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Moyamoya Disease

Cerebrovascular Moyamoya Disease

Moyamoya disease (MMD) is a rare disease that causes transient ischemic attacks (TIA) or strokes due to progressive narrowing of the cerebral blood vessels found at the base of the brain.


Presentation

The age of onset for moyamoya disease (MMD) follows a bimodal distribution with incidence peaks during childhood, from five to 10 years of age, and during adulthood, from 30 to 50 years of age. Patients with MMD usually present with transient ischemic attacks (TIA) or strokes along with other symptoms of decreased cerebral blood flow including headaches, seizures, involuntary movements and developmental delay in children [13]. Adults have a higher chance of developing an intracranial hemorrhage than children which may be attributed to the relatively higher blood pressure levels in adults [14].

Short Stature
  • Noonan-like syndrome with loose anagen hair (NSLH) is characterized by short stature, characteristic facial phenotype, darkly pigmented and hairless skin, mild psychomotor delay with attention deficit disorder, and easily pluckable, sparse, thin, slow[ncbi.nlm.nih.gov]
Hypertension
  • Pulmonary hypertension is a rare progressive vasculopathy with an unknown etiology.[ncbi.nlm.nih.gov]
Palpitations
  • A 16-year-old girl complaining of dizziness and palpitations visited the emergency department and was diagnosed with DKA combined with hyperthyroidism. A thyroid storm occurred 6 h after the start of DKA management.[ncbi.nlm.nih.gov]
Tinnitus
  • A 52-year-old woman presented with two-week spontaneous exophthalmos, chemosis and tinnitus, and cerebral angiography showed a right CDAVF coexisting with ipsilateral moyamoya disease.[ncbi.nlm.nih.gov]
  • CLINICAL PRESENTATION A 44-year-old man presented with headache, tinnitus, and an intraventricular hemorrhage, as seen on computed tomographic scans.[dx.doi.org]
Sudden Hearing Loss
  • To our knowledge, this is the first article in the literature reporting a case of sudden hearing loss as the first manifestation of Moyamoya disease in a young adult.[ncbi.nlm.nih.gov]
Chemosis
  • A 52-year-old woman presented with two-week spontaneous exophthalmos, chemosis and tinnitus, and cerebral angiography showed a right CDAVF coexisting with ipsilateral moyamoya disease.[ncbi.nlm.nih.gov]
Episodic Headache
  • Episodic headache is common in childhood moyamoya disease (MMD). The onset, mechanism, cause of headache and the effect of revascularization surgery on headache are not yet clear.[ncbi.nlm.nih.gov]
Wide Neck
  • Emergent cerebral angiography demonstrated moyamoya disease associated with a wide-necked basilar trunk aneurysm.[ncbi.nlm.nih.gov]
Headache
  • Episodic headache is common in childhood moyamoya disease (MMD). The onset, mechanism, cause of headache and the effect of revascularization surgery on headache are not yet clear.[ncbi.nlm.nih.gov]
Intracranial Hemorrhage
  • Association between CBNS and intracranial hemorrhage was analyzed. RESULTS: Of 76 patients with MMD, intracranial hemorrhage was found in 44 of 152 (28.9%) hemispheres, and 6.8% (3/44) had multiple events.[ncbi.nlm.nih.gov]
  • Severe immediate problems include the risk of transient ischemic attack (TIA or “mini-stroke”), in which the blood flow to the brain is temporarily completely blocked; stroke, in which the blockage is sustained; or intracranial hemorrhage, bleeding in[neurosurgeonsofnewjersey.com]
  • The second most frequent cause of intracranial hemorrhage is rupture of saccular aneurysms around the circle of Willis.[surgicalneurologyint.com]
Hemichorea
  • The authors describe two cases of pediatric moyamoya disease, both of which presented with hemichorea in the stable phase after successful bypass surgery.[ncbi.nlm.nih.gov]

Workup

Physicians should attempt to determine whether patients have primary or secondary moyamoya disease (MMD) by performing detailed neurological and genetic exams. Brain imaging should be performed following special stroke protocol to detect signs of ischemic brain damage or stroke. Computerized tomography (CT) scan, magnetic resonance angiogram (MRA) and/or cerebral angiograms (gold standard) should be performed to image the blood vessels within the brain [15]. Physicians may perform perfusion studies to measure the amount of hypoperfusion in the brain using CT or MRA perfusion scans, Diamox SPECT scans and positron emission tomography (PET) scans.

Treatment

Treatment for moyamoya disease (MMD) mainly targets symptoms including headaches, seizures and blood clots. Headaches are typically relieved with calcium channel blockers which may also relieve symptoms of transient ischemic attacks (TIA) and blood blots may be prevented by administering aspirin [13]. If patients are experiencing seizures anti-seizure medication should be administered. Anticoagulants, lovenox and coumadin, may be given in extremely unstable patients but should be avoided long term due to increased chances of brain hemorrhage with these medications. Progressive narrowing of intracranial arteries cannot be stopped.
There are a number of surgical procedures that may be performed to redirect the scalp blood supply to the brain which are either direct or indirect. Direct procedures involve suturing of the scalp blood vessels, most commonly the superficial temporal artery to a branch of the middle cerebral artery. Indirect procedures rely on the growth of new blood vessels after surgery and are usually performed in children. Examples of indirect procedures include pial synangiosis, encephalomyosynangiosis (EMS), encephaloduroarteriosynangiosis (EDAS) and dural inversions [16]. Both types of surgeries in children and adults have excellent long-term outcomes with a significant decrease in strokes.

Prognosis

Patients with moyamoya disease (MMD) that present with hemorrhage have a poor prognosis and usually develop neurological decline and disability. MMD patients who present with cerebral ischemia have a better prognosis that is improved with surgery. Around 30% of patients with unilateral MMD will develop cranial angiopathy on the other side in an average of 2.2 years depending on various risk factors, such as contralateral abnormalities observed with initial imaging, family history, Asian ancestry, cranial irradiation and congenital heart abnormalities [12]. In such cases patients should be regularly monitored with magnetic resonance imaging (MRI) and magnetic resonance angiogram (MRA). Cause of death for patients with MMD is most often hemorrhage which occurs in 5% of children and 10% of adults.

Etiology

The etiology of moyamoya disease (MMD) is largely unknown although it is thought to be hereditary. Some studies have indicated 10% of patients with MMD have a family history and the disease trait is autosomal dominant with incomplete penetrance [3]. Some of the loci involved in MMD have been found on chromosomes 3p, 6p, 8q and 17q and the specific locus 17q25.3 correlates with increased genetic susceptibility [4]. It has been difficult to isolate specific genes associated with MMD due to the complicated genetics of this disease, however, genome-wide association studies (GWAS) and meat-analyses have identified the RNF213 gene, specifically polymorphisms between p.R4859K and p.R4810K. Some patients with MMD display immune abnormalities, such as elevated thyroid antibodies, indicating a possible association with MMD and immune dysfunction. Other disease states that may be associated with MMD include Graves disease [5], leptospirosis, tuberculosis, anemias, systemic lupus erythematosus, apert syndrome, down syndrome, Marfan syndrome, tuberous sclerosis, Hirschsprung's disease, Recklinghausen disease, Turner syndrome, atherosclerosis, coarctation of the aorta, hypertension, parasellar tumors, radiation injury, head trauma and fibromuscular dysplasia. Although links between these diseases and MMD are unclear, other disease states have a huge impact on treatment decisions. When MMD is observed in association with the conditions listed above this is refered to as moyamoya syndromes (MMS).

Epidemiology

The highest incidence of moyamoya disease (MMD) are observed in Japan. Therefore, numerous largescale epidemiological studies have been performed in Japan, whereas, other countries have only performed studies with smaller sample sizes making these studies difficult to compare. Although MMD may affect any ethnic group this disease is rare in Western countries and has a much higher prevalence in East Asian Countries (ten times higher). In Japan the prevalence of MMD is roughly 3.16-10.5 in every 100,000 individuals with an incidence per year of around 0.35-1.13 out of every 100,000 people [6]. In the United States (US) MMD prevalence is much lower and affects around 0.086 out of every 100,000 people [7]. US studies on residence of California and Hawaii who originated from Asia demonstrated a significantly higher prevalence in those individuals compared to Caucasian populations which indicates a strong genetic link with this disease. Other studies in Europe and France also show a decreased prevalence of MMD compared to Japan [6] [8]. The prevalence in Europe and France were estimated to be 10 and 20 times lower than Japan, respectively, and a family history was observed less frequently (around 7.5%) [6] [8]. Females are twice as likely to develop MMD than males. The age of onset for MMD clusters around two ages, one in childhood from five to 10 years of age and one in adulthood from ages 30 to 40. Japanese patients diagnosed with MMD have a family history in 10% to 15% of cases.

Sex distribution
Age distribution

Pathophysiology

No definitive pathophysiological mechanisms have been established for moyamoya disease (MMD), however, there are a number of hypotheses available [9]. MMD is widely thought to have a strong genetic component based on the presence of family history in some patients as well as a high prevalence in Asians, especially Japanese. Recent molecular data seems to corroborate this assortment, however, the genetics seem to be very complex and conflicting evidence, including studies with monozygotic twins, does exist. In many patient’s proangiogenic factors, including fibroblast growth factor (FGF) and hepatocyte growth factor (HGF), are found at much higher levels in the cerebrospinal fluid (CSF) and other tissues, however, it is unknown whether this precedes or proceeds cerebral ischemia [10]. Nonetheless, some have hypothesized that the genetic polymorphisms associated with MMD lead to increased expression or stability of proangiogenic factors which results in over vascularization in the brain. No studies to date have shown an association between MMD mutation and FGF or HGF levels. An association has been found between genetic polymorphisms affecting the platelet-derived growth factor receptor B (PDGFRB) gene and the transforming growth factor beta 1 (TGFβ1) gene which may influence vascular cell growth. Another explanation for increased levels of PDGF in MMD patients is due to a compensation mechanism for decreased vascular smooth muscle cell (SMC) expression of PDGFRB [11].

Prevention

No preventative measures exist for moyamoya disease.

Summary

Moyamoya disease (MMD) is classified as an intracranial arteriopathy that may be inherited or acquired. MMD is described as progressive narrowing or occlusion of certain arteries in the brain, including the internal carotid artery (ICA), anterior cerebral artery (ACA) and/or middle cerebral artery (MCA). Due to the narrowing or blockage of blood vessels observed in MMD the body tries to compensate for the diminished blood flow by forming new blood vessels (angiogenesis) at the base of the brain which can be observed on an angiography as a “puff of smoke” which translates to moyamoya in Japanese [1] [2]. Although, moyamoya phenomenon refers to numerous intracranial arteriopathies, MMD specifically refers to primary, isolated and usually bilateral areteriopathies. MMD may cause neurological or extra-neurological manifestations which are known as moyamoya syndromes (MMS).

MMD is associated with increased risk of brain damage due to transient ischemic attacks (TIA) or strokes. The primary treatment is revascularization surgery which is done to prevent complications associated with MMD. Currently, the pathophysiology of MMD remains unclear, however, advances in genetic research are revealing genes associated with MMD which may help elucidate the mechanisms for this disease and lead to subsequent treatment discoveries.

Patient Information

Moyamoya disease (MMD) is a neurological disease that causes transient ischemic attacks (TIA) or strokes due to narrowing of the blood vessels that supply the brain. In order to compensate for the reduced blood flow caused by this narrowing the body will form new blood vessels at the base of the brain. The origin of this disease is unknown but a family history is observed in some patients indicating a genetic association. In particular, Japanese patients have the highest prevalence of MMD and a family history is observed in 15% of these patients. Certain genetic mutations have been identified, including mutations in the RNF213 and ACTA2 genes, although the mechanistic role in MMD remains unclear. Symptoms of MMD are caused by narrowing of the arteries that supply the brain and may include stroke, transient ischemic attack (TIA), seizures, long-lasting and severe headaches and learning deficiencies in children.
MMD is a rare disorder and due to the nonexclusive symptoms it is often difficult to diagnose. Patients are diagnosed through a combination of symptoms and brain imaging results. The gold standard for diagnosing MMD is a cerebral angiogram which will identify new blood vessel formation at the base of the brain that looks like a “puff of smoke” (moyamoya in Japanese). Another way to detect this abnormal blood vessel formation is through magnetic resonance angiography (MRA). Patients with MMD may also have other associated diseases such as neurofibromatosis, down syndrome, sickle cell anemia, along with a number of other conditions.
There are no cures for MMD but physicians may be able to effectively treat some of the symptoms associated with MMD. Drugs to treat stroke and TIA are often given in an effort to minimize brain damage and ease associated symptoms. After attacks patients may require physical, occupational and/or speech therapy to improve quality of life. Surgeries are available to increase blood flow to the brain which have been shown to decrease the risk of brain damage due to ischemia. There are multiple types of surgery for MMD which may be performed depending on a variety of factors such as age and degree of symptoms.

References

Article

  1. Takeuchi K, Shimizu K. Hypoplasia of the bilateral internal carotid arteries. Brain Nerve. 1957; 9:37–43.
  2. Suzuki J, Takaku A. Cerebrovascular “moyamoya” disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol. 1969; 20(3):288–299.
  3. Mineharu Y, Takenaka K, Yamakawa H, et al. Inheritance pattern of familial moyamoya disease: autosomal dominant mode and genomic imprinting. J Neurol Neurosurg Psychiatry. 2006; 77(9):1025-9.
  4. Mineharu Y, Liu W, Inoue K, et al. Autosomal dominant moyamoya disease maps to chromosome 17q25.3. Neurology. 2008; 70(24 Pt 2):2357-63.
  5. Im SH, Oh CW, Kwon OK, et al. Moyamoya disease associated with Graves disease: special considerations regarding clinical significance and management. J Neurosurg. 2005; 102(6):1013-7.
  6. Wakai K, Tamakoshi A, Ikezaki K, et al. Epidemiological features of moyamoya disease in Japan: findings from a nationwide SURVEY. Clin Neurol Neurosurg. 1997; 99(Suppl 2):S1–S5.
  7. Yonekawa Y, Ogata N, Kaku Y, et al. Moyamoya disease in Europe, past and present status. Clin Neurol Neurosurg. 1997; 99(Suppl 2):S58–S60.
  8. Kossorotoff M, Hervé D, Toulgoat F, et al. Paediatric moyamoya in mainland France: a comprehensive survey of academic neuropaediatric centres. Cerebrovasc Dis. 2012; 33(1):76–79.
  9. Houkin K, Ito M, Sugiyama T, et al. Review of past research and current concepts on the etiology of moyamoya disease. Neurol Med Chir (Tokyo). 2012; 52(5):267–277.
  10. Kang HS, Kim JH, Phi JH, et al. Plasma matrix metalloproteinases, cytokines and angiogenic factors in moyamoya disease. J Neurol Neurosurg Psychiatr. 2010; 81(6):673–678.
  11. Roder C, Nayak NR, Khan N, et al. Genetics of Moyamoya disease. J Hum Genet. 2010; 55(11):711–716.
  12. Smith ER, Scott RM. Progression of disease in unilateral moyamoya syndrome. Neurosurg Focus. 2008; 24(2):E17.
  13. Smith ER, Scott RM. Spontaneous occlusion of the circle of Willis in children: pediatric moyamoya summary with proposed evidence-based practice guidelines. A review. J Neurosurg Pediatr. 2012; 9(4):353–360.
  14. Hallemeier CL, Rich KM, Grubb RL Jr, et al. Clinical features and outcome in North American adults with moyamoya phenomenon. Stroke. 2006; 37(6):1490–1496.
  15. Lee YS, Jung KH, Roh JK. Diagnosis of moyamoya disease with transcranial Doppler sonography: correlation study with magnetic resonance angiography. J Neuroimaging. 2004; 14(4):319–323.
  16. Starke RM, Komotar RJ, Hickman ZL, et al. Clinical features, surgical treatment, and long-term outcome in adult patients with moyamoya disease. Clinical article. J Neurosurg. 2009; 111(5):936-42.

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Last updated: 2019-06-28 12:08