Letters COMMENT & RESPONSE
Reversible Cerebral Vasoconstriction Syndrome To the Editor We congratulate Katz and colleagues for their article about reversible cerebral vasoconstriction syndrome (RCVS).1 This study confirmed that RCVS is common, similar to our own experience of more than 420 patients accumulated within a similar time span across 4 centers. 2-5 We recently emphasized that RCVS has a “uniphasic course without new symptoms more than 1 month after clinical onset.”5 Katz et al1 seemed to have misinterpreted the term uniphasic and described initial progression as a new observation, although their results confirm our previous descriptions of the dynamic clinicoradiological course of RCVS. Stroke can occur a few days after benign presentation, and cerebral vasoconstriction is at a maximum 2 to 3 weeks after clinical onset. 2 - 5 Importantly, regardless of this initial clinical-angiographic worsening, approximately 95% of our patients have had good neurological outcome. In the study by Katz et al, 1 the degree of clinical worsening was not quantified, and the percentage with worsening or poor outcome likely overestimated owing to the inpatient setting and referral biases. Fortunately, their discussion appropriately stated that initial worsening is usually mild and self-limited and should not prompt consideration of alternate diagnosis, such as primary angiitis of the central nervous system, or warrant aggressive intervention. The ideal duration of observation or the management of patients who do worsen was not discussed. Based on our experience, it seems prudent to eliminate any precipitating or aggravating factors since admission and to discharge patients only after their onset headache subsides significantly, provided there is no recurrence for about 3 days while ambulating and toileting. We advocate against blood pressure manipulations or intra-arterial therapies unless the patient shows clinically significant and progressive worsening. The literature is replete with reports of dramatic recovery from interventional procedures, likely reflecting publication bias. “Less is more” should be the mantra. Treat the patient, not the brain scan or angiogram. Finally, we draw attention to an important result that was not discussed: 8 of 12 (67%) steroid-treated patients showed clinical worsening. 1 We previously showed that disease progression occurred in 11 of 23 (48%) steroidtreated patients within 2 to 6 days after starting treatment.3 Clinicians should note that worsening is usually mild and transient in RCVS and progressive in vasculitis; hence, a period of observation is justified. Recent studies characterizing RCVS and primary angiitis of the central nervous system have made it easier to distinguish these conditions in 368
t h e a c u t e s e tt i ng . B a s e d o n t h e s e d at a , e m p i r i c a l glucocorticoids should be avoided whenever RCVS is suspected. Anne Ducros, MD, PhD Rula A. Hajj-Ali, MD Aneesh Bhim Singhal, MD Shuu-Jiun Wang, MD Author Affiliations: Department of Neurology, Montpellier University Hospital, Montpellier, France (Ducros); Center for Vasculitis Care and Research, Cleveland Clinic Foundation, Cleveland, Ohio (Hajj-Ali); Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts (Singhal); Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan (Wang). Corresponding Author: Anne Ducros, MD, PhD, Département de Neurologie, Hôpital Gui de Chauliac, 80 Ave Augustin Fliche, 34295 Montpellier Cedex 05, France ([email protected]). Conflict of Interest Disclosures: None reported. 1. Katz BS, Fugate JE, Ameriso SF, et al. Clinical worsening in reversible cerebral vasoconstriction syndrome. JAMA Neurol. 2014;71(1):68-73. 2. Ducros A, Boukobza M, Porcher R, Sarov M, Valade D, Bousser MG. The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome: a prospective series of 67 patients. Brain. 2007;130(pt 12):3091-3101. 3. Singhal AB, Hajj-Ali RA, Topcuoglu MA, et al. Reversible cerebral vasoconstriction syndromes: analysis of 139 cases. Arch Neurol. 2011;68(8):1005-1012. 4. Chen SP, Fuh JL, Wang SJ, et al. Magnetic resonance angiography in reversible cerebral vasoconstriction syndromes. Ann Neurol. 2010;67(5): 648-656. 5. Ducros A. Reversible cerebral vasoconstriction syndrome. Lancet Neurol. 2012;11(10):906-917.
In Reply We appreciate the comments from Ducros and colleagues. Their combined efforts have greatly enhanced our knowledge of reversible cerebral vasoconstriction syndrome (RCVS). We certainly agree with most of their comments, although they do not seem to have understood the purpose of our study.1 We neither misinterpreted the term uniphasic in the definition of RCVS nor claimed novelty in our observations. Instead, our purpose was to describe with greater detail how common it is for patients with RCVS to have recurrent neurological events and neurological worsening after they are appropriately diagnosed as having this disorder. In fact, we pursued this study because we have seen other clinicians often attempting to revisit the diagnosis of RCVS when new symptoms occur or patients worsen. All too often, the frightening specter of vasculitis is invoked and this generates the risk that the patient may unnecessarily be treated with immunosuppressants or even have a brain biopsy. We do not advocate for aggressive or invasive interventions either and coincide in endorsing the “less is more” principle in the management of these patients, with the exception of those with progressive and severe worsening. In our
JAMA Neurology March 2014 Volume 71, Number 3
Copyright 2014 American Medical Association. All rights reserved.
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experience, such cases are mostly seen in postpartum women.2 In most instances, the diagnosis can be established based on a combination of clinical findings and noninvasive angiography. The use of catheter angiograms for patients with RCVS has become increasingly sparing in our practice. Finally, we agree that steroids are not indicated in RCVS and they should be avoided because of their adverse effects. Yet, we do not think our data (or results from previous studies) can substantiate the hypothesis that steroids may worsen the disease. It is often patients with more severe RCVS who get steroids. This selection bias may account for the high proportion of steroid-treated patients who were noted to have symptom progression. Alejandro A. Rabinstein, MD Author Affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota. Corresponding Author: Alejandro A. Rabinstein, MD, Department of Neurology, Mayo Clinic, 200 First St SW, 8WB, Rochester, MN 55905 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Katz BS, Fugate JE, Ameriso SF, et al. Clinical worsening in reversible cerebral vasoconstriction syndrome. JAMA Neurol. 2013;71(1):68-73. 2. Fugate JE, Wijdicks EF, Parisi JE, et al. Fulminant postpartum cerebral vasoconstriction syndrome. Arch Neurol. 2012;69(1):111-117.
Establishing Comparable Requirements and Treatment Groups Before Applying Statistical Comparison To the Editor With interest we read the article by Chatterjee et al,1 who performed a meta-analysis to quantitatively assess the rates of intracranial hemorrhage (ICH) occurring in randomized trials investigating the new oral anticoagulants (NOACs)
dabigatran, rivaroxaban, and apixaban in patients with atrial fibrillation. They found that each of the 3 drugs reduced the risk for ICH and concluded that any of the currently available NOACs can be considered first line for patients at high risk for ICH. However, these conclusions are a fallacy because patients at high risk for ICH were excluded from NOAC-investigating trials. A history of intracranial, intraocular, spinal, retroperitoneal, or atraumatic intra-articular bleeding was an exclusion criterion, as well as many other comorbidities, as listed in the Table, which are known to increase the risk for ICH.2-5 Thus, patients at risk for ICH were mainly excluded from NOAC-investigating trials. Further concerns are that the authors stratified ICH events into intracerebral, intraparenchymatous, and intraventricular bleedings but intraparenchymatous and intraventricular bleedings are both intracerebral, and it remains unclear whether the latter were counted twice. Furthermore, the AVERROES (Apixaban Versus Acetylsalicylic Acid to Prevent Strokes) Study compared abixaban with aspirin.5 It is problematic to include the 2808 patients to the pooled data for comparing NOACs with vitamin K antagonists (VKAs). In the NOAC-investigating trials, the mean time of international normalized ratio (INR) in the therapeutic range was only 55% to 64% for the patients who were randomized to oral anticoagulation with the VKA warfarin.2-4 It would be very interesting to know the INR values of the VKA-randomized patients in the trials when they experienced ICH. Differences in the rates of bleeding and embolic events between the warfarin- and NOAC-treated patients could be simply owing to poor quality of VKA therapy. This assumption is substantiated by data from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) and RE-LY (Randomized Evaluation of Long Term Anticoagulant Therapy with Dabigatran Etexilate) trials showing that the ad-
Table. Several Exclusion Criteria of NOAC Investigating Trials RE-LY2
ROCKET-AF3
ARISTOTLE4
NL
3d
NL
NL
Any stroke within
14 d
14 d
7d
10 d
Severe stroke within
6 mo
3 mo
NL
NL
Reversible Cerebral Vasoconstriction Syndrome To the Editor We congratulate Katz and colleagues for their article about reversible cerebral vasoconstriction syndrome (RCVS).1 This study confirmed that RCVS is common, similar to our own experience of more than 420 patients accumulated within a similar time span across 4 centers. 2-5 We recently emphasized that RCVS has a “uniphasic course without new symptoms more than 1 month after clinical onset.”5 Katz et al1 seemed to have misinterpreted the term uniphasic and described initial progression as a new observation, although their results confirm our previous descriptions of the dynamic clinicoradiological course of RCVS. Stroke can occur a few days after benign presentation, and cerebral vasoconstriction is at a maximum 2 to 3 weeks after clinical onset. 2 - 5 Importantly, regardless of this initial clinical-angiographic worsening, approximately 95% of our patients have had good neurological outcome. In the study by Katz et al, 1 the degree of clinical worsening was not quantified, and the percentage with worsening or poor outcome likely overestimated owing to the inpatient setting and referral biases. Fortunately, their discussion appropriately stated that initial worsening is usually mild and self-limited and should not prompt consideration of alternate diagnosis, such as primary angiitis of the central nervous system, or warrant aggressive intervention. The ideal duration of observation or the management of patients who do worsen was not discussed. Based on our experience, it seems prudent to eliminate any precipitating or aggravating factors since admission and to discharge patients only after their onset headache subsides significantly, provided there is no recurrence for about 3 days while ambulating and toileting. We advocate against blood pressure manipulations or intra-arterial therapies unless the patient shows clinically significant and progressive worsening. The literature is replete with reports of dramatic recovery from interventional procedures, likely reflecting publication bias. “Less is more” should be the mantra. Treat the patient, not the brain scan or angiogram. Finally, we draw attention to an important result that was not discussed: 8 of 12 (67%) steroid-treated patients showed clinical worsening. 1 We previously showed that disease progression occurred in 11 of 23 (48%) steroidtreated patients within 2 to 6 days after starting treatment.3 Clinicians should note that worsening is usually mild and transient in RCVS and progressive in vasculitis; hence, a period of observation is justified. Recent studies characterizing RCVS and primary angiitis of the central nervous system have made it easier to distinguish these conditions in 368
t h e a c u t e s e tt i ng . B a s e d o n t h e s e d at a , e m p i r i c a l glucocorticoids should be avoided whenever RCVS is suspected. Anne Ducros, MD, PhD Rula A. Hajj-Ali, MD Aneesh Bhim Singhal, MD Shuu-Jiun Wang, MD Author Affiliations: Department of Neurology, Montpellier University Hospital, Montpellier, France (Ducros); Center for Vasculitis Care and Research, Cleveland Clinic Foundation, Cleveland, Ohio (Hajj-Ali); Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts (Singhal); Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan (Wang). Corresponding Author: Anne Ducros, MD, PhD, Département de Neurologie, Hôpital Gui de Chauliac, 80 Ave Augustin Fliche, 34295 Montpellier Cedex 05, France ([email protected]). Conflict of Interest Disclosures: None reported. 1. Katz BS, Fugate JE, Ameriso SF, et al. Clinical worsening in reversible cerebral vasoconstriction syndrome. JAMA Neurol. 2014;71(1):68-73. 2. Ducros A, Boukobza M, Porcher R, Sarov M, Valade D, Bousser MG. The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome: a prospective series of 67 patients. Brain. 2007;130(pt 12):3091-3101. 3. Singhal AB, Hajj-Ali RA, Topcuoglu MA, et al. Reversible cerebral vasoconstriction syndromes: analysis of 139 cases. Arch Neurol. 2011;68(8):1005-1012. 4. Chen SP, Fuh JL, Wang SJ, et al. Magnetic resonance angiography in reversible cerebral vasoconstriction syndromes. Ann Neurol. 2010;67(5): 648-656. 5. Ducros A. Reversible cerebral vasoconstriction syndrome. Lancet Neurol. 2012;11(10):906-917.
In Reply We appreciate the comments from Ducros and colleagues. Their combined efforts have greatly enhanced our knowledge of reversible cerebral vasoconstriction syndrome (RCVS). We certainly agree with most of their comments, although they do not seem to have understood the purpose of our study.1 We neither misinterpreted the term uniphasic in the definition of RCVS nor claimed novelty in our observations. Instead, our purpose was to describe with greater detail how common it is for patients with RCVS to have recurrent neurological events and neurological worsening after they are appropriately diagnosed as having this disorder. In fact, we pursued this study because we have seen other clinicians often attempting to revisit the diagnosis of RCVS when new symptoms occur or patients worsen. All too often, the frightening specter of vasculitis is invoked and this generates the risk that the patient may unnecessarily be treated with immunosuppressants or even have a brain biopsy. We do not advocate for aggressive or invasive interventions either and coincide in endorsing the “less is more” principle in the management of these patients, with the exception of those with progressive and severe worsening. In our
JAMA Neurology March 2014 Volume 71, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of St. Andrews Library User on 05/25/2015
jamaneurology.com
Letters
experience, such cases are mostly seen in postpartum women.2 In most instances, the diagnosis can be established based on a combination of clinical findings and noninvasive angiography. The use of catheter angiograms for patients with RCVS has become increasingly sparing in our practice. Finally, we agree that steroids are not indicated in RCVS and they should be avoided because of their adverse effects. Yet, we do not think our data (or results from previous studies) can substantiate the hypothesis that steroids may worsen the disease. It is often patients with more severe RCVS who get steroids. This selection bias may account for the high proportion of steroid-treated patients who were noted to have symptom progression. Alejandro A. Rabinstein, MD Author Affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota. Corresponding Author: Alejandro A. Rabinstein, MD, Department of Neurology, Mayo Clinic, 200 First St SW, 8WB, Rochester, MN 55905 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Katz BS, Fugate JE, Ameriso SF, et al. Clinical worsening in reversible cerebral vasoconstriction syndrome. JAMA Neurol. 2013;71(1):68-73. 2. Fugate JE, Wijdicks EF, Parisi JE, et al. Fulminant postpartum cerebral vasoconstriction syndrome. Arch Neurol. 2012;69(1):111-117.
Establishing Comparable Requirements and Treatment Groups Before Applying Statistical Comparison To the Editor With interest we read the article by Chatterjee et al,1 who performed a meta-analysis to quantitatively assess the rates of intracranial hemorrhage (ICH) occurring in randomized trials investigating the new oral anticoagulants (NOACs)
dabigatran, rivaroxaban, and apixaban in patients with atrial fibrillation. They found that each of the 3 drugs reduced the risk for ICH and concluded that any of the currently available NOACs can be considered first line for patients at high risk for ICH. However, these conclusions are a fallacy because patients at high risk for ICH were excluded from NOAC-investigating trials. A history of intracranial, intraocular, spinal, retroperitoneal, or atraumatic intra-articular bleeding was an exclusion criterion, as well as many other comorbidities, as listed in the Table, which are known to increase the risk for ICH.2-5 Thus, patients at risk for ICH were mainly excluded from NOAC-investigating trials. Further concerns are that the authors stratified ICH events into intracerebral, intraparenchymatous, and intraventricular bleedings but intraparenchymatous and intraventricular bleedings are both intracerebral, and it remains unclear whether the latter were counted twice. Furthermore, the AVERROES (Apixaban Versus Acetylsalicylic Acid to Prevent Strokes) Study compared abixaban with aspirin.5 It is problematic to include the 2808 patients to the pooled data for comparing NOACs with vitamin K antagonists (VKAs). In the NOAC-investigating trials, the mean time of international normalized ratio (INR) in the therapeutic range was only 55% to 64% for the patients who were randomized to oral anticoagulation with the VKA warfarin.2-4 It would be very interesting to know the INR values of the VKA-randomized patients in the trials when they experienced ICH. Differences in the rates of bleeding and embolic events between the warfarin- and NOAC-treated patients could be simply owing to poor quality of VKA therapy. This assumption is substantiated by data from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) and RE-LY (Randomized Evaluation of Long Term Anticoagulant Therapy with Dabigatran Etexilate) trials showing that the ad-
Table. Several Exclusion Criteria of NOAC Investigating Trials RE-LY2
ROCKET-AF3
ARISTOTLE4
NL
3d
NL
NL
Any stroke within
14 d
14 d
7d
10 d
Severe stroke within
6 mo
3 mo
NL
NL
