|Year : 2016 | Volume
| Issue : 2 | Page : 220-224
Stroke in pheochromocytoma: A novel mechanism
Mark William Fegley1, Rodrigo Duarte-Chavez2, Sahil Agrawal2, Amitoj Singh2, Santo Longo3, Sudip Nanda2
1 Department of Family Medicine, St. Luke's University Health Network, Bethlehem, Pennsylvania, USA
2 Department of Internal Medicine, St. Luke's University Health Network, Bethlehem, Pennsylvania, USA
3 Department of Pathology, St. Luke's University Health Network, Bethlehem, Pennsylvania, USA
|Date of Submission||27-Dec-2015|
|Date of Acceptance||01-Mar-2016|
|Date of Web Publication||28-Dec-2016|
Department of Internal Medicine, St. Luke's University Health Network, 801 Ostrum Street, Bethlehem, Pennsylvania 18015
Source of Support: None, Conflict of Interest: None
Central nervous system manifestations of pheochromocytomas usually result from hypertension, hemorrhage, and tumors when it is part of heritable syndromes. We describe a unique case where obvious causes are lacking for an ischemic stroke. Recent advances in cell biology have elucidated the role of endothelium and vascular smooth muscle cell in vascular flow regulation. We propose a novel mechanism for an increased risk of ischemic stroke that occurs during the hyperadrenergic state. New pharmacological agents used to treat stroke that act on the various pathways proposed in our mechanism are reviewed.
The following core competencies are addressed in this article: Patient care and medical knowledge.
Keywords: Endothelin antagonists, pheochromocytoma, Rho-kinase inhibitors, vascular smooth muscle cells
|How to cite this article:|
Fegley MW, Duarte-Chavez R, Agrawal S, Singh A, Longo S, Nanda S. Stroke in pheochromocytoma: A novel mechanism. Int J Acad Med 2016;2:220-4
|How to cite this URL:|
Fegley MW, Duarte-Chavez R, Agrawal S, Singh A, Longo S, Nanda S. Stroke in pheochromocytoma: A novel mechanism. Int J Acad Med [serial online] 2016 [cited 2020 Apr 6];2:220-4. Available from: http://www.ijam-web.org/text.asp?2016/2/2/220/196872
| Introduction|| |
Pheochromocytomas can cause central nervous system (CNS) symptoms through varied mechanisms. The most common mechanisms include uncontrolled hypertension (HTN) causing intracranial hemorrhage, multiple endocrine neoplasia Type 2 with metastasis, neurofibromatosis Type 1 with CNS tumors, and von Hippel–Lindau syndrome with hemangioblastomas. Rarer syndromes include dilated cardiomyopathy with mural thrombus that embolizes, multiple cranial aneurysms, and malignant thromboembolization from metastatic aortic arch involvement. We present a case where none of these predispositions were present, and yet the patient developed an ischemic stroke. We propose a novel hypothesis for the stroke and analyze available data which may be relevant for future treatment.
| Case Report|| |
A 37-year-old female presented with right-sided weakness. Her pulse was 52/min and blood pressure was 130/60 mmHg. She had motor aphasia, upper motor neuron facial palsy, and right hemiplegia. Computed tomography scan of the head revealed dense left middle cerebral artery infarct [Figure 1]a. She was an active healthy female with normal body mass index. She did not use tobacco, alcohol, or any other recreational drugs. She was not diabetic and did not use oral contraceptives. She had an 11-month-old child. Complete blood count and metabolic panel were normal. There was no evidence of hemoconcentration. Echocardiogram revealed normal valves, normal ventricular function without mural thrombus, and absence of patent foramen ovale or any right to left shunts. Carotid Dopplers were normal. Thrombophilic workup of antithrombin III deficiency, protein C deficiency, protein S deficiency, factor V Leiden mutation, prothrombin 20210 mutation, anticardiolipin antibodies, lupus anticoagulant, and elevated homocysteine were negative. A workup for vasculitis was also negative. Physical examination and radiologic studies revealed bilateral adrenal masses [Figure 1]b. She had markedly elevated metanephrine up to 130,896 pg/ml (normal 12–60 pg/ml) and plasma normetanephrine ranged up to 25,938 pg/ml (normal 18–111 pg/ml). A urine level of epinephrine (E) was 223 µg/24 h (normal 0–24 µg/24 h), norepinephrine (NE) was 87 µg/24 h (normal 0–140 µg/24 h), and dopamine was 575 µg/24 h (normal 65–610 µg/24 h). Chromogranin level was 413 nmol/L (normal 0–5 nmol/L). Histopathology confirmed pheochromocytoma and chromogranin A staining was positive [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d. The patient underwent laparotomy with removal of the two tumors.
|Figure 1: Computed tomography imaging. (a) Computed tomography scan of the head reveals dense infarct involving the left middle cerebral artery territory. (b) Computed tomography scan of the abdomen shows bilateral pheochromocytomas|
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|Figure 2: Pathology staining of adrenal masses. (a) Nests of “Zellballen” between thin walled vessels (H and E, ×10). (b) Nests of “Zellballen” between thin walled vessels (H and E, ×40). (c) Negative chromogranin a control. (d) The tumor shows uniform positive cytoplasmic staining for chromogranin A|
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| Discussion|| |
Pheochromocytoma causes significant overproduction and intermittent release of inappropriately high levels of catecholamines leading to a hyperadrenergic state. Epinephrine comprises 80% of catecholamines in the adrenal medulla. NE is produced in situ in organs innervated by sympathetic nerves. The synthesis is detailed in [Figure 3].
|Figure 3: In situ biological synthesis of catecholamines. Synthesis begins with the rate limiting step, hydroxylation of tyrosine to dopa by tyrosine hydroxylase (TH). Decarboxylation of dopa to dopamine by dopa decarboxylase (DDC). Hydroxylation of dopamine to norepinephrine by dopamine beta hydroxylase (DBH) and lastly methylation of norepinephrine to epinephrine by phenylethanolamine N methyl transferase (PNMT). Adaptation from Harper's Illustrated Biochemistry, 29th edition|
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Free catecholamine levels can be useful to detect pheochromocytoma. Our patient had mildly elevated epinephrine level (9 times upper limit) and a normal NE level. Chromogranin levels are a sensitive and specific screening tool; our patient had a level of 413 mmol/L (normal 0–5 mmol/L). Free metanephrine levels are also useful markers for detection of disease, and our patient had markedly elevated levels, metanephrine (130,896 pg/ml, normal 12–60 pg/ml) and normetanephrine (25,938 pg/ml, normal 18–111 pg/ml). A complete list of screening methods is shown in [Table 1].
HTN is the most common clinical presentation of pheochromocytoma. It can be sustained or paroxysmal. It is primarily mediated by NE, the principal catecholamine in most patients; however, in a subset of patients, epinephrine is the predominant catecholamine. Blood pressure is normal in <20% of patients. Our patient lacked HTN and epinephrine was the predominant hormone suggested by higher elevations of epinephrine and metanephrine.
Pheochromocytoma is known to cause severe life-threatening medical complications and often the life-threatening event is the presenting sign. A study by Riester et. al., which analyzed 130 patients from a 10 year period in three separate German referral centers, revealed 15 patients (11%), required intensive care for a life-threatening complication from previously unknown pheochromocytoma. The complications included Tako-Tsubo cardiomyopathy - 4, cerebrovascular stroke - 2, myocardial infarction - 2, renal failure - 2, acute pulmonary edema - 2, ischemic ileus - 1, multi-organ failure – 1, and HTN crisis with pulmonary edema during delivery - 1. This subset of patients had larger tumor size (7.0 vs. 4.5 cm), higher levels of catecholamines (20-fold vs. 9-fold upper limit) and were significantly younger (42-year-old vs. 51-year-old). Our patient fit two of these criteria, age (37-year-old) and tumor size (left adrenal gland 16 cm × 11.5 cm × 7 cm and right adrenal 22 cm × 16 cm × 7 cm).
Cerebrovascular stroke concurrent with pheochromocytoma has been described in the literature. Several predisposing factors are attributed to comorbid diseases such as multiple endocrine neoplasia Type 2, neurofibromatosis and von Hippel–Lindau disease. In addition, there was no metastasis of tumor, chronic HTN, or evidence of cardiomyopathy.,, The most likely explanation and mechanism of stroke in our patient are elevated catecholamines synthesized locally in the CNS which had profound vasoconstrictive effects on the cerebrovasculature likely precipitating stasis and thrombosis.
Catecholamines are synthesized locally in the brain. Peripheral catecholamines do not cross the blood-brain barrier, hence cannot directly affect cerebral vasculature. However, elevated catecholamines peripherally induce a state of stress and induce synthesis of tyrosine hydroxylase (TH) in the locus ceruleus, mid-brain and other areas of the CNS., This induction of local catecholamine synthesis provides a basis for vasoconstriction of cerebral vasculature and is the root of our hypothesis.
The vascular endothelium plays a central antithrombotic role through nitric oxide, prostacyclin, and endothelins (ETs). Nitric oxide synthase 1 and ET-1 are preferentially distributed in the CNS. Recent research has highlighted the role of vascular smooth muscle cell (VSMC) in hemostasis. Increased intracellular calcium promotes VSMC contraction. NE increases calcium within VSMC by phospholipase C pathway which activates myosin light chain kinase causing contraction. Activation of Rho-kinase is a calcium independent pathway mediating VSMC contraction [Figure 4]. The complex interaction of catecholamines on the VSMC likely precipitated vascular stasis, thrombus formation, and stroke in our patient. Selective involvement of cerebral vasculature with sparing of other vascular beds is secondary to differential distribution of endothelial products in different vascular beds.
|Figure 4: Vascular smooth muscle cell activation. A vascular smooth muscle cell is shown with receptor that can be activated by norepinephrine, angiotensin II, or endothelin 1. Actomyosin contraction is activated by myosin light chain kinase and inhibited by myosin light chain phosphatase. Calcium activates myosin light chain kinase while Rho-kinase inhibits myosin light chain phosphatase promoting contraction. Sustained unregulated contraction can lead to vascular stasis and thrombosis. Drugs that reduce intracellular calcium, endothelin receptor antagonists, and Rho-kinase inhibitors can regulate and reduce such pathological sustained contraction of the vascular smooth muscle cell. Adaptation from Vascular Medicine: Therapy and Practice 2nd edition|
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A significant detractor of this probable pathway is the rarity of CNS venous thrombosis in other patients with pheochromocytomas. The human catecholamine secretory trait is heritable. Secretion is influenced by genetic variation of enzymes in the catecholamine synthetic pathway, of which variations in TH is well documented.
Medications effective in countering cerebral vasospasm confirm the pathogenic pathways described [Table 2]. One such class is calcium antagonists which reduce the proportion of ischemic neurologic deficits. Nimodipine improves overall outcome within 3 months of aneurysmal subarachnoid hemorrhage (SAH) and is effective in preventing provoked vasospasm.,
The second major mediator of vasoconstriction is ET-1. Substantial recent evidence now implicates ET in the pathophysiology of cerebrovascular disorders such as vasospasm associated with SAH and ischemic stroke. Recent clinical trials have demonstrated prevention of vasospasm with the ET receptor antagonist clazosentan.
The third mechanism of injury prevention is the protein kinase and Rho-kinase inhibitors. Activation of Rho-kinase is a calcium independent pathway mediating VSMC contraction [Figure 4]. The efficacy and safety of fasudil hydrochloride, a novel protein kinase inhibitor, was evaluated for the treatment of cerebral vasospasm in patients with ruptured cerebral aneurysm. With nimodipine as control, both drugs significantly improved consciousness levels and neurological deficits such as aphasia. However, fasudil hydrochloride improved motor disturbance more than nimodipine without serious adverse events.
Further research is needed to investigate the significance of the mechanism and pathway we propose. Pheochromocytoma is a rare disease, and it would be difficult to study in a human subject. Experimental rat models where chromaffin cell proliferation can be easily induced will help corroborate this hypothesis.
| Conclusion|| |
Our patient had an ischemic stroke with concurrent pheochromocytoma but lacked underlying comorbid diseases and mechanisms described in literature. We describe and hypothesize that dysregulation of intracellular processes involving the endothelium and vascular smooth muscle function led to her stroke. Further studies are needed, to elucidate the proposed mechanisms of such large ischemic stroke in patients with pheochromocytomas, when none of the other usual causes of stroke are identified.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]