup. With regard to acetazolamide adverse events, patients were told to increase study drug dosage until adverse events interfered with their activities of daily living, and then to decrease the dosage, resulting generally in successful management. That is one reason why significantly better quality-of-life scores were observed in acetazolamide-treated patients. Sinclair and colleagues misinterpreted the mediation analysis, which showed that the effect of acetazolamide on visual field function was independent of its effect on weight loss. The effect of acetazolamide on PMD does not relate to the anorexigenic adverse event profile of acetazolamide. The coefficient of 0.03 (P = .64) represents the indirect effect of treatment (ie, that mediated through an effect on weight), not the effect of treatment on PMD adjusted for change in weight. The direct effect of acetazolamide on PMD (0.72 dB) remained virtually unchanged and significant (P = .04); this effect would have been greatly reduced if weight loss were a significant mediator. Even though diet also may improve visual outcome, this has never been established in a randomized clinical trial and cannot be discerned from our study. In our study, acetazolamide significantly improved visual field function, lessened papilledema grade, improved general and visual quality-of-life measures, and lowered cerebrospinal fluid pressure. Adverse events associated with acetazolamide were relatively mild and generally well tolerated with no permanent morbidity. We stand by our conclusion that acetazolamide is an effective treatment for IIH in patients with mild visual loss. Michael Wall, MD Michael McDermott, PhD Mark Kupersmith, MD Author Affiliations: Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City (Wall); University of Rochester School of Medicine and Dentistry, Rochester, New York (McDermott); Roosevelt Hospital, New York, New York (Kupersmith). Corresponding Author: Michael Wall, MD, Department of Neurology, University of Iowa Hospitals and Clinics, 200 Hawkins Dr, Iowa City, IA 52242 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr McDermott reported receiving personal fees from Teva Pharmaceutical Industries, Impax Pharmaceuticals, Biotie Therapies Corporation, Bioness Inc, Isis Pharmaceuticals, Biogen Idec Inc, Novartis Pharmaceuticals Corporation, and Asubio Pharmaceuticals; and grants from Rhythm Pharmaceuticals and the SMA Foundation. No other disclosures are reported. 1. Ball AK, Howman A, Wheatley K, et al. A randomised controlled trial of treatment for idiopathic intracranial hypertension. J Neurol. 2011;258(5):874-881.
Diagnosis of Herpes Simplex Virus in Patients With Erythema Multiforme To the Editor In their JAMA Clinical Challenge, Drs Ladizinski and Lee 1 presented a patient with herpes simplex virus (HSV)-induced erythema multiforme and suggested viral cultures or polymerase chain reaction (PCR) analysis of the oral vesicles to diagnose herpes. I would suggest a Tzanck smear first.
JAMA September 10, 2014 Volume 312, Number 10
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/24/2015
jama.com
