A 29 Year Old Woman with Acute Mental Status Changes

Clinical History

The patient was a 29 year old Caucasian female with a past medical history of poorly controlled hypertension and diabetes mellitus who presented with a one week history of marked confusion and ataxia. She was brought to the hospital by local authorities who found her wandering in a nearby creek, completely disoriented with regards to where she was or how she had gotten there.

Upon admission, she was found to have a urinary tract infection (Citrobacter sp.) and possible pneumonia, for which Levaquin and Zosyn were initiated. Initial imaging of her head showed multifocal white matter changes suggestive of multiple sclerosis or infarcts (not shown). High dose steroids were initiated, yet her mental status continued to decline. She became febrile (up to 105°F), though blood and CSF microbial cultures were repeatedly negative. Other pertinent negative lab values included: anti‐nuclear antibodies, C‐ and P‐ANCAs, Rocky Mountain Spotted Fever IgM and IgG, Ehrlichia chaffeensis IgM and IgG, West Nile Virus IgM, HIV, and fungal serologies.

A repeat MRI showed marked progression of the white matter lesions within the bilateral anterior frontal lobes, corpus callosum, and basal ganglia (Fig. 1 [FLAIR] and 2 [T2]). Magnetic resonance angiography showed severe attenuation of the supraclinoid internal carotid arteries (ICAs), with absence of flow‐related signal within the M1 segments of the middle cerebral arteries (MCAs) and the proximal anterior cerebral arteries (ACAs) bilaterally (Fig. 3, short and long arrows, respectively).

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Unfortunately the patient continued to decline and expired fifteen days after her initial presentation. An autopsy was requested by the family for the purposes of determining the etiology of her decline.

Pathologic Findings

At autopsy, the brain weighed 1250 grams. There was marked occlusion of both ICAs extending into the proximal MCA and ACA branches bilaterally (Fig. 4 [right ICA] and Fig. 5 [left ICA]). Other vessels, including the basilar and vertebral arteries, were unremarkable. No aneurysms or hemorrhage was present. Consistent with the aforementioned premortem imaging, there was marked softening and edema within the bilateral ACA distribution with some extension into bilateral MCA territories, with involvement of the bilateral anterior medial frontal and parietal lobes, basal ganglia, thalami, and corpus callosum. There was also tonsillar herniation with associated Duret hemorrhages within the pons and medulla (not shown).

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Microscopically there was striking intimal proliferation of MCA/ACA/ICA intima with medial thinning (Fig. 6, 7, 8). Trichrome stains highlight the undulating intact internal elastic lamina (IEL), which was thickened and rarely showed focal splitting (Fig. 9, 10). No atherosclerotic plaques or inflammation was seen. The softened areas in the cerebrum showed edema, “dead red” neurons, and early neutrophil infiltration, but no macrophages, neovascularization, or reactive gliosis (not shown). What is the diagnosis?

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Diagnosis

Moyamoya Disease

Discussion

The differential diagnosis for the vascular pathology in this case includes a resolving vasculitis or an intimal variant of fibromuscular dysplasia; however, both of these processes should lead to fragmentation of the IEL. Despite the patient's history of hypertension and diabetes mellitus, no atherosclerotic changes were present. This pattern of vascular occlusion, the fibrointimal hyperplasia, attenuated media, and intact undulating IEL are classic for moyamoya disease 5, 7, 8.

Moyamoya disease is a rare cerebrovascular disorder that results in the occlusion of the supraclinoid internal carotid arteries and its branches within the Circle of Willis 5, 7, 8. As a compensatory mechanism, multiple fine collateral vessels form at the base of the brain. These collateral vessels were originally described in Japan by Suzuki and Takaku in 1969 8, who termed it “moyamoya.” This loosely translates into “hazy puff of smoke,” describing the cloudy/smoky appearance of the neovascularized network on angiography.

This disease is very rare in patients of non‐Asian descent. In the United States, there is an estimated incidence of 0.086 cases per 100,000 9. Within Europe, the incidence is found to be approximately 10% that of Japan 10. It is much more common in east Asian countries (particularly Japan), where the incidence and prevalence is up to 0.94 and 10.5 cases per 100,000, respectively 1. In these regions it is considered the most common cerebrovascular disease in the pediatric population 7. However, it is found in both children and adults, with a bimodal age distribution peaking at the ages of 5 and 40. It is seen more commonly in women, with a female to male ratio of 1.8 5. Clinical presentations vary, but usually appear as transient ischemic attacks (TIAs) or overt infarctions. Adults have a tendency to hemorrhage, typically from the fragile collateral vessels at the brain's base 3, 5, 7, 9. Diagnosis is usually made radiographically through angiogram or MRA, according to the guidelines issued by the Research Committee on Spontaneous Occlusion of the Circle of Willis (Moyamoya Disease) 2.

While the majority of cases are sporadic, up to 15% of patients show familial inheritance patterns. The pedigrees usually show either a polygenic or autosomal dominant with incomplete penetrance patterns 5. A recent study discovered a founder missense mutation in RNF213 (p.R4859K) which is the first susceptibility gene to be strongly associated with familial Moyamoya disease 4. Other linkage studies have shown possible candidate loci at 3p24–26, 6q25, 8q13–24, 12p12–13, and 17q25 4. Some pedigrees also suggest that anticipation effect can happen. For example, in one epidemiologic study, there was a subset of eight cases in which both a mother and one of her offspring had moyamoya. In each of these cases, the mother presented as an adult (mean age 31 years) while all the offspring presented in childhood (mean age 7 years) 5.

Treatment for patients with bilateral and symptomatic disease is generally surgical, via vascular bypass. There are multiple possible bypass options, including direct, indirect, and combined procedures 5, 6. The direct bypass involves the anastomosis of the superficial temporal and middle cerebral arteries, which provides rapid revascularization but is associated with an increased risk of hyperperfusion syndrome. Indirect bypass methods use donor tissues such as dura mater, temporal muscle, and galeal tissue to induce spontaneous angiogenesis in the undervascularized cerebral tissue. The most common of these is the encephaloduroarteriosynangiosis (EDAS) procedure, which involves suturing a superficial temporal artery and soft tissue pedicle to a dural incision. While this method has a much lower risk of hyperperfusion syndrome, it often takes up to four months for these new vessels to grow 5. The last option involves a mix of both direct and indirect, offering the benefits of both procedures 5, 6. Though the literature is limited with respect to prospective randomized trials, this latter approach seems to decrease the incidence of TIAs and infarctions 3, 5, 10. In the absence of surgery, patients have a high risk of recurrent infarction and hemorrhage, exceeding 80% for those patients who present with bilateral disease and ischemic symptoms) 3.

Abstract

Moyamoya disease is a rare cerebrovascular disease that causes occlusion of the supraclinoid internal carotid arteries and its branches within the Circle of Willis. While rare in the United States and Europe, moyamoya disease is much more common in eastern Asian populations. We present a 29 year‐old Caucasian woman who initially presented with severe mental status changes and ataxia. MRI and MRA imaging, as well as pathologic examination at autopsy, revealed occlusion of the middle cerebral and anterior cerebral arteries bilaterally with associated infarctions. This case underscores the importance considering this diagnosis as an etiologic possibility during the workup of multiple infarcts, even in non‐Asian populations