CASE STUDY
Moyamoya disease: A case of vanishing cerebral vessels Joanne L. Thanavaro, DNP, ANP-BC, ACNP-BC, DCC (Associate Professor)1 , Nimish Nemani, MD (Director)2 , & Hilton I. Price, MD (Chief)3 1
School of Nursing, St. Louis University, St. Louis, Missouri Intensive Care Unit, Midwest Acute Care Consultants, St. Anthony’s Medical Center, St. Louis, Missouri 3 Department of Radiology, Christian Northeast Hospital, St. Louis, Missouri 2
Keywords Neurology; neuroradiology; neurosurgery; vascular disease. Correspondence Joanne L. Thanavaro, DNP, ANP-BC, ACNP-BC, DCC, School of Nursing, St. Louis University, 3525 Caroline Avenue, Room 321, St. Louis, Missouri 63104. Tel: 314-977-8993; Fax: 314-977-8840; E-mail: [email protected] Received: October 2010; accepted: March 2011 doi: 10.1111/j.1745-7599.2012.00782.x
Abstract Purpose: To provide an overview of moyamoya disease (MMD) including pathophysiology, epidemiology, clinical presentation, diagnosis, treatment, and prognosis. Data sources: Selected clinical and epidemiological studies, review articles, and diagnostic guidelines for MMD. Conclusions: MMD is a rare cerebrovascular disease characterized by progressive stenosis of the distal internal carotid arteries and their major branches. The dilated and fragile basal collateral circulations display a “puff of smoke” appearance and thus are called moyamoya vessels. Other unique features of MMD include 2:1 female preponderance and its peak incidence in two age groups: early childhood and adults in their mid-40s. The pathophysiology of MMD is unclear and possible causes include genetic linkage, angiogenesis, autoimmune disease, cranial radiation, and infection of the head and neck. Most patients are symptomatic and may present with ischemic or hemorrhagic strokes, seizure, or headache. The diagnosis depends on clinical presentation and radiographic imaging, and disease progression may be halted with direct or indirect cerebral revascularization. Implications for practice: It is important to make a correct diagnosis and provide appropriate treatment to reduce the morbidity and mortality associated with MMD. A prompt referral for possible surgical revascularization offers the best chance to reduce additional cerebral injuries and improve clinical outcomes.
Case presentation ES is a 26-year-old female with a history of diabetes mellitus, Von Willebrand disease, and a seizure disorder. She presented to the emergency department (ED) with nonspecific symptoms including headache, dizziness, lightheadedness, nausea, and vertigo-type symptoms. She was discharged home with symptomatic treatment since there was no indication of a serious illness. She returned to the ED 2 days later because of a progressively worsening headache and stiff neck. The patient was afebrile and normotensive (120/70 mmHg). She was alert and oriented to person, place, and time; and she had no meningismus or focal neurological deficits. Complete blood count (including white blood cells and platelets), prothrombin time,
partial thromboplastin time, and complete metabolic profiles were within normal limits. She had an episode of seizure in the ED, treated with intravenous lorazepam administration. A lumbar puncture was performed as an initial workup because of the presenting symptoms of progressive headache, nausea, and stiff neck. The cerebrospinal fluid (CSF) was grossly bloody, indicative of intracerebral hemorrhage (ICH). A cerebral computed tomography (CT) scan was obtained based on prior studies indicating that this imaging technique readily identifies cerebral intravascular etiologies of ICH, the most likely causes of ICH in a young female patient without hypertension or coagulation abnormalities (Chalela et al., 2007; Delgado
C 2012 The Author(s) Journal of the American Academy of Nurse Practitioners 00 (2012) 1–7 C 2012 American Academy of Nurse Practitioners Journal compilation
1
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Figure 1 Anterior–posterior views of carotid angiograms demonstrate occluded right internal carotid artery (A) at the supraclinoid portion and occluded left internal carotid artery (B) at the parasellar portion.
Almandoz, 2009). The patient’s CT scan demonstrated evidence of intraventricular hemorrhage, an old right frontal and parietal lobe infarct, and right periventricular white matter hypodensity. CT angiogram showed diminished blood flow within the intracranial distribution of the internal carotid arteries (ICAs), suggestive of vascular occlusive disease such as moyamoya disease (MMD). The cerebral angiography revealed bilateral occlusion of terminal ICAs and absent flow into both anterior cerebral artery (ACA) and middle cerebral artery (MCA) (Figure 1). The networks of moyamoya vessels characteristic of the diagnosis of MMD were not present and both ACA and MCA were filled by the collateral circulations from the vertebral artery, compatible with an advanced stage of MMD (Figure 2). Based on the presence of bilateral occlusion of terminal ICAs, absent major cerebral arteries (ACA and MCA), absent moyamoya vessels, and evidence of extracranial collateral circulations, the patient was diagnosed with Stage V–VI MMD on the Suzuki Grading System. ES was admitted to the intensive care unit and was eventually discharged from the hospital with full recovery and without residual neurological deficits. She was subsequently referred to a University hospital for additional evaluation and had a successful right superficial temporal artery (STA) to right MCA revascularization procedure 2 months later.
Background MMD is a rare chronic cerebrovascular disease which is characterized by progressive bilateral stenosis or occlusion of the terminal part of the ICAs or their main branches including the ACA and MCA (Burke et al., 2009; Kuroda & Houkin, 2008; Scott & Smith, 2009; Suzuki & Takaku, 1969). Many collateral networks provide an alternative route for cerebral perfusion; however, they are imperfect and fragile and may predispose pa2
Figure 2 Lateral view of left vertebral artery (dark arrow) providing collateral circulations to the anterior (thick white arrow) and middle cerebral arteries (thin white arrow).
tients to transient ischemic attacks (TIAs) and ischemic or hemorrhagic strokes (Burke et al., 2009; Lee et al., 2009; Smith & Scott, 2005). At the early stage of the disease, the intracranial collateral circulations that develop at the base of the brain display a “puff of smoke” appearance and are called moyamoya vessels (Figure 3; Burke et al., 2009; Kuroda & Houkin, 2008; Smith & Scott, 2005; Suzuki & Takaku, 1969). Moyamoya is Japanese and translates to “puff of smoke.” The condition was initially identified in Japan, thus the reason for a Japanese name (Caldarelli et al., 2001; Kraemer et al., 2008; Suzuki & Takaku, 1969; Yilmaz et al., 2001). As the disease progresses, the
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Pathophysiology
Figure 3 Left carotid angiogram from a 53-year-old oriental woman who became unresponsive with left hemiparalysis from a massive intracerebral hemorrhage. The angiogram shows an occluded left internal carotid artery (thick dark arrow) with collateral circulation to an anterior cerebral artery (white thick arrow) and a middle cerebral artery (white thin arrow) via moyamoya vessels (surrounded by dark thin arrows).
antegrade blood flow decreases with gradually diminishing moyamoya vessels and the cerebral blood flow is more dependent on the development of extracranial collateral circulations. MMD is most prevalent in Japan and even though this disease is now recognized throughout the world, it remains underdiagnosed as a cause of ischemic or hemorrhagic stroke in Western countries (Kraemer et al., 2008; Kuriyama et al., 2008; Yilmaz et al., 2001). The clinical diagnosis of MMD requires a strong suspicion for the disease when treating ischemic or hemorrhagic cerebrovascular accident (CVA) in children or young females without other risk factors for strokes such as age >55 years, history of atrial fibrillation or heart disease, hypertension, dyslipidemia, smoking history, diabetes mellitus, contraceptive pills, or hormone therapy (Reeves et al., 2009; Smith & Scott, 2005). While some advanced practice nurses (APNs) may encounter MMD patients with suspected strokes in the acute care setting, other APNs may care for these patients with milder ischemic and nonischemic MMD symptoms in a primary care setting before or after the diagnosis is established. Additionally, more patients are surviving the acute event and doing well after cerebral revascularization. These patients may appear at various pediatric or adult primary care practices for other healthcare needs. It is important that APNs are wellarmed with knowledge of MMD so they will be able to make a correct diagnosis and provide appropriate treatment.
The pathophysiology of MMD is unclear. The pathological findings of thickened intima, smooth muscle cell hyperplasia, and luminal thrombosis without atherosclerotic or inflammatory changes in the affected vessels indicate a significant role of angiogenesis in the development of MMD (Scott & Smith, 2009; Ullrich et al., 2007). Luminal microthrombi may lead to endothelial injury, thickening of the intima, and smooth muscle cell proliferation. Protein S deficiency, lupus anticoagulant, and anticardiolipin antibodies have been found in other cases, suggesting a possible autoimmune mechanism in MMD (Kuroda & Houkin, 2008). A possible genetic association of MMD to chromosome 17 has been demonstrated in familial MMD (Burke et al., 2009; Kuroda & Houkin, 2008; Yamauchi et al., 2000). Two forms of MMD have been recognized including primary and secondary forms of the disease. The primary form is more common and is also referred to as true MMD. While most cases are idiopathic, familial MMD has been reported in 12–15% of cases in the Japanese population (Burke et al., 2009; Kuriyama et al., 2008; Kuroda & Houkin, 2008; Yamauchi et al., 2000). The secondary form of this disease is known as moyamoya syndrome or quasi-moyamoya. This secondary form has been described in association with sickle cell disease, neurofibromatosis type I, Down’s syndrome, infection of the head and neck, and cranial therapeutic irradiation (Baba, Houkin, & Kuroda, 2008; Scott & Smith, 2009; Uchino et al., 2005 Ullrich et al., 2007; Yamada et al., 1997). MMD is often associated with bilateral angiographic findings and unilateral findings are more commonly found in moyamoya syndrome (Fukui, 1997; Ueki et al., 1994).
Epidemiology Prior reported incidence and prevalence of this disease varies depending on the population selected for the study (Baba et al., 2008; Kuriyama et al., 2008; Kuroda & Houkin, 2008). An all-inclusive survey of a large Japanese island reported an annual incidence of 0.94 per 100,000 people and a prevalence of 10.5 per 100,000 people (Baba et al., 2008). However, a recent nationwide survey of the Japanese population reported an annual detection rate of the disease of 0.54 per 100,000 patients and a prevalence of 6 per 100,000 patients (Kuriyama et al., 2008). A gender difference has been established with a female to male ratio of approximately 2:1 (Baba et al., 2008; Kuroda & Houkin, 2008). There are two peaks of age distribution; prior studies have reported the highest peak in children between the ages of 5 and 9 years but recent data reveal a significant increase in the adult 3
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population with the largest peak between 45 and 49 years old (Baba et al., 2008; Kuroda & Houkin, 2008; Wakai et al., 1997). One study from the western United States (Washington and California) that included patients from various ethnic backgrounds reported a lower incidence (0.086 per 100,000), a similar female to male ratio and a similar early peak but a later second peak between 55 and 59 years old (Uchino et al., 2005). The incidence was higher in Asian Americans (4.6 times) and African Americans (2.2 times) than the Caucasian population. Fortyeight percent of African Americans in the study also had a diagnosis of sickle cell disease. The data for MMD in Caucasians are limited with the incidence of this disease estimated to be one-tenth of that observed in the Japanese population (Kraemer et al., 2008; Uchino et al., 2005). A retrospective study in 21 Caucasian patients treated for MMD in a German institution reported a female predominance of 4.25:1 and all the females presented with an ischemic event (Kraemer et al., 2008). The available data indicate that Caucasian patients do not demonstrate the two peaks of age distributions at the onset of the disease, have more benign symptoms at presentation, have more ischemic symptoms at all ages, and respond better to surgical treatment (Hallemeier et al., 2006; Kraemer et al., 2008; Mesiwala et al., 2008; Yilmaz et al., 2001).
Clinical presentation Over 80% of patients with MMD are symptomatic and their clinical presentation may include ischemic, hemorrhagic or “other” symptoms such as headache, seizure, choreiform movements, cognitive, or psychiatric changes (Baba et al., 2008; Burke et al., 2009). Most childhood MMD cases present with ischemic events that are often precipitated by hyperventilation or crying and occur repetitively over several years (Burke et al., 2009; Kuroda & Houkin, 2008; Han et al., 2000; Smith & Scott, 2005). Adult patients may present with ischemic symptoms, intracranial bleeding, or both (Han et al., 2000; Kuroda & Houkin, 2008). Two-thirds of these adult patients suffer from intracranial bleeding which may be attributed to the rupture of moyamoya vessels, aneurysms in the circle of Willis, dilated perforators, or dilated collateral arteries on the brain surface (Burke et al., 2009; Kuroda & Houkin, 2008; Osanai et al., 2008). Intracerebral hematoma is the major cause of death in patients with MMD (Burke et al., 2009). Various types of collateral circulation may contribute to other symptoms of MMD. The dilated meningeal and leptomeningeal collateral vessels may predispose patients to migraine-like headaches that are frequently unresponsive to medical therapy (Seol et al., 2005). Choreiform movements in 4
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some patients may be attributed to dilated moyamoya vessels in the basal ganglion (Parmar et al., 2000; Scott et al., 2004).
Diagnosis Strict guidelines for the diagnosis of MMD have been established (Burke et al., 2009; Fukui, 1997). The diagnosis is normally made on the basis of clinical presentation of ischemic or hemorrhagic stroke in children or young female patients together with primary and secondary radiographic findings (Burke et al., 2009; Kuriyama et al., 2008; Scott & Smith, 2009; Smith & Scott 2005). The presenting symptoms and physical findings depend on the age of patients as previously described (Burke et al., 2009; Kuroda & Houkin, 2008; Han et al., 2000). Fundoscopic examination may reveal a “morning glory disk,” which is an enlarged optic disk occasionally seen in those who develop vascular anomalies in the retina (Lee et al., 2009, Scott & Smith, 2009). The electroencephalogram (EEG) in 50% of the children with this disease may demonstrate a distinctive pattern of ”buildup” and ”rebuild-up” phenomenon that occurs when the child is asked to hyperventilate. Specifically at the beginning of hyperventilation, the EEG displays high voltage slow waves which disappear during hyperventilation but return within 20–60 s after stopping hyperventilation (Kodama et al., 1979; Smith & Scott, 2005). The workup of a suspected case of MMD usually begins with cerebral CT scan, which can readily identify the secondary findings (Burke et al., 2009; Smith & Scott, 2005). It is possible that patients with TIAs may not demonstrate any abnormalities (Scott & Smith, 2009). CT angiography may be used to visualize the intracranial stenoses but cerebral angiography remains the gold-standard imaging technique that will best demonstrate the primary findings of MMD (Burke et al., 2009; Kuriyama et al., 2008; Scott & Smith, 2009). These primary findings consist of bilateral stenosis or occlusion of the terminal portion of the ICAs or their major branches and abundant collateral formation with basal moyamoya vessels (Burke et al., 2009; Fukui, 1997; Kuriyama et al., 2008). Magnetic resonance imaging (MRI) and angiography (MRA) are reliable methods for the visualization of the primary and secondary findings as well as postoperative results of revascularization procedure for MMD (Burke et al., 2009). Because of its excellent diagnostic yield and noninvasive nature of the procedure, MRA is now recommended as the primary diagnostic imaging procedure for MMD (Smith & Scott 2005). Conventional cerebral angiography may be necessary in a few patients when smaller vessel occlusions and moyamoya collateral vessels are not well visualized with MRI and MRA (Kuriyama
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Table 1 Suzuki Staging System of moyamoya disease Stage I Stage II Stage III
Stage IV
Stage V Stage VI
Bilateral internal carotid artery (ICA) stenosis distally at the carotid forks Development of basal moyamoya vessels Increasing ICA stenosis involving anterior and middle cerebral arteries Intensification of moyamoya vessels Occlusion of ICAs and the entire circle of Willis—disappearance of all major cerebral arteries Diminished basal moyamoya vessels Development of extracranial collaterals Further reduction of basal moyamoya vessels Intensification of extracranial collaterals Disappearance of basal moyamoya vessels Collateral circulation solely from the external carotid arteries
Note. Burke et al., 2009; Scott & Smith, 2009; Suzuki & Kodama, 1983; Zipfel et al., 2005.
et al., 2008; Smith & Scott 2005). A definitive diagnosis of MMD requires the presence of bilateral distal ICA stenosis or occlusion and intra- or extracranial collateral circulations demonstrated by cerebral angiography or MRI and MRA (Kuriyama et al., 2008). While bilateral ICA obstruction is characteristic of MMD, some patients may initially present with unilateral vascular abnormalities and approximately one-third of them will eventually develop contralateral disease (Kelly et al., 2006; Kuroda et al., 2005). In a study of 120 adults, female sex was the only risk for progression of the disease, whereas a study with predominantly children in the sample reported the association of progression of the disease to contralateral abnormalities on initial imaging, congenital cardiac anomaly, previous cranial radiation, Asian ancestry, and familial moyamoya syndrome (Kuroda et al., 2005; Smith & Scott, 2008). The secondary radiographic findings include cerebral infarction, white matter lesions, atrophy, and hemorrhage (Burke et al., 2009; Scott et al., 2004; Smith & Scott 2005; Suzuki & Kodama, 1983). The Suzuki Grading System describes six angiographic stages, which indicate the severity of the disease (Burke et al., 2009; Scott & Smith, 2009; Suzuki & Kodama, 1983). The grading system begins with bilateral ICA stenosis distally at the carotid forks in Stage I, progressive development and disappearance of basal moyamoya vessels over Stage II–V, and final deterioration to complete absence of major cerebral arteries and basal moyamoya vessels with collateral circulation produced solely from the external carotid arteries in Stage VI (Table 1). Most symptomatic cases of MMD are diagnosed at Stage III of this grading system (Burke et al., 2009). Extra to intracranial collaterals in some patients may form netlike vessels; two forms have been described including eth-
moidal and vault moyamoya (Suzuki & Kodama, 1983). Ethmoidal moyamoya communicates with basal moyamoya via ophthalmic, anterior, and posterior ethmoidal arteries. Vault moyamoya develops transdural anastomosis from the middle meningeal artery and STA. These extra- to intracranial moyamoya vessels poorly develop in adults as compared to children and this may be attributed to the loss of the capacity to form these collaterals with increasing age (Suzuki & Kodama, 1983). The case presentation in this report demonstrates that the diagnosis of MMD can be difficult and requires a strong clinical suspicion. The initial presentation of headache, dizziness, and nausea without any other neurological deficits were subtle and nonspecific. Even with a progressive worsening headache and stiff neck, the patient continued to have a normal neurological examination without meningismus. The diagnosis of ICH was made primarily because of grossly bloody CSF, which was attributed to MMD on the basis of the primary findings of complete ICA occlusion involving ACA and MCA with extra- to intracranial collateral circulations, as well as the secondary findings of prior infarct and intraventricular hemorrhage on CT scan.
Treatment Patients with milder symptoms are usually treated conservatively with medical therapy but there is little evidence of short-term or long-term efficacy (Burke et al., 2009). Antiplatelet agents have been used to prevent emboli but chronic anticoagulation with warfarin is rarely used (Bowen et al., 2005; Scott et al., 2004; Smith & Scott, 2005). Calcium-channel blockers may relieve intractable headaches or reduce the incidence and severity of TIAs (Scott & Smith, 2009; Shirane et al., 1997). Patients with more severe symptoms are treated with one of the three surgical revascularization procedures: direct, indirect, and combined techniques (Burke et al., 2009; Hallemeier et al., 2006, Kuroda & Houkin, 2008; Smith & Scott, 2005; Yilmaz et al., 2001). Direct revascularization involves extra- to intracranial arterial bypass with anastomosis of the STA to MCA or other grafttype procedures (Burke et al., 2009; Kuroda & Houkin, 2008; Smith & Scott, 2005). This type of revascularization is limited to adults or older children with acceptable calibers of donor and recipient vessels (Burke et al., 2009). Indirect revascularization involves placing vascularized tissues such as dura, temporalis muscle, or STA itself, in direct contact with the brain to promote neovascularization to the underlying cerebral cortex (Burke et al., 2009; Kuroda & Houkin, 2008; Smith & Scott, 2005). This procedure is more suitable for patients with poor cortical branches for anastomosis or for younger 5
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patients with smaller donor or recipient vessels (Burke et al., 2009). Encephaloduroarteriosynangiosis (EDAS) is the most commonly performed indirect revascularization procedure, in which a segment of a scalp artery is transposed on to the surface of the brain to improve collateral blood flow (Yilmaz et al., 2001). Combined direct and indirect procedures have been employed to promote better revascularization and prevent ischemia in some patients (Burke et al., 2009). The revascularization procedure is usually recommended for ischemic strokes or TIAs in patients with good neurological ability to perform daily activities, small area of cerebral infarctions (
Moyamoya disease: A case of vanishing cerebral vessels Joanne L. Thanavaro, DNP, ANP-BC, ACNP-BC, DCC (Associate Professor)1 , Nimish Nemani, MD (Director)2 , & Hilton I. Price, MD (Chief)3 1
School of Nursing, St. Louis University, St. Louis, Missouri Intensive Care Unit, Midwest Acute Care Consultants, St. Anthony’s Medical Center, St. Louis, Missouri 3 Department of Radiology, Christian Northeast Hospital, St. Louis, Missouri 2
Keywords Neurology; neuroradiology; neurosurgery; vascular disease. Correspondence Joanne L. Thanavaro, DNP, ANP-BC, ACNP-BC, DCC, School of Nursing, St. Louis University, 3525 Caroline Avenue, Room 321, St. Louis, Missouri 63104. Tel: 314-977-8993; Fax: 314-977-8840; E-mail: [email protected] Received: October 2010; accepted: March 2011 doi: 10.1111/j.1745-7599.2012.00782.x
Abstract Purpose: To provide an overview of moyamoya disease (MMD) including pathophysiology, epidemiology, clinical presentation, diagnosis, treatment, and prognosis. Data sources: Selected clinical and epidemiological studies, review articles, and diagnostic guidelines for MMD. Conclusions: MMD is a rare cerebrovascular disease characterized by progressive stenosis of the distal internal carotid arteries and their major branches. The dilated and fragile basal collateral circulations display a “puff of smoke” appearance and thus are called moyamoya vessels. Other unique features of MMD include 2:1 female preponderance and its peak incidence in two age groups: early childhood and adults in their mid-40s. The pathophysiology of MMD is unclear and possible causes include genetic linkage, angiogenesis, autoimmune disease, cranial radiation, and infection of the head and neck. Most patients are symptomatic and may present with ischemic or hemorrhagic strokes, seizure, or headache. The diagnosis depends on clinical presentation and radiographic imaging, and disease progression may be halted with direct or indirect cerebral revascularization. Implications for practice: It is important to make a correct diagnosis and provide appropriate treatment to reduce the morbidity and mortality associated with MMD. A prompt referral for possible surgical revascularization offers the best chance to reduce additional cerebral injuries and improve clinical outcomes.
Case presentation ES is a 26-year-old female with a history of diabetes mellitus, Von Willebrand disease, and a seizure disorder. She presented to the emergency department (ED) with nonspecific symptoms including headache, dizziness, lightheadedness, nausea, and vertigo-type symptoms. She was discharged home with symptomatic treatment since there was no indication of a serious illness. She returned to the ED 2 days later because of a progressively worsening headache and stiff neck. The patient was afebrile and normotensive (120/70 mmHg). She was alert and oriented to person, place, and time; and she had no meningismus or focal neurological deficits. Complete blood count (including white blood cells and platelets), prothrombin time,
partial thromboplastin time, and complete metabolic profiles were within normal limits. She had an episode of seizure in the ED, treated with intravenous lorazepam administration. A lumbar puncture was performed as an initial workup because of the presenting symptoms of progressive headache, nausea, and stiff neck. The cerebrospinal fluid (CSF) was grossly bloody, indicative of intracerebral hemorrhage (ICH). A cerebral computed tomography (CT) scan was obtained based on prior studies indicating that this imaging technique readily identifies cerebral intravascular etiologies of ICH, the most likely causes of ICH in a young female patient without hypertension or coagulation abnormalities (Chalela et al., 2007; Delgado
C 2012 The Author(s) Journal of the American Academy of Nurse Practitioners 00 (2012) 1–7 C 2012 American Academy of Nurse Practitioners Journal compilation
1
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Figure 1 Anterior–posterior views of carotid angiograms demonstrate occluded right internal carotid artery (A) at the supraclinoid portion and occluded left internal carotid artery (B) at the parasellar portion.
Almandoz, 2009). The patient’s CT scan demonstrated evidence of intraventricular hemorrhage, an old right frontal and parietal lobe infarct, and right periventricular white matter hypodensity. CT angiogram showed diminished blood flow within the intracranial distribution of the internal carotid arteries (ICAs), suggestive of vascular occlusive disease such as moyamoya disease (MMD). The cerebral angiography revealed bilateral occlusion of terminal ICAs and absent flow into both anterior cerebral artery (ACA) and middle cerebral artery (MCA) (Figure 1). The networks of moyamoya vessels characteristic of the diagnosis of MMD were not present and both ACA and MCA were filled by the collateral circulations from the vertebral artery, compatible with an advanced stage of MMD (Figure 2). Based on the presence of bilateral occlusion of terminal ICAs, absent major cerebral arteries (ACA and MCA), absent moyamoya vessels, and evidence of extracranial collateral circulations, the patient was diagnosed with Stage V–VI MMD on the Suzuki Grading System. ES was admitted to the intensive care unit and was eventually discharged from the hospital with full recovery and without residual neurological deficits. She was subsequently referred to a University hospital for additional evaluation and had a successful right superficial temporal artery (STA) to right MCA revascularization procedure 2 months later.
Background MMD is a rare chronic cerebrovascular disease which is characterized by progressive bilateral stenosis or occlusion of the terminal part of the ICAs or their main branches including the ACA and MCA (Burke et al., 2009; Kuroda & Houkin, 2008; Scott & Smith, 2009; Suzuki & Takaku, 1969). Many collateral networks provide an alternative route for cerebral perfusion; however, they are imperfect and fragile and may predispose pa2
Figure 2 Lateral view of left vertebral artery (dark arrow) providing collateral circulations to the anterior (thick white arrow) and middle cerebral arteries (thin white arrow).
tients to transient ischemic attacks (TIAs) and ischemic or hemorrhagic strokes (Burke et al., 2009; Lee et al., 2009; Smith & Scott, 2005). At the early stage of the disease, the intracranial collateral circulations that develop at the base of the brain display a “puff of smoke” appearance and are called moyamoya vessels (Figure 3; Burke et al., 2009; Kuroda & Houkin, 2008; Smith & Scott, 2005; Suzuki & Takaku, 1969). Moyamoya is Japanese and translates to “puff of smoke.” The condition was initially identified in Japan, thus the reason for a Japanese name (Caldarelli et al., 2001; Kraemer et al., 2008; Suzuki & Takaku, 1969; Yilmaz et al., 2001). As the disease progresses, the
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Pathophysiology
Figure 3 Left carotid angiogram from a 53-year-old oriental woman who became unresponsive with left hemiparalysis from a massive intracerebral hemorrhage. The angiogram shows an occluded left internal carotid artery (thick dark arrow) with collateral circulation to an anterior cerebral artery (white thick arrow) and a middle cerebral artery (white thin arrow) via moyamoya vessels (surrounded by dark thin arrows).
antegrade blood flow decreases with gradually diminishing moyamoya vessels and the cerebral blood flow is more dependent on the development of extracranial collateral circulations. MMD is most prevalent in Japan and even though this disease is now recognized throughout the world, it remains underdiagnosed as a cause of ischemic or hemorrhagic stroke in Western countries (Kraemer et al., 2008; Kuriyama et al., 2008; Yilmaz et al., 2001). The clinical diagnosis of MMD requires a strong suspicion for the disease when treating ischemic or hemorrhagic cerebrovascular accident (CVA) in children or young females without other risk factors for strokes such as age >55 years, history of atrial fibrillation or heart disease, hypertension, dyslipidemia, smoking history, diabetes mellitus, contraceptive pills, or hormone therapy (Reeves et al., 2009; Smith & Scott, 2005). While some advanced practice nurses (APNs) may encounter MMD patients with suspected strokes in the acute care setting, other APNs may care for these patients with milder ischemic and nonischemic MMD symptoms in a primary care setting before or after the diagnosis is established. Additionally, more patients are surviving the acute event and doing well after cerebral revascularization. These patients may appear at various pediatric or adult primary care practices for other healthcare needs. It is important that APNs are wellarmed with knowledge of MMD so they will be able to make a correct diagnosis and provide appropriate treatment.
The pathophysiology of MMD is unclear. The pathological findings of thickened intima, smooth muscle cell hyperplasia, and luminal thrombosis without atherosclerotic or inflammatory changes in the affected vessels indicate a significant role of angiogenesis in the development of MMD (Scott & Smith, 2009; Ullrich et al., 2007). Luminal microthrombi may lead to endothelial injury, thickening of the intima, and smooth muscle cell proliferation. Protein S deficiency, lupus anticoagulant, and anticardiolipin antibodies have been found in other cases, suggesting a possible autoimmune mechanism in MMD (Kuroda & Houkin, 2008). A possible genetic association of MMD to chromosome 17 has been demonstrated in familial MMD (Burke et al., 2009; Kuroda & Houkin, 2008; Yamauchi et al., 2000). Two forms of MMD have been recognized including primary and secondary forms of the disease. The primary form is more common and is also referred to as true MMD. While most cases are idiopathic, familial MMD has been reported in 12–15% of cases in the Japanese population (Burke et al., 2009; Kuriyama et al., 2008; Kuroda & Houkin, 2008; Yamauchi et al., 2000). The secondary form of this disease is known as moyamoya syndrome or quasi-moyamoya. This secondary form has been described in association with sickle cell disease, neurofibromatosis type I, Down’s syndrome, infection of the head and neck, and cranial therapeutic irradiation (Baba, Houkin, & Kuroda, 2008; Scott & Smith, 2009; Uchino et al., 2005 Ullrich et al., 2007; Yamada et al., 1997). MMD is often associated with bilateral angiographic findings and unilateral findings are more commonly found in moyamoya syndrome (Fukui, 1997; Ueki et al., 1994).
Epidemiology Prior reported incidence and prevalence of this disease varies depending on the population selected for the study (Baba et al., 2008; Kuriyama et al., 2008; Kuroda & Houkin, 2008). An all-inclusive survey of a large Japanese island reported an annual incidence of 0.94 per 100,000 people and a prevalence of 10.5 per 100,000 people (Baba et al., 2008). However, a recent nationwide survey of the Japanese population reported an annual detection rate of the disease of 0.54 per 100,000 patients and a prevalence of 6 per 100,000 patients (Kuriyama et al., 2008). A gender difference has been established with a female to male ratio of approximately 2:1 (Baba et al., 2008; Kuroda & Houkin, 2008). There are two peaks of age distribution; prior studies have reported the highest peak in children between the ages of 5 and 9 years but recent data reveal a significant increase in the adult 3
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population with the largest peak between 45 and 49 years old (Baba et al., 2008; Kuroda & Houkin, 2008; Wakai et al., 1997). One study from the western United States (Washington and California) that included patients from various ethnic backgrounds reported a lower incidence (0.086 per 100,000), a similar female to male ratio and a similar early peak but a later second peak between 55 and 59 years old (Uchino et al., 2005). The incidence was higher in Asian Americans (4.6 times) and African Americans (2.2 times) than the Caucasian population. Fortyeight percent of African Americans in the study also had a diagnosis of sickle cell disease. The data for MMD in Caucasians are limited with the incidence of this disease estimated to be one-tenth of that observed in the Japanese population (Kraemer et al., 2008; Uchino et al., 2005). A retrospective study in 21 Caucasian patients treated for MMD in a German institution reported a female predominance of 4.25:1 and all the females presented with an ischemic event (Kraemer et al., 2008). The available data indicate that Caucasian patients do not demonstrate the two peaks of age distributions at the onset of the disease, have more benign symptoms at presentation, have more ischemic symptoms at all ages, and respond better to surgical treatment (Hallemeier et al., 2006; Kraemer et al., 2008; Mesiwala et al., 2008; Yilmaz et al., 2001).
Clinical presentation Over 80% of patients with MMD are symptomatic and their clinical presentation may include ischemic, hemorrhagic or “other” symptoms such as headache, seizure, choreiform movements, cognitive, or psychiatric changes (Baba et al., 2008; Burke et al., 2009). Most childhood MMD cases present with ischemic events that are often precipitated by hyperventilation or crying and occur repetitively over several years (Burke et al., 2009; Kuroda & Houkin, 2008; Han et al., 2000; Smith & Scott, 2005). Adult patients may present with ischemic symptoms, intracranial bleeding, or both (Han et al., 2000; Kuroda & Houkin, 2008). Two-thirds of these adult patients suffer from intracranial bleeding which may be attributed to the rupture of moyamoya vessels, aneurysms in the circle of Willis, dilated perforators, or dilated collateral arteries on the brain surface (Burke et al., 2009; Kuroda & Houkin, 2008; Osanai et al., 2008). Intracerebral hematoma is the major cause of death in patients with MMD (Burke et al., 2009). Various types of collateral circulation may contribute to other symptoms of MMD. The dilated meningeal and leptomeningeal collateral vessels may predispose patients to migraine-like headaches that are frequently unresponsive to medical therapy (Seol et al., 2005). Choreiform movements in 4
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some patients may be attributed to dilated moyamoya vessels in the basal ganglion (Parmar et al., 2000; Scott et al., 2004).
Diagnosis Strict guidelines for the diagnosis of MMD have been established (Burke et al., 2009; Fukui, 1997). The diagnosis is normally made on the basis of clinical presentation of ischemic or hemorrhagic stroke in children or young female patients together with primary and secondary radiographic findings (Burke et al., 2009; Kuriyama et al., 2008; Scott & Smith, 2009; Smith & Scott 2005). The presenting symptoms and physical findings depend on the age of patients as previously described (Burke et al., 2009; Kuroda & Houkin, 2008; Han et al., 2000). Fundoscopic examination may reveal a “morning glory disk,” which is an enlarged optic disk occasionally seen in those who develop vascular anomalies in the retina (Lee et al., 2009, Scott & Smith, 2009). The electroencephalogram (EEG) in 50% of the children with this disease may demonstrate a distinctive pattern of ”buildup” and ”rebuild-up” phenomenon that occurs when the child is asked to hyperventilate. Specifically at the beginning of hyperventilation, the EEG displays high voltage slow waves which disappear during hyperventilation but return within 20–60 s after stopping hyperventilation (Kodama et al., 1979; Smith & Scott, 2005). The workup of a suspected case of MMD usually begins with cerebral CT scan, which can readily identify the secondary findings (Burke et al., 2009; Smith & Scott, 2005). It is possible that patients with TIAs may not demonstrate any abnormalities (Scott & Smith, 2009). CT angiography may be used to visualize the intracranial stenoses but cerebral angiography remains the gold-standard imaging technique that will best demonstrate the primary findings of MMD (Burke et al., 2009; Kuriyama et al., 2008; Scott & Smith, 2009). These primary findings consist of bilateral stenosis or occlusion of the terminal portion of the ICAs or their major branches and abundant collateral formation with basal moyamoya vessels (Burke et al., 2009; Fukui, 1997; Kuriyama et al., 2008). Magnetic resonance imaging (MRI) and angiography (MRA) are reliable methods for the visualization of the primary and secondary findings as well as postoperative results of revascularization procedure for MMD (Burke et al., 2009). Because of its excellent diagnostic yield and noninvasive nature of the procedure, MRA is now recommended as the primary diagnostic imaging procedure for MMD (Smith & Scott 2005). Conventional cerebral angiography may be necessary in a few patients when smaller vessel occlusions and moyamoya collateral vessels are not well visualized with MRI and MRA (Kuriyama
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Table 1 Suzuki Staging System of moyamoya disease Stage I Stage II Stage III
Stage IV
Stage V Stage VI
Bilateral internal carotid artery (ICA) stenosis distally at the carotid forks Development of basal moyamoya vessels Increasing ICA stenosis involving anterior and middle cerebral arteries Intensification of moyamoya vessels Occlusion of ICAs and the entire circle of Willis—disappearance of all major cerebral arteries Diminished basal moyamoya vessels Development of extracranial collaterals Further reduction of basal moyamoya vessels Intensification of extracranial collaterals Disappearance of basal moyamoya vessels Collateral circulation solely from the external carotid arteries
Note. Burke et al., 2009; Scott & Smith, 2009; Suzuki & Kodama, 1983; Zipfel et al., 2005.
et al., 2008; Smith & Scott 2005). A definitive diagnosis of MMD requires the presence of bilateral distal ICA stenosis or occlusion and intra- or extracranial collateral circulations demonstrated by cerebral angiography or MRI and MRA (Kuriyama et al., 2008). While bilateral ICA obstruction is characteristic of MMD, some patients may initially present with unilateral vascular abnormalities and approximately one-third of them will eventually develop contralateral disease (Kelly et al., 2006; Kuroda et al., 2005). In a study of 120 adults, female sex was the only risk for progression of the disease, whereas a study with predominantly children in the sample reported the association of progression of the disease to contralateral abnormalities on initial imaging, congenital cardiac anomaly, previous cranial radiation, Asian ancestry, and familial moyamoya syndrome (Kuroda et al., 2005; Smith & Scott, 2008). The secondary radiographic findings include cerebral infarction, white matter lesions, atrophy, and hemorrhage (Burke et al., 2009; Scott et al., 2004; Smith & Scott 2005; Suzuki & Kodama, 1983). The Suzuki Grading System describes six angiographic stages, which indicate the severity of the disease (Burke et al., 2009; Scott & Smith, 2009; Suzuki & Kodama, 1983). The grading system begins with bilateral ICA stenosis distally at the carotid forks in Stage I, progressive development and disappearance of basal moyamoya vessels over Stage II–V, and final deterioration to complete absence of major cerebral arteries and basal moyamoya vessels with collateral circulation produced solely from the external carotid arteries in Stage VI (Table 1). Most symptomatic cases of MMD are diagnosed at Stage III of this grading system (Burke et al., 2009). Extra to intracranial collaterals in some patients may form netlike vessels; two forms have been described including eth-
moidal and vault moyamoya (Suzuki & Kodama, 1983). Ethmoidal moyamoya communicates with basal moyamoya via ophthalmic, anterior, and posterior ethmoidal arteries. Vault moyamoya develops transdural anastomosis from the middle meningeal artery and STA. These extra- to intracranial moyamoya vessels poorly develop in adults as compared to children and this may be attributed to the loss of the capacity to form these collaterals with increasing age (Suzuki & Kodama, 1983). The case presentation in this report demonstrates that the diagnosis of MMD can be difficult and requires a strong clinical suspicion. The initial presentation of headache, dizziness, and nausea without any other neurological deficits were subtle and nonspecific. Even with a progressive worsening headache and stiff neck, the patient continued to have a normal neurological examination without meningismus. The diagnosis of ICH was made primarily because of grossly bloody CSF, which was attributed to MMD on the basis of the primary findings of complete ICA occlusion involving ACA and MCA with extra- to intracranial collateral circulations, as well as the secondary findings of prior infarct and intraventricular hemorrhage on CT scan.
Treatment Patients with milder symptoms are usually treated conservatively with medical therapy but there is little evidence of short-term or long-term efficacy (Burke et al., 2009). Antiplatelet agents have been used to prevent emboli but chronic anticoagulation with warfarin is rarely used (Bowen et al., 2005; Scott et al., 2004; Smith & Scott, 2005). Calcium-channel blockers may relieve intractable headaches or reduce the incidence and severity of TIAs (Scott & Smith, 2009; Shirane et al., 1997). Patients with more severe symptoms are treated with one of the three surgical revascularization procedures: direct, indirect, and combined techniques (Burke et al., 2009; Hallemeier et al., 2006, Kuroda & Houkin, 2008; Smith & Scott, 2005; Yilmaz et al., 2001). Direct revascularization involves extra- to intracranial arterial bypass with anastomosis of the STA to MCA or other grafttype procedures (Burke et al., 2009; Kuroda & Houkin, 2008; Smith & Scott, 2005). This type of revascularization is limited to adults or older children with acceptable calibers of donor and recipient vessels (Burke et al., 2009). Indirect revascularization involves placing vascularized tissues such as dura, temporalis muscle, or STA itself, in direct contact with the brain to promote neovascularization to the underlying cerebral cortex (Burke et al., 2009; Kuroda & Houkin, 2008; Smith & Scott, 2005). This procedure is more suitable for patients with poor cortical branches for anastomosis or for younger 5
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patients with smaller donor or recipient vessels (Burke et al., 2009). Encephaloduroarteriosynangiosis (EDAS) is the most commonly performed indirect revascularization procedure, in which a segment of a scalp artery is transposed on to the surface of the brain to improve collateral blood flow (Yilmaz et al., 2001). Combined direct and indirect procedures have been employed to promote better revascularization and prevent ischemia in some patients (Burke et al., 2009). The revascularization procedure is usually recommended for ischemic strokes or TIAs in patients with good neurological ability to perform daily activities, small area of cerebral infarctions (
