Moya moya disease (MMD) is a condition first described in 1957, which predisposes affected individuals to suffer from stroke due to progressive stenosis most commonly of branches of the carotid arteries(8). This disease has a higher prevalence in females than in males, and the highest prevalence was found in Japan, where moya-moya translates to “hazy puff of smoke”(9). This translation refers to the characteristic appearance of the vessels seen in angiography. The stenosis of larger vascular branches caused by this disease triggers neovascularization, and these thin new vessels cause a cloudy appearance.
Incidence rates are highest in eastern Asia; Japan reported 0.35 cases per 100,000 individuals.
On the other hand incidence rate in the United States is 0.09 per 10,000 individuals, and the highest incidence and prevalence is among Asian Americans (0.28/100,000), followed by African Americans (0.13/100,000), Caucasian Americans (0.06/100,000), and Hispanics (0.03/100,000). Furthermore, the incidence reported between Asian and Asian American descendants was similar. (10) (11), meaning that genetic factors have to be implicated in disease development. (12).
The pathophysiology of MMD is still unknown. Since the discovery of this disease, multiple studies have been conducted showing that the RNF213 gene is implicated, and further studies have demonstrated that different genetic variants have more potential than others to trigger the disease. (13) (14)
The RNF213 was the first identifiable gene linked to an increased risk of MMD, but the exact mechanism is still not well understood. (15) (16). Several studies exist. The first one published in 2012 was a case-control looking at RNF213 variant c.14576G>A in patients with non-MMD intracranial major artery stenosis/occlusion (ICASO); authors found an association between c.14576G>A and non-MMD ICASO.
In 2013 the same group investigated the occurrence rate of the c.14576G>A variant in 323 ICASO patients and noted that some patients with distinct ICASO phenotypes might have a common genetic variant, RNF213 c.14576G>A, suggesting that the RNF213 c.14576G>A variant may be a high-risk allele for ICASO. Two years later, another study was done on 78 MMD patients; nine had non-atherosclerotic MMS showing the absence of the RNF213 c.14576G, a genetic variant in nonatherosclerotic MMS patients. In the absence of this particular genetic variant, patients with MMD did not present atherosclerosis, but RNF213 was present. (17) (16) (18)
Furthermore, even in patients who have RNF213 mutations, its presence does mean predict the development of this disease, which is the reason why some investigators believe that this genetic variant might be a trigger and a second “hit” is necessary for the disease to develop. (19) How exactly MMD develops is still a mystery. The association between this disease and prothrombotic states is even less well understood and documented.
We performed an extensive search for associations between immune-mediated diseases (SLE, APL, acquired and congenital TTP, etc.) and MMD, and we found only one case of acquired TTP in the setting of MMD (20).
Congenital TTP in association with MMD has been more documented, but the association between ALP, TTP, and MMD has never been described.
Moya Moya terms refer to the characteristic pathological findings of stenosis and collateralization; MMD has often been associated with multiple other medical conditions, and in this case, it is described as a moya-moya syndrome (MMS). (19)
The usual treatment for MMD or MMS, if asymptomatic, is aspirin. However, patients with proven decreased perfusion or once symptomatic should undergo a revascularization procedure. As seen in the case presented before, this patient underwent extracranial-intracranial bypass surgery after presenting with multiple strokes in the past.
MMD/MMS is associated with thrombophilic predispositions. H. Tsuda et al. conducted a study with 20 patients with either Moyamoya disease or quasi-Moyamoya disease. Thrombophilia was assessed by measuring the activity and antigen levels of antithrombin III, protein C, protein S, fibrinogen, and plasminogen as well as detecting lupus anticoagulants. One-third (four definite cases and three quasi-cases) of the examined patients had either a congenital or acquired thrombophilic tendency. (21).
The link between MMD/MMS and APS is unclear. The formation of aPL antibodies could be associated with damage to the vascular endothelial or sub-endothelial structures, secondary to the abnormal vasculature and/or altered flow. Furthermore, APS may play a role in promoting further thrombosis and recurrent ischemic events. (3) (22)
Most cases of APS and MMD/MMS cases coexist with other medical conditions; a substantial prevalence of up to 65% of other conditions like diabetes mellitus, hypothyroidism, Down syndrome, etc was noted. (3) (23)
Hematologic disorders have been described in 16% of patients with MMD. We found 16 papers describing an association between moyamoya and hematologic disorders (spherocytosis, beta-thalassemia, Fanconi anemia, etc.) (11).
Congenital TTP in association with MMD has been described, but the pathophysiology mechanism is unclear (24) (25). Some of the theories suggest that increases in the proinflammatory and angiogenic cytokines further stimulate the synthesis of growth factor-β and basic fibroblast growth factor, leading to angiogenesis and neovascularization. It is further hypothesized that microangiopathic changes are followed by macroangiopathic changes leading to the ischemic manifestations of moyamoya syndrome. (24)
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of several autoantibodies targeting phospholipids or phospholipid-binding proteins. This syndrome is characterized by a procoagulant state, often leading to pregnancy loss and venous or arterial thrombosis. These antibodies are anticardiolipin, lupus anticoagulant, and beta2-glycoprotein antibodies (26). Diagnosis is usually made by detecting the presence of one or several of these antibodies and one or more episodes of arterial or venous thrombosis. In our patient, around the time she was diagnosed with MMD, she presented with elevated values of multiple anticardiolipin antibodies as well as a history of stillbirth, second-trimester pregnancy loss, and multiple CVA; she was diagnosed with APS.
On this occasion, the presentation of a patient with MMS to the ED with abdominal pain was associated with nausea, autoimmune hemolytic anemia (positive direct Coombs test), decreased haptoglobin, and severe thrombocytopenia. The positivity of Coombs suggests autoimmune hemolysis; however, in this patient, this may be related to autoimmune para-phenomena seen with APS. Furthermore, the presence of schistocytes made us believe this hemolysis was most likely microangiopathic, raising the urge to rule out any possibility of thrombotic microangiopathy (TMA).
Thrombotic thrombocytopenic purpura (TTP) is a disorder that can either be acquired or hereditary. It consists of a protein deficiency involved in the cleaving of Von Willebrand factor known as ADAMTS13. This causes an increase in VWF levels, which leads to platelet aggregation and thrombus formation. It usually presents with nonspecific symptoms such as abdominal pain, nausea, vomiting, and weakness. A classic pentad of thrombocytopenia, MAHA, renal involvement, severe neurologic manifestations, and fever was described in TTP. Nevertheless, TTP frequently presents without the full pentad. Fever and renal impairment are generally uncommon in the presentation, and in approximately 35% of patients with TTP, neurological signs are not seen (2). Thrombocytopenia and MAHA are enough diagnostic criteria to raise concern for TTP (27), although this presentation can be associated with any TMA.
TMA-related disorders are characterized by the presence of microvascular thrombosis, which can be local or diffuse. Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening condition in patients with APS due to the rapid development of multiple thromboses. It often involves several vital organs such as the kidneys, lungs, or heart. Most commonly, CAPS affects small vessels, resembling TMA, specifically very similar to the TTP presentation. This presentation, often challenging, has several life-threatening differential diagnoses. Already mentioned above are TTP and CAPS, which were the main differentials in the case presented above. However, the differential also includes other entities like hemolytic uremic syndrome, disseminated intravascular coagulation, syndromes related to hypertension, pregnancy or drug-induced, and even heparin-induced thrombocytopenia (28).
The main challenge in the above case was to establish a diagnosis and to identify a potentially life-threatening condition promptly. In our patient with an established diagnosis of APS, we had to consider CAPS. Diagnosis of CAPS requires four criteria: evidence of involvement of three or more organs, the onset of manifestations are simultaneous or within a week of each other, histopathologic confirmation of small vessel occlusion of at least one organ, and laboratory confirmation of antiphospholipid antibodies (29). Another severe condition to contemplate in this case was TTP. The PLASMIC score (Table 2), was developed to estimate the likelihood of severe ADAMTS13 deficiency (30) and our patient had a PLASMIC score of 6 indicating a high likelihood of severe ADAMTS13 deficiency. The main concern initially was to differentiate between CAPS and TTP.
Table 2. PLASMIC score
|
Points
|
Platelet count <30,000/microL
|
1
|
Indicator of hemolysis: Reticulocyte count of >2.5%, or undetectable haptoglobin, or indirect bilirubin >2.0mg/dl
|
1
|
No active cancer
|
1
|
No history of solid organ or hematopoietic stem cell transplant
|
1
|
MCV <90 fL
|
1
|
INR <1.5
|
1
|
Creatinine <2.0 mg/dl
|
1
|
A score of 0-4 points denotes low risk; a score of 5 denotes intermediate risk; a score of 6-7 denotes high risk
|
Clinically, differentiating between TTP and CAPS is impossible; therefore we initiated treatment with plasma exchange and steroids which are effective in both conditions. In the case of CAPS, anticoagulation (AC) and high-dose glucocorticoids (GC) are also known to be effective. The use of AC alone has demonstrated a significant positive effect on prognosis. In life-threatening situations, the use of plasma exchange (PE) and or intravenous immunoglobulin (IVIG) should be considered as well. Overall, evidence has shown superior survival rates when combining AC and GC with PE and/or IVIG. In patients with SLE and CAPS, the addition of cyclophosphamide is recommended based on evidence supporting a reduction in mortality. Several studies were done using Rituximab and eculizumab, but at the moment, not enough evidence supporting either treatment is available. (28). In the case of TTP, the international society of thrombosis and hemostasis (ISTH) guidelines for treatment recommend using GC with PE when treating a first acute event. This recommendation is made even in the context of relapse and despite the lack of evidence due to potential reductions in mortality with this treatment. Rituximab is a conditional recommendation due to the meager evidence of benefit in treatment. Nonetheless, in patients with known autoimmune disorders, more practitioners tend to consider the addition of Rituximab to PE and steroids. Caplacizumab is a monoclonal antibody against VWF and studies support its use in cases of TTP refractory to plasma exchange therapy and glucocorticoids, but there is limited data regarding the treatment of acute events of TTP. Due to a lack of availability and evidence, the guidelines do not provide specific recommendations. (31). In this case, therapy was initiated with PE and GC. Regarding anticoagulation, the patient was being treated with warfarin as an outpatient, but her compliance was unclear. While hospitalized, the patient began AC treatment with enoxaparin, and she was later transitioned to warfarin.
Our patient responded clinically and with laboratory improvement to a treatment regimen of plasma exchange, glucocorticoids, and anticoagulation. This improvement, along with evidence of decreased ADAMTS13 and elevated ADAMTS13 antibody levels, was consistent with the diagnosis of TTP.