- Email: [email protected]
Clinical impact and therapeutic implications of cerebral microbleeds in patients on warfarin
Letters to the Editor / Clinical Neurology and Neurosurgery 115 (2013) 2549–2556
2553
Fig. 2. Repeated T2 and post-gadolinium T1-weighted brain and spine MRI showing no abnormalities.
In conclusion, SIH includes a broad range of symptoms, making it sometimes difficult to diagnose. Spinal MRI can be helpful in making the diagnosis and should be included in standard evaluation of SIH.
E-mail address: [email protected] (R. Lefaucheur) 5 July 2013 Available online 20 September 2013
Financial disclosures All authors report no financial disclosures. Author contributions All the authors worked for data acquisition, analysis and interpretation. Ozlem Ozkul, Alaina Borden, Evelyne Guégan Massardier and Romain Lefaucheur had done critical revision of the manuscript for important intellectual content. Finally, Alaina Borden, Evelyne Guégan Massardier and Romain Lefaucheur made study supervision.
http://dx.doi.org/10.1016/j.clineuro.2013.07.046
Clinical impact and therapeutic implications of cerebral microbleeds in patients on warfarin Keywords: Intracranial hemorrhages Stroke Warfarin Anticoagulants
References
Dear Sir,
[1] Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders, vol. 24 (suppl. 1), 2nd ed. Cephalalgia; 2004. p. 1–160. [2] Medina JH, Abrams K, Falcone S, Bhatia RG. Spinal imaging findings in spontaneous intracranial hypotension. American Journal of Roentgenology 2010;195:459–64. [3] Schievink WI. Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension. Journal of the American Medical Association 2006;295(19):2286–96.
I have read, with great interest, a recently published article in Clinical Neurology and Neurosurgery by Orken et al. titled ‘New cerebral microbleeds in ischemic stroke patients on warfarin treatment: Two-year follow-up’ [1]. The study follows 204 patients on warfarin therapy over a period of two years with neuroimaging to quantify the rate of cerebral microbleeds (CMB). During a mean follow-up period of 24.7 months, 29 patients developed new CMBs (10.4%). More advanced patient age (P = 0.04), increased leukoaraiosis (P = 0.02), and prior CMBs (P = 0.03) were significantly associated with development of new CMBs. Two important issues closely related to the data presented in this study were not addressed. First, is there a correlation between CMB and future intracerebral hemorrhage (ICH)? While still a subject of debate, some literature suggest patients with CMBs have a predilection toward future ICHs due to shared pathophysiological mechanisms between the two lesions [2]. Second, what is the neurocognitive impact of CMBs? Patel et al. did not find a significant correlation between the number of CMBs and executive function based on neuropsychological assessment, but patients with at least nine CMBs were found to have poorer executive function than those with fewer than nine CMBs (P = 0.043) [3]. As the current population continues to age, the prevalence of chronic medical conditions, most notably atrial fibrillation (AF), necessitating long-term anticoagulation rises concurrently [4]. Warfarin-associated ICH accounts for approximately 20% of all intracranial hemorrhages with a 0.3–1.0% annual risk of occurrence in AF patients [5]. Compared to non-anticoagulated patients, ICHs in patients on warfarin therapy are larger at presentation and expand more rapidly, and they are ultimately associated with increased morbidity and mortality [5]. New oral direct thrombin inhibitors (i.e. dabigatran) and factor Xa inhibitors (i.e. apixaban and rivaroxaban) have shown promising reductions in ischemic stroke rates for AF patients compared to warfarin in prospective, randomized trials
Ozlem Ozkul Alaina Borden Evelyne Guégan-Massardier Department of Neurology, Rouen University Hospital and University of Rouen, France Franc¸ois Proust Department of Neurosurgery, Rouen University Hospital and University of Rouen, France David Wallon Department of Neurology, Rouen University Hospital and University of Rouen, France Guillaume Perot Department of Radiology, Rouen University Hospital and University of Rouen, France David Maltête Romain Lefaucheur ∗ Department of Neurology, Rouen University Hospital and University of Rouen, France ∗ Corresponding author at: Department of Neurology, Rouen University Hospital, 76031 Rouen Cedex, France. Tel.: +33 2 32 88 87 40; fax: +33 2 32 88 87 41.
2554
Letters to the Editor / Clinical Neurology and Neurosurgery 115 (2013) 2549–2556
[6–8]. However, the same studies have not shown a decreased incidence of hemorrhagic complications with these new agents. While direct coagulation pathway inhibitors (DCPI) do not require routine monitoring of prothrombin time, they are also not as readily reversible as warfarin [9]. In combination with the lack of familiarity with DCPI-associated ICH, the management of and outcomes from this unique pathology remain poorly understood [10]. Future studies are warranted to determine the rate of CMB development in patients on DCPIs and their correlation with ICH.
References [1] Orken DN, Uysal E, Timer E, Kuloglu-Pazarci N, Mumcu S, Forta H. New cerebral microbleeds in ischemic stroke patients on warfarin treatment: two-year follow-up. Clin Neurol Neurosurg 2013;115(9):1682–5. [2] Jeon SB, Kang DW, Cho AH, Lee EM, Choi CG, Kwon SU, et al. Initial microbleeds at MR imaging can predict recurrent intracerebral hemorrhage. J Neurol 2007;254(4):508–12. [3] Patel B, Lawrence AJ, Chung AW, Rich P, Mackinnon AD, Morris RG, et al. Cerebral microbleeds and cognition in patients with symptomatic small vessel disease. Stroke 2013;44(2):356–61. [4] Garcia-Rodriguez LA, Gaist D, Morton J, Cookson C, Gonzalez-Perez A. Antithrombotic drugs and risk of hemorrhagic stroke in the general population. Neurology 2013;81(6):566–74. [5] Flaherty ML. Anticoagulant-associated intracerebral hemorrhage. Semin Neurol 2010;30(5):565–72. [6] Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365(11):981–92. [7] Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361(12):1139–51. [8] Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364(9):806–17. [9] Aguilar MI, Kuo RS, Freeman WD. New anticoagulants (dabigatran: apixaban, rivaroxaban) for stroke prevention in atrial fibrillation. Neurol Clin 2013;31(3):659–75. [10] El Ahmadieh TY, Aoun SG, Daou MR, El Tecle NE, Rahme RJ, Graham RB, et al. New-generation oral anticoagulants for the prevention of stroke: Implications for neurosurgery. J Clin Neurosci 2013.
Dale Ding ∗ University of Virginia, Department of Neurosurgery, Charlottesville 22908, USA ∗ Correspondence to: University of Virginia, Department of Neurosurgery, P.O. Box 800212, Charlottesville, VA 22908, USA. Tel.: +1 434 924 2203; fax: +1 434 982 5753. E-mail address: [email protected]
‘Effect of progesterone administration on prognosis of patients with diffuse axonal injury due to severe head trauma’ [1]. In their article, the authors reinforce available evidence on the neuroprotective effects of progestins in patients with traumatic brain injury (TBI). However, it has an important issue that should not be overlooked. In the design of the study, the authors reported the use of medroxyprogesterone tablets (1 mg/kg gavaged via nasogastric tube every 12 h for five days) instead of intravenous or intramuscular progesterone. Authors mentioned that the therapeutic dose was selected based on the study by Xiao et al., who included in their protocol natural progesterone (1.0 mg/kg via intramuscular injection and then once per 12 h for five days) [2]. Progesterone is synthesized from cholesterol by the brain as a neurosteroid, where is metabolized to molecules 5␣DHprogesterone and 3␣,5␣TH-progesterone; the last also known as allopregnanolone. These compounds are deemed as critical mediators in the neuroprotective mechanism of progesterone [3]. However, synthetic progestins (as medroxyprogesterone) exhibit different chemical and biological properties, and cannot be converted to neuroactive metabolites such as allopregnanolone. Therefore, their effects may not be deemed identical [4]. Additionally, medroxyprogesterone is near 10-fold as potent as natural progesterone and thus, the dosage must not be considered strictly equivalent to the same dose of natural progesterone [1]. Several studies had showed that medroxyprogesterone acetate has not beneficial effects on neurodegeneration, because it antagonizes the mechanisms of estrogen against glutamate toxicity [3]. To the best of our knowledge, there are no clinical studies comparing the effectiveness of medroxyprogesterone and natural progesterone in patients with TBI. However, a preliminary study using a murine model was carried out to determine whether medroxyprogesterone acetate and natural progesterone exert similar effects as a treatment after bilateral injury to the frontal cortex [5]. In that study, medroxyprogesterone produced a dose-related reduction of cerebral edema at 48 h post-TBI, but neither doses enhanced behavioral recovery, suggesting that natural progesterone should not be replaced by medroxyprogesterone [5]. The results published by Shakeri et al. provides an extremely valuable evidence of potential usefulness of other progestins (medroxyprogesterone), as an alternative to natural progesterone when parenteral administration is not practical or feasible [1]. However, since studies comparing the clinical effectiveness and safety of those two progestins are lacking, the evidence provided by this study should not be deemed conclusive.
11 September 2013 13 September 2013 Available online 20 September 2013 http://dx.doi.org/10.1016/j.clineuro.2013.09.006
Different pharmacological effects of progestins should be considered when applied in traumatic brain injury patients Keywords: Progesterone Traumatic brain injury Medroxyprogesterone
Dear Editor, We have read with great interest a recently published article in Clinical Neurology and Neurosurgery by Shakeri et al. entitled
References [1] Shakeri M, Boustani MR, Pak N, Panahi F, Salehpour F, Lotfinia I, et al. Effect of progesterone administration on prognosis of patients with diffuse axonal injury due to severe head trauma. Clin Neurol Neurosurg 2013 [Epub ahead of print]. [2] Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care 2008;12:R61. [3] Herson PS, Koerner IP, Hurn PD. Sex, sex steroids, and brain injury. Semin Reprod Med 2009;27:229–39. [4] Singh M. Progestins and neuroprotection: are all progestins created equal? Minerva Endocrinol 2007;32:95–102. [5] Wright DW, Hoffman SW, Virmani S, Stein DG. Effects of medroxyprogesterone acetate on cerebral oedema and spatial learning performance after traumatic brain injury in rats. Brain Inj 2008;22:107–13.
Gabriel Alcalá-Cerra ∗ Grupo de Investigación en Ciencias de la Salud y Neurociencias (CISNEURO), Cartagena, Colombia ∗ Tel.:
+57 6726017x301; fax: +57 6726017.
2553
Fig. 2. Repeated T2 and post-gadolinium T1-weighted brain and spine MRI showing no abnormalities.
In conclusion, SIH includes a broad range of symptoms, making it sometimes difficult to diagnose. Spinal MRI can be helpful in making the diagnosis and should be included in standard evaluation of SIH.
E-mail address: [email protected] (R. Lefaucheur) 5 July 2013 Available online 20 September 2013
Financial disclosures All authors report no financial disclosures. Author contributions All the authors worked for data acquisition, analysis and interpretation. Ozlem Ozkul, Alaina Borden, Evelyne Guégan Massardier and Romain Lefaucheur had done critical revision of the manuscript for important intellectual content. Finally, Alaina Borden, Evelyne Guégan Massardier and Romain Lefaucheur made study supervision.
http://dx.doi.org/10.1016/j.clineuro.2013.07.046
Clinical impact and therapeutic implications of cerebral microbleeds in patients on warfarin Keywords: Intracranial hemorrhages Stroke Warfarin Anticoagulants
References
Dear Sir,
[1] Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders, vol. 24 (suppl. 1), 2nd ed. Cephalalgia; 2004. p. 1–160. [2] Medina JH, Abrams K, Falcone S, Bhatia RG. Spinal imaging findings in spontaneous intracranial hypotension. American Journal of Roentgenology 2010;195:459–64. [3] Schievink WI. Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension. Journal of the American Medical Association 2006;295(19):2286–96.
I have read, with great interest, a recently published article in Clinical Neurology and Neurosurgery by Orken et al. titled ‘New cerebral microbleeds in ischemic stroke patients on warfarin treatment: Two-year follow-up’ [1]. The study follows 204 patients on warfarin therapy over a period of two years with neuroimaging to quantify the rate of cerebral microbleeds (CMB). During a mean follow-up period of 24.7 months, 29 patients developed new CMBs (10.4%). More advanced patient age (P = 0.04), increased leukoaraiosis (P = 0.02), and prior CMBs (P = 0.03) were significantly associated with development of new CMBs. Two important issues closely related to the data presented in this study were not addressed. First, is there a correlation between CMB and future intracerebral hemorrhage (ICH)? While still a subject of debate, some literature suggest patients with CMBs have a predilection toward future ICHs due to shared pathophysiological mechanisms between the two lesions [2]. Second, what is the neurocognitive impact of CMBs? Patel et al. did not find a significant correlation between the number of CMBs and executive function based on neuropsychological assessment, but patients with at least nine CMBs were found to have poorer executive function than those with fewer than nine CMBs (P = 0.043) [3]. As the current population continues to age, the prevalence of chronic medical conditions, most notably atrial fibrillation (AF), necessitating long-term anticoagulation rises concurrently [4]. Warfarin-associated ICH accounts for approximately 20% of all intracranial hemorrhages with a 0.3–1.0% annual risk of occurrence in AF patients [5]. Compared to non-anticoagulated patients, ICHs in patients on warfarin therapy are larger at presentation and expand more rapidly, and they are ultimately associated with increased morbidity and mortality [5]. New oral direct thrombin inhibitors (i.e. dabigatran) and factor Xa inhibitors (i.e. apixaban and rivaroxaban) have shown promising reductions in ischemic stroke rates for AF patients compared to warfarin in prospective, randomized trials
Ozlem Ozkul Alaina Borden Evelyne Guégan-Massardier Department of Neurology, Rouen University Hospital and University of Rouen, France Franc¸ois Proust Department of Neurosurgery, Rouen University Hospital and University of Rouen, France David Wallon Department of Neurology, Rouen University Hospital and University of Rouen, France Guillaume Perot Department of Radiology, Rouen University Hospital and University of Rouen, France David Maltête Romain Lefaucheur ∗ Department of Neurology, Rouen University Hospital and University of Rouen, France ∗ Corresponding author at: Department of Neurology, Rouen University Hospital, 76031 Rouen Cedex, France. Tel.: +33 2 32 88 87 40; fax: +33 2 32 88 87 41.
2554
Letters to the Editor / Clinical Neurology and Neurosurgery 115 (2013) 2549–2556
[6–8]. However, the same studies have not shown a decreased incidence of hemorrhagic complications with these new agents. While direct coagulation pathway inhibitors (DCPI) do not require routine monitoring of prothrombin time, they are also not as readily reversible as warfarin [9]. In combination with the lack of familiarity with DCPI-associated ICH, the management of and outcomes from this unique pathology remain poorly understood [10]. Future studies are warranted to determine the rate of CMB development in patients on DCPIs and their correlation with ICH.
References [1] Orken DN, Uysal E, Timer E, Kuloglu-Pazarci N, Mumcu S, Forta H. New cerebral microbleeds in ischemic stroke patients on warfarin treatment: two-year follow-up. Clin Neurol Neurosurg 2013;115(9):1682–5. [2] Jeon SB, Kang DW, Cho AH, Lee EM, Choi CG, Kwon SU, et al. Initial microbleeds at MR imaging can predict recurrent intracerebral hemorrhage. J Neurol 2007;254(4):508–12. [3] Patel B, Lawrence AJ, Chung AW, Rich P, Mackinnon AD, Morris RG, et al. Cerebral microbleeds and cognition in patients with symptomatic small vessel disease. Stroke 2013;44(2):356–61. [4] Garcia-Rodriguez LA, Gaist D, Morton J, Cookson C, Gonzalez-Perez A. Antithrombotic drugs and risk of hemorrhagic stroke in the general population. Neurology 2013;81(6):566–74. [5] Flaherty ML. Anticoagulant-associated intracerebral hemorrhage. Semin Neurol 2010;30(5):565–72. [6] Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365(11):981–92. [7] Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361(12):1139–51. [8] Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364(9):806–17. [9] Aguilar MI, Kuo RS, Freeman WD. New anticoagulants (dabigatran: apixaban, rivaroxaban) for stroke prevention in atrial fibrillation. Neurol Clin 2013;31(3):659–75. [10] El Ahmadieh TY, Aoun SG, Daou MR, El Tecle NE, Rahme RJ, Graham RB, et al. New-generation oral anticoagulants for the prevention of stroke: Implications for neurosurgery. J Clin Neurosci 2013.
Dale Ding ∗ University of Virginia, Department of Neurosurgery, Charlottesville 22908, USA ∗ Correspondence to: University of Virginia, Department of Neurosurgery, P.O. Box 800212, Charlottesville, VA 22908, USA. Tel.: +1 434 924 2203; fax: +1 434 982 5753. E-mail address: [email protected]
‘Effect of progesterone administration on prognosis of patients with diffuse axonal injury due to severe head trauma’ [1]. In their article, the authors reinforce available evidence on the neuroprotective effects of progestins in patients with traumatic brain injury (TBI). However, it has an important issue that should not be overlooked. In the design of the study, the authors reported the use of medroxyprogesterone tablets (1 mg/kg gavaged via nasogastric tube every 12 h for five days) instead of intravenous or intramuscular progesterone. Authors mentioned that the therapeutic dose was selected based on the study by Xiao et al., who included in their protocol natural progesterone (1.0 mg/kg via intramuscular injection and then once per 12 h for five days) [2]. Progesterone is synthesized from cholesterol by the brain as a neurosteroid, where is metabolized to molecules 5␣DHprogesterone and 3␣,5␣TH-progesterone; the last also known as allopregnanolone. These compounds are deemed as critical mediators in the neuroprotective mechanism of progesterone [3]. However, synthetic progestins (as medroxyprogesterone) exhibit different chemical and biological properties, and cannot be converted to neuroactive metabolites such as allopregnanolone. Therefore, their effects may not be deemed identical [4]. Additionally, medroxyprogesterone is near 10-fold as potent as natural progesterone and thus, the dosage must not be considered strictly equivalent to the same dose of natural progesterone [1]. Several studies had showed that medroxyprogesterone acetate has not beneficial effects on neurodegeneration, because it antagonizes the mechanisms of estrogen against glutamate toxicity [3]. To the best of our knowledge, there are no clinical studies comparing the effectiveness of medroxyprogesterone and natural progesterone in patients with TBI. However, a preliminary study using a murine model was carried out to determine whether medroxyprogesterone acetate and natural progesterone exert similar effects as a treatment after bilateral injury to the frontal cortex [5]. In that study, medroxyprogesterone produced a dose-related reduction of cerebral edema at 48 h post-TBI, but neither doses enhanced behavioral recovery, suggesting that natural progesterone should not be replaced by medroxyprogesterone [5]. The results published by Shakeri et al. provides an extremely valuable evidence of potential usefulness of other progestins (medroxyprogesterone), as an alternative to natural progesterone when parenteral administration is not practical or feasible [1]. However, since studies comparing the clinical effectiveness and safety of those two progestins are lacking, the evidence provided by this study should not be deemed conclusive.
11 September 2013 13 September 2013 Available online 20 September 2013 http://dx.doi.org/10.1016/j.clineuro.2013.09.006
Different pharmacological effects of progestins should be considered when applied in traumatic brain injury patients Keywords: Progesterone Traumatic brain injury Medroxyprogesterone
Dear Editor, We have read with great interest a recently published article in Clinical Neurology and Neurosurgery by Shakeri et al. entitled
References [1] Shakeri M, Boustani MR, Pak N, Panahi F, Salehpour F, Lotfinia I, et al. Effect of progesterone administration on prognosis of patients with diffuse axonal injury due to severe head trauma. Clin Neurol Neurosurg 2013 [Epub ahead of print]. [2] Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care 2008;12:R61. [3] Herson PS, Koerner IP, Hurn PD. Sex, sex steroids, and brain injury. Semin Reprod Med 2009;27:229–39. [4] Singh M. Progestins and neuroprotection: are all progestins created equal? Minerva Endocrinol 2007;32:95–102. [5] Wright DW, Hoffman SW, Virmani S, Stein DG. Effects of medroxyprogesterone acetate on cerebral oedema and spatial learning performance after traumatic brain injury in rats. Brain Inj 2008;22:107–13.
Gabriel Alcalá-Cerra ∗ Grupo de Investigación en Ciencias de la Salud y Neurociencias (CISNEURO), Cartagena, Colombia ∗ Tel.:
+57 6726017x301; fax: +57 6726017.