Stroke Alert: A Review of Current Clinical Stroke Literature
By Matthew E. Fink, MD, Professor and Chairman, Department of Neurology, Weill Cornell Medical College, and Neurologist-in-Chief, New York Presbyterian Hospital
What is the Best Treatment for Cerebral Cavernous Malformations?
Abstract & Commentary
Synopsis: Cerebral cavernous malformations are common lesions, often asymptomatic, with a low risk for spontaneous hemorrhage. The most effective treatment is uncertain.
Sources: Jeon JS, et al. A risk factor analysis of prospective symptomatic haemorrhage in adult patients with cerebral cavernous malformations. J Neurol Neurosurg Psychiatry 2014 Mar 28; doi:10.1136/jnnp-2013-306844 [Epub ahead of print].
Poorthuis MH, et al. Treatment of cerebral cavernous malformations: A systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2014 Mar 25; doi:10.1136/jnnp-2013-307349 [Epub ahead of print].
Cerebral cavernous malformations are common brain lesions that are found in 0.5-1% of the general adult population. The natural history of these lesions is uncertain, as is the long-term risk of hemorrhage. In addition to intracranial hemorrhage, patients are also at risk for epileptic seizures and nonhemorrhagic focal neurological deficits. Two recent studies have attempted to determine the long-term risk of symptomatic hemorrhage as well as the best treatment to prevent recurrent hemorrhages.
The study by Jeon and colleagues, from the Seoul National University College of Medicine in Seoul, Korea, retrospectively studied 326 patients older than 18 years of age, seen at their center from 1998 until 2010, for a total of 410 cerebral cavernous malformations. Symptomatic hemorrhages were defined as new clinical symptoms with radiographic features of hemorrhage. The patients were divided into three groups. Type I was defined as a cavernous malformation showing acute or subacute hemorrhage. Type II was defined as a loculated hemorrhagic lesion with the typical mulberry appearance and thrombosis. Type III was defined as showing chronic resolved hemorrhage without typical mulberry appearance and a small punctate lesion surrounded by a residual hemosiderin rim. Type III was considered to be a remote hemorrhage, while types I and II were believed to be acute and subacute. One hundred seven (32.8%) and 219 (67.2%) patients, respectively, presented with hemorrhage-related symptoms and hemorrhage-unrelated symptoms. Ninety-five patients had seizures, 54 had a neurological deficit, 48 had headache or vertigo, and 22 were asymptomatic or found incidentally. Two patients died without any relationship to the cavernous malformation. Seventy-nine patients underwent surgical management with 27 undergoing surgical resection and 52 treated with gamma-knife radiosurgery. The indications for intervention were symptomatic hemorrhage in 34, intractable seizures in 26, and progressive neurological deficits in 19.
The overall rate of hemorrhage in this group was 4.46% per lesion-year. The overall annual rate of hemorrhage according to the MR appearance was 9.47% for type I, 4.74% for type II, and 1.43% for type III. There was no clinically significant difference in the rate of hemorrhage between type I and type II. Other variables that were analyzed, including female gender, age, location, multiplicity, hypertension, size, and associated venous angioma, were not significant risk factors for hemorrhage. The study authors concluded that prior symptomatic hemorrhage indicated by the MR appearance could be related to the risk of a prospective recurrent symptomatic hemorrhage in adults, but felt that this could only be confirmed with a prospective multicenter observational study.
The study by Poorthuis MHF et al attempted to analyze the relative benefits of treatment for cerebral cavernous malformations by performing a systematic review of the reported case series and a meta-analysis of those cases. The authors were able to identify 63 cohorts, involving 3424 patients. They looked at a composite outcome, consisting of death, nonfatal intracranial hemorrhage, and new or worse persistent focal neurological deficits. By combining all of the cohorts, they determined that the overall incidence for the composite outcome was 6.6 (95% confidence interval [CI], 5.7-7.5) per 100 person-years, after neurosurgical excision of the lesion and a median follow-up of 3.3 years. After stereotactic radiosurgery treatment, with a median follow-up of 4.1 years, the incidence of the composite outcome was 5.4 (95% CI, 4.5-6.4). The authors also note that patients with brainstem cavernous malformations had a higher risk of reaching the composite endpoint compared to patients with cavernous malformations in the cerebral hemispheres, whether superficial or deep.
Commentary
Although these two recent studies shed some additional light on the natural history of cavernous malformations and give us some information about how treatment may affect the natural history of these lesions, we still do not know if treatment gives a long-term benefit with reduced risk of bleeding or other complications, compared to the untreated lesions. Cavernous malformations are common, and the overall risk of bleeding is quite low, in the range of 1% per year. It appears that the risk of recurrent hemorrhages is higher in the first 2-3 years, but this information is not validated, and it is not clear if interventional therapies, such as surgical excision or stereotactic radiosurgery, will improve the long-term outcome compared to the natural history. A prospective randomized trial will have to be initiated to answer these questions with any certainty.
Cerebrovascular Consequences of Beta- Amyloid Deposition
Abstract & Commentary
Synopsis: Beta-amyloid deposition, as documented by PET amyloid imaging, correlates with increasing arterial stiffness and may explain some of the relationship between vascular disease and Alzheimer’s disease.
Source: Hughes TM, et al. Arterial stiffness and beta-amyloid progression in nondemented elderly adults. JAMA Neurol 2014;71:562-568.
It has been known for many years that cardiovascular risk factors, particularly hypertension, are related to the cognitive impairments and pathological features of Alzheimer's disease. In addition, there is a link between chronic hypertension and the development of white matter hyperintensities in the brain, which are then associated with progressive cognitive impairment during aging. Additional evidence has implicated the development of arterial stiffness in the pathogenesis of the aging brain, the development of cerebrovascular disease, and impaired cognitive functioning in the elderly. At the current time, positron emission tomography (PET) imaging, using a beta-amyloid radiolabeled isotopes such as the Pittsburgh compound B, has demonstrated that more than half of non-demented older adults > 80 years of age have a significant deposition of A-beta in the brain. Other than the known risk factor of APOE-4 positive genotyping and aging, other risk factors are poorly understood and not identified. However, the effects of high blood pressure may be evaluated with the measurement of arterial stiffness, measured as higher pulse-wave velocities in the brain. The authors of this study recruited participants who were originally involved in the Ginkgo Memory Study to undergo PET scanning for A-beta, as well as testing of arterial stiffness using a noninvasive and automated waveform analyzer of pulse-wave velocity.
Pulse-wave velocity was measured in the central (carotid-femoral) vascular bed, as well as the peripheral vascular bed as measured in the femoral-ankle distribution and the brachial-ankle vascular beds. This was calculated as the distance in centimeters between arterial sites of interest over time, in seconds, that the pressure waveforms traveled from the heart to the respective arterial sites. The more rapidly the wave forms traveled down the vascular tree, the more arterial stiffness was present in that vascular bed. These measurements were then correlated with the presence of A-beta on PET scanning and the development of A-beta deposition on repeated measures.
Eighty-one non-demented individuals who were ≥ 83 years participated in this study. The main outcome measures were the change in A-beta deposition over 2 years and the presence of peripheral pulse-wave velocity changes in the central and peripheral vascular beds.
At baseline, 48% of the elderly patients had significant A-beta deposition demonstrated by PET scan, and on 2-year follow-up this number increased to 75%. Brachial-ankle peripheral wave velocities were significantly higher among A-beta positive participants at baseline and at follow-up. Femoral-ankle peripheral wave velocities were only higher among the A-beta positive participants in follow-up. Each standard deviation increase in central stiffness of the carotid-femoral and heart-femoral vascular beds was linked with increases in A-beta deposition on repeat study after 2 years.
Commentary
This intriguing study shows a possible mechanism for the relationship between Alzheimer's disease and vascular risk factors, such as hypertension. The change in arterial stiffness, as demonstrated by measurements of pulse wave velocity in this study, may be the mechanism by which A-beta effects blood vessels and may be one mechanism to explain the development of amyloid angiopathy. It is difficult to distinguish A-beta deposition, demonstrated by PET scanning, from amyloid plaques in the brain parenchyma, compared to deposition of A-beta in the walls of blood vessels, but arterial stiffness measurements may identify which patients are developing significant amyloid angiopathy, as opposed to traditional Alzheimer's disease. Randomized trials of treatment are being developed using this measurement as a biomarker for possible amyloid angiopathy, but confirmation of this correlation will ultimately depend on examination and correlation of pathology in those patients who are followed to death and undergo postmortem examination. In the meantime, the measurement of arterial pulse-wave velocity appears to be a valid and noninvasive way to measure the effects of both high blood pressure as well as amyloid deposition on the brain arteries.
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