Treatment of stroke related refractory brain edema using mixed vasopressin antagonism: a case report and review of the literature

Vishnumurthy Shushrutha Hedna 0 Sharathchandra Bidari 2 David Gubernick 0 Saeed Ansari 0 1 Irawan Satriotomo 0 Asif A Khan 3 Adnan I Qureshi 3 0 Departments of Neurology, College of Medicine, University of Florida , Room L3-100 , McKnight Brain Institute , 1149 Newell Drive, Gainesville, FL 32611 , USA 1 Surgery, University of Florida , Gainesville, FL , USA 2 Radiology, University of Florida , Gainesville, FL , USA 3 Department of Neurology, Central Care Health , St. Cloud, MN , USA Background: Elevated intracranial pressure from cerebral edema is the major cause of early mortality in acute stroke. Current treatment strategies to limit cerebral edema are not particularly effective. Some novel anti-edema measures have shown promising early findings in experimental stroke models. Vasopressin antagonism in stroke is one such target which has shown some encouraging preliminary results. The aim of this report is to highlight the potential use of vasopressin antagonism to limit cerebral edema in patients after acute stroke. Case presentation: A 57-year-old Caucasian man with new onset diplopia was diagnosed with vertebral artery aneurysm extending into the basilar circulation. He underwent successful elective vertebral artery angioplasty and coiling of the aneurysm. In the immediate post-operative period there was a decline in his neurological status and brain imaging revealed new midbrain and thalamic hemorrhage with surrounding significant brain edema. Treatment with conventional anti-edema therapy was initiated with no significant clinical response after which conivaptan; a mixed vasopressin antagonist was started. Clinical and radiological evaluation following drug administration showed rapid clinical improvement without identification of significant adverse effects. Conclusions: The authors have successfully demonstrated the safety and efficacy of using mixed vasopressin antagonist in treatment of stroke related brain edema, thereby showing its promise as an alternative anti-edema agent. Preliminary findings from this study suggest mixed vasopressin antagonism may have significant utility in the management of cerebral edema arising from cerebrovascular accident. Larger prospective studies are warranted to explore the role of conivaptan in the treatment of brain edema and neuroprotection. - Background Stroke is the fourth leading cause of death in United States [1]. Brain edema and herniation are implicated in the majority of these cases [2]. No effective agents exist that have altered the management of brain edema to the satisfaction of clinicians involved in stroke care. Decompressive hemicraniectomy has reduced mortality in malignant middle cerebral artery (MCA) stroke, but only when used in younger populations within 48 hours of symptom onset [3]. In the neurocritical care setting, mannitol and hypertonic saline are used extensively for managing brain edema due to the lack of more effective options, rather than its therapeutic superiority [4]. Significant controversy about the advantages and disadvantages of these agents in long term patient outcomes following brain edema further complicate the clinical picture [5]. Hence there is a great need for alternative agents to rapidly decrease increased intracranial pressure as a result of stroke-related brain edema, thereby reducing brain herniation and its subsequent morbidity and mortality. Arginine-vasopressin (AVP), a potent endogenous hormone responsible for regulating plasma osmolality and volume, has demonstrated a role in the pathophysiological mechanisms in stroke [6,7]. Evidence of AVPs significant role in cerebral edema has made it a promising drug target in the management of this condition [8]. Chang et al. found time-dependent increases in serum AVP levels after brain injury as well as attenuation of AVP levels following administration of 7.5% hypertonic saline in an experimental stroke model [7]. These studies also found that osmotherapy is effective in reducing intracranial pressure (ICP) through a common AVP-mediated pathway. The mechanism of action of AVP is mainly mediated by 2 receptor subtypes: V1a and V2 which are expressed in the brain, pituitary gland, myocardium, vasculature and kidneys. Experimental models have demonstrated the utility of V1a and V2 AVP receptor antagonism in attenuation of ischemia related cerebral edema and infarct volume by aquaporin (AQP) 4 expression modulation. Even though appealing, the evidence for clinical utility of vasopressin antagonism in stroke related brain edema is sparse. Conivaptan is a mixed vasopressin receptor (V1a and V2) antagonist that belongs to the group of non-peptide vasopressin antagonists referred to as Vaptans [9]. This class has been approved by Food and Drug Administration (FDA) for use in hypervolemic/euvolemic hyponatremia [10]. We report a case of a disabling stroke after an endovascular procedure who received conivaptan as last resort to reduce his brain edema. This patients clinical course and radiological findings were serially monitored and recorded. Adverse events and safety data from this medication were also monitored and documented. Case presentation A 57-year-old Caucasian male with residual right-sided hemiparesis from a cerebrovascular event, 1 month prior to this admission, presented with sudden onset of vision changes. He complained his vision was upside down with associated headache, nausea and vomiting. His past medical history included pacemaker implantation, and multiple sclerosis in remission. On neurological exam, his National Institutes of Health Stroke Scale (NIHSS) was 9 when including his previous residual neurological deficits. Higher cognitive function was mostly intact except for dysarthria, and diplopia on horizontal gaze with right internuclear opthalmoplegia. His old deficits from recent stroke included partial right facial palsy with right hemiparesis (motor system examinations using the Medical Research Council (MRC) grade: 2/5 in right upper and lower extremity), hemi body numbness and intact cerebellar function. Computed tomography (CT) scan of the head without contrast revealed left precentral gyrus hypodensity extending to the hand area, most consistent with an evolving late subacute infarct corresponding to the patient's right upper extremity weakness. Most prominent was the finding of a partially calcified 16 mm fusiform aneurysm of the left vertebral artery (VA) with extension to the basilar junction and beyond. On day 1 of admission, he was complaining of severe intractable headaches and depression. On day 6, he had a sudden decline in his neurological exam wherein he developed complete facial weakness, became somnolent, and suffered a 25 minutes generalized tonic clonic seizure (which was treated with a standard status epilepticus treatment regimen). Repeat head CT demonstrated new hypodensity in the mesial aspect of the left midbrain compared to the admission study. This was most consistent with (...truncated)