Moyamoya Disease
March  2015

​​​​​​​​​​​​​A 37-year-old female is applying for $1 million of life insurance. Very few medical records are provided; however, there is mention of a hospitalization six months previously for evaluation of the sudden onset of weakness in her left arm and associated clumsiness in her left hand. This event lasted for 15 minutes with complete resolution of the symptoms, but it prompted an emergency room visit and subsequent hospitalization.

Her primary care physician’s notes after she was released mention an abnormal MRI of the brain, finding a few small white-matter lesions, possibly vascular infarcts. In addition, a cerebral angiogram report describes some early occlusive lesions in the distal carotid arteries and around the circle of Willis. Prominent collateral vessels were noted in the basal ganglia. The radiologist comments that although the degree of stenosis is mild, the findings suggest the possibility of moyamoya disease (MMD).

Brain 

Figure from UpToDate.com accessed 2/13/15

The recent office visit note documents no post-hospitalization symptoms, normal BP and a completely normal neurological exam. The family history is positive for an uncle experiencing a cerebrovascular accident in his early 50s without further details. There are no significant cardiovascular risk factors present.


What are the mortality implications of moyamoya disease if the diagnosis is confirmed?

Moyamoya disease (MMD) is a rare disease of the cerebrovascular circulation occurring at an annual incidence of .35 to .94 per 100,000 in Japan and .086 per 100,000 based on hospital records from California and the state of Washington. There is approximately a 2:1 female:male predominance.

MMD is associated with two major anatomic findings. The first is the occlusion of multiple vessels around the circle of Willis. The second is the presence of very prominent collateral arterial circulation. This collateral circulation frequently creates a characteristic appearance on an angiogram, often referred to as a “puff of smoke” (moyamoya in Japanese).

collateral arterial circulation 

Figure 2 - Moyamoya "Puff of Smoke" like appearance

MMD was first described by Japanese physicians in 1957. Since then, cases have been discovered throughout the world, but the incidence of the disease is highest in Asian populations. While the etiology of MMD is unknown, there is suggestive evidence that a genetic etiology might be involved. Ten to 15% of patients with MMD report a relative with the disease. Specifically, the RNF213 gene on the 17q25.3 chromosome may be involved, but associations with chromosomes 3, 6, and 8 are possible.

Moyamoya syndrome is different from moyamoya disease. Moyamoya syndrome describes typical moyamoya-type angiographic findings in the setting of an associated condition. These associated conditions include Down syndrome, sickle cell disease, neurofibromatosis type I and previous exposure to radiation treatment, among others. MMD is diagnosed when none of these associated conditions is present.

Moyamoya disease can occur in children or manifest itself in adulthood. In fact, the incidence appears bimodal with peaks in two age groups: in children approximately 5 years old and in adults in their mid-40s. The initial clinical findings of MMD are variable, most often presenting with ischemic events ranging from TIAs to severe ischemic or hemorrhagic strokes. Epilepsy and/or headaches may also be presenting symptoms. A small 2014 study evaluating MMD in the US found that problems in 19 of the 31 adults involved ischemic symptoms.

Suspicion for MMD is elevated when there are clinical findings of recurrent ischemic attacks in the same arterial region or intracerebral hemorrhage in the caudate region. Intraventricular hemorrhage within the lateral ventricles is also a red flag. Also, MMD is strongly considered in the differential diagnosis when stroke occurs in children or young adults.


Diagnosis and Treatment

Diagnosing MMD frequently involves brain imaging with transcranial Doppler ultrasonography, CT, MRI, MRA, CTA and/or conventional angiography. MMD is diagnosed when angiographic imagery indicates significant bilateral occlusive disease of the intracranial internal carotid and circle of Willis arteries, along with the presence of prominent basal collateral vessels.

The significance of MMD versus some other types of transient ischemic attacks or cerebrovascular attacks is that MMD tends to be a progressive cerebrovascular disease and a more diffuse vascular disease. The onset of symptoms occurs at a younger age than the more common atherosclerotic disease. All of these characteristics have relative mortality implications. The small observational studies that have been done indicate that the risk of stroke after an initial ischemic event may be up to 10% per year and 3.2% after diagnosis in an asymptomatic person.

Treatment of MMD is challenging. No curative treatment currently is available for the disorder. Medical treatment has unproven benefit. Antiplatelet therapy is occasionally used. Surgical procedures may be performed to try to improve blood flow, with some success. The surgical procedures range from evacuation of a brain hematoma to direct and indirect bypass procedures involving the arterial circulation. Unfortunately, the progressive nature of this disorder does impact mortality and morbidity despite treatment in most individuals. Factors that have been described as affecting prognosis include the speed and degree of arterial narrowing, extent of the infarct (including evidence of bilateral involvement), age at diagnosis and the neurological status at the time of diagnosis.

Screening family members of an individual diagnosed with MMD is not currently advocated by most clinicians. The familial incidence of first-degree relatives is felt to be about 7%-12% in Japan and approximately 6% in the US. Therefore, individual consideration for screening is recommended.

Its rarity

Annual incidence reported to be approximately:                                              0.086/100,000 in US                                                                                                                
0.35 to 0.94/100,000 in Japan

Its occurance
Biomodal age distribution with peak in:                                                                        Childhood from 5-14                                                                                                     Adulthood from 35-49 years of age
Its clinical expression

Variable and include hemorrhagic strokes or ischemic strokes  Epilepsy, headaches and TIAs are not common             

Its diagnosis

Neurovascular imaging with characteristic findings of stenosis in the distal carotid arteries and arteries close to the circle of Willis often with prominent collateral vessels in the basal region

Its course
Progressive typically
Its prognosis
No cure. Medical treatment has had poor results. Surgical treatments offer some success. Prognosis is variable and is impacted, it seems, by speed and severity of the arterial narrowing, as well as the age, extent of infarct and neurological condition at the time of diagnosis.

Figure 3 - Major Features of Moyamoya Disease

Returning to the Case

In this case the proposed insured’s abnormal imaging results are very worrisome. The mention of a moyamoya-like angiographic appearance with stenosis accompanied by bilateral prominent collateral vessels is not common with a TIA. Despite the quick resolution of the symptoms, the current symptom-free state and the normal neurological exam, there is a high index of suspicion for MMD.

The MRI report should be reviewed for details of the possible vascular infarcts. The family history of a relative with early onset cerebrovascular disease raises the question of whether there might be a hereditary component. This case would best be handled differently than one with normal imaging after a TIA-like event. Given the typically poor long term prognosis of MMD, postponement and reevaluation appear to be a prudent course.


References

Hallemeier, Christopher L, et al. “Clinical features and outcome in North American Adults with moyamoya phenomenon.” Stroke. 2006;37:1490-1496

Scott R. Michael, Smith, Edward R. “Moyamoya disease and moyamoya syndrome.” N Engl J Med. 2009; 360: 1226-1237.
 
Scott R. Michael, Smith, Edward R. “Moyamoya: Epidemiology, Presentation, and Diagnosis.” Neurosurg Clin N Am 21 (2010) 543-551

Suwanwela, Nijasri, et al. “Moyamoya disease: Treatment and prognosis.” UpToDate.com. Acccessed 2/5/2015.

Yoshida, Yasuko, et al. “Clinical course, surgical management, and long-term outcome of moyamoya patients with rebleeding after and episode of intracerebral hemorrhage; An extensive follow-up study.” Stroke. 1999;30:2272-2276

Zafar, SF, et al. “Adult moyamoya disease in an urban center in the United States is associated with a high burden of watershed ischemia.” J AM Heart Assoc. 2014;3(4)

Suwanwela, Nijasri, et al. “Moyamoya disease: Etiology, clinical features, and diagnosis.”