Moyamoya Vasculopathy in Indian Children: Our Experience.

BACKGROUND: Moyamoya vasculopathy is a chronic progressive vaso-occlusive disease affecting the distal intracranial carotid arteries and their proximal branches. It is an important cause of recurrent strokes in children. Surgical revascularization procedures are now considered as the treatment option for moyamoya vasculopathy. The data from Indian children with moyamoya vasculopathy are limited to a very few studies. STUDY
DESIGN: We analyzed the records of children with moyamoya vasculopathy treated at our tertiary care center from 2000 to 2014. Our study population included all patients (aged 0-18 years) with moyamoya disease/syndrome (MMD/MMS). The demographic data, clinical characteristics, imaging, treatment details, and surgical procedures performed were reviewed.
RESULTS: A total of 41 patients (females-19, males-22) were identified. Thirty-three (80.48%) had MMD and eight (19.5%) had MMS. The mean age (±standard deviation) at presentation was 6.26 ± 3.79 years (range: 6 months-14 years). Majority had ischemic events at onset; none had hemorrhagic manifestations. Twenty-eight (68.29%) patients underwent surgery (a total of 33 surgical procedures, bilateral in five and unilateral in 23) and 13 (31.7%) were managed conservatively. The median duration of follow-up was 2.2 ± 1.85 years (range: 4 months-7 years). Two/thirteen patients (15%), who were managed conservatively, had recurrent strokes as against none (0/28) in the operated patients. No mortality was observed in our cohort.
CONCLUSION: We agree with previous studies that Indian patients with moyamoya vasculopathy differ from their Asian and European counterparts. The availability of expertise in revascularization surgeries in various centers should prompt surgery as an efficient and safe treatment option.

INTRODUCTION

Moyamoya vasculopathy is a chronic progressive vaso-occlusive disease of the cerebral vasculature causing stenosis of the apices of the intracranial internal carotid arteries (ICAs), including the proximal anterior cerebral arteries (ACAs) and middle cerebral arteries (MCAs). This leads to the formation of collateral vessels, which resemble the appearance of a “puff of smoke” on angiography.[1] It was first described by Takeuchi and Shimizu as ‘‘hypoplasia of the bilateral ICAs.”[2] More than a decade later, Suzuki and Takaku gave the descriptive title of moyamoya.[3]

The prevalence of moyamoya disease (MMD) is about 10.5/100,000 in Japan.[4] A European study (Yonekawa et al.) had cited an incidence of 0.3 patients per center per year, which was approximately one-tenth of the Japanese incidence.[156] The disease has now been found to be prevalent throughout the world.[5] Patients with characteristic moyamoya vasculopathy who also have well-recognized associated conditions are categorized as having moyamoya syndrome (MMS), whereas those patients with no known associated risk factors are said to have MMD.[157] Maki and Enomoto have classified the clinical features in children into four types: bleeding type, epileptic type, infarction type, and transient ischemic attack (TIA) type.[89] The natural course of disease is slow with progressive neurological and cognitive deterioration due to recurrent TIAs/stroke. Sometimes, a fulminant course with rapid neurological decline and death has been noted.[11011]

Surgical revascularization procedures have shown good results and have proven beneficial in the reduction of ischemic events. The indications for surgery include recurrent ischemic events, severe deficit at onset, early disease, progressive mental deterioration/decline, angiographically detected low blood flow to the brain, and cerebral atrophy on imaging.[41213]

The clinical features, treatment, and long-term outcome of Indian patients with moyamoya vasculopathy have been reported in the recent years. However, these data have been limited to very few studies and case reports, those from the pediatric population even lesser.[7141516171819202122] We present the data of 41 children with moyamoya vasculopathy from our tertiary care center over a period of 14 years.

METHODS

The records of patients (aged 0–18 years) diagnosed with angiographically proven moyamoya vasculopathy presenting to the pediatric neurology clinic of a tertiary center in Mumbai from 2000 to 2014 were reviewed retrospectively. The permission from Institutional Ethics Committee was obtained prior to commencement of the study. Data were recorded in a predetermined pro forma, after obtaining appropriate consent and assent from parents and children. The patients with distal bilateral/unilateral internal carotid occlusion without any underlying secondary cause were considered as having MMD and those patients having secondary causes were diagnosed as having MMS. The demographic details, clinical features, and investigations including magnetic resonance imaging (MRI) brain, MR angiography study, and digital subtraction angiography (DSA) (wherever applicable) were obtained from these records. The relevant investigations to rule out a secondary cause including sickling test, lipid profile, complete blood counts, coagulation profile, serum homocysteine, anti-neutrophil cytoplasmic antibodies, antinuclear antibody, anticardiolipin antibody, cerebrospinal fluid study, workup for tuberculosis (wherever applicable), echocardiography, carotid Doppler, and karyotype (in relevant cases), which had been performed, too, were noted. The clinical course, treatment given, details of surgical revascularization procedures, and outcomes were evaluated. Patients had been followed up regularly in the pediatric neurology clinic at 3 months after the initial event or after revascularization procedure and later 6 monthly. Those patients who were operated were compared to the nonoperated group for functional outcome using the modified Rankin score (mRS), pediatric modification.

Modified Rankin score, pediatric modification

No symptoms at all

No significant disabilities despite symptoms in clinical examination; age-appropriate behavior and further development

Slight disability; unable to carry out all previous activities, but same independence as other age- and sex-matched children (no reduction of levels on the gross motor function scale)

Moderate disability; requiring some help, but able to walk without assistance; in younger patients, adequate motor development despite mild functional impairment (reduction of one level on the gross motor function scale)

Moderately severe disability; unable to walk without assistance; in younger patients, reduction of at least 2 levels on the gross motor function scale

Severe disability; bedridden, requiring constant nursing care and attention

Dead.

RESULTS

Demographic features and clinical characteristics

A total of 41 patients (females-19, males-22) with moyamoya vasculopathy (MMD or MMS) proven on angiography were identified. The mean age (±standard deviation) of patients at presentation was 6.26 ± 3.79 years (age range: 6 months–14 years). The demographic details, clinical features, and neuroimaging studies of these patients are summarized in Table 1. Majority of the patients had ischemic events at onset; none had presented with hemorrhages. The most common presentation was TIA/stroke (92.68%) followed by seizures (19.5%) and headache (4.8%). One patient presented with status epilepticus at the onset of symptoms. None had a positive family history of stroke. The secondary causes for MMS found in our patients were Down syndrome, congenital nephrotic syndrome, metaphyseal dysplasia, sickle cell disease, tuberculous vasculitis, and immunodeficiency, namely, hyper IgE syndrome-related vasculitis. MRI brain imaging revealed predominant anterior circulation affection (75.6%), while only posterior circulation affection was seen in 4.87% of patients.

Table 1

Clinical and imaging characteristics of children with moyamoya vasculopathy

Treatment

Of the 41 patients, 28 (68.29%) underwent surgery [Table 2]. Thirteen patients (31.7%) were managed with antiplatelets and antiepileptics depending on the presentation. Among the nonoperated group, six patients were awaiting surgery primarily secondary to financial constraints; three were lost to follow-up and surgery was refused by parents in four patients. The mean interval between the onset of symptoms and surgical procedure was 6.28 ± 8.47 months (range: 1 month to 4 years). Majority of patients underwent indirect procedures, encephalo-duro-arterio-synangiosis (EDAS) being the most common procedure performed. All except one of the operated patients presented with ischemic events; he presented with repeated focal seizures. Postoperatively, three patients had neurological events (TIA/stroke). The other complications seen were pseudomeningocele formation and transient scalp fluid collection (in a patient who underwent multiple burr-hole surgery).

Table 2

Surgical revascularization procedures performed

Follow-up and outcome

The details of follow-up and outcome in the study patients are shown in Table 3. Three patients in the conservatively managed group were lost to follow-up. Residual deficit was found in 25/41 (60.97%) patients. Among the surgically treated group, 60.7% patients had visual, cognitive, or motor deficit on follow-up. Poor outcome was observed in those who had severe stroke at onset, status epilepticus, with underlying sickle cell disease, postoperative event, and recurrent neurological events. A young girl developed major ischemic stroke in the immediate postoperative period after EDAS procedure and was left with severe neurological and cognitive deficit on follow-up. Among the conservatively managed patients, 2/13 (15.3%) continued to have repeated TIAs; both had MMS (metaphyseal dysplasia and sickle cell disease). No mortality was observed in our cohort during the follow-up. Of the 41 patients, a good outcome (mRS ≤2) was observed in 89.28% of the surgically treated patients and 70% of the conservatively treated patients. None of the operated patients had ischemic events on follow-up. Majority of the patients showed good post-operative revascularization [Figures 1–3].

Table 3

Outcome of patients (operated as compared to nonoperated group)

Figure 1

(a and b) Digital subtraction angiography (right internal carotid artery, lateral view) and magnetic resonance angiography images of an 8-year-old boy showing total occlusion of right internal carotid artery, right middle cerebral artery with collaterals (c and d) Magnetic resonance angiography image of the same patient 2 years postrevascularization surgery (left encephalo-duro-arterio-synangiosis surgery with multiple burr holes) showing good revascularization (small arrows)

Figure 3

(a) Magnetic resonance angiography images of a 4-year-old boy showing long-segment occlusion of the right internal carotid artery, middle cerebral arteries, and their branches with extensive collateral vessels (b and c) Magnetic resonance angiography image of the same patient (7 years after bilateral encephalo-duro-arterio-synangiosis surgery) showing good revascularization

(a and b) Magnetic resonance angiography image (14 months postrevascularization surgery) of a patient with moyamoya disease who underwent left encephalo-duro-arterio-synangiosis surgery showing good revascularization

Illustrative cases

Case 1

A 10-year-old boy, born of a nonconsanguineous union, with normal birth and developmental history, presented with the complaints of painless progressive bilateral vision loss (left more than right) for 1 month. He had a history of recurrent episodes of TIAs and seizures 5 years back and was diagnosed to have MMD. The parents were given an option of revascularization surgery at the initial diagnosis; however, they were reluctant for surgery. On admission, he was noted to have impaired vision (right eye – finger counting at three feet; left eye – finger counting at one foot). Rest of the general and systemic examination was normal. MRI brain revealed subacute infarct in the left occipital lobe. MR angiography showed complete occlusion of the right supraclinoid ICA and severe narrowing of the left supraclinoid ICA. A month later, he underwent bilateral EDAS (posterior branch of superficial temporal artery based) and multiple bilateral fronto-parietal burr holes [Figure 4]. He had an uneventful postoperative period. He had minimal residual visual deficit and no ischemic events on follow-up 1.5 years later.

Figure 4

(Illustrative case 1): (a) Magnetic resonance imaging brain, diffusion-weighted image of the case showing subacute infarct in the left occipital region (b) Magnetic resonance angiography image showing complete occlusion of the right supraclinoid internal carotid artery and severe narrowing of the left supraclinoid internal carotid artery with collateral formation (c and d) Intraoperative images of the same patient depicting encephalo-duro-arterio-synangiosis (posterior branch of superficial temporal artery based) and multiple bilateral fronto-parietal burr holes

Case 2

An 8-year-old boy, born of a third-degree consanguineous union, with normal birth and developmental history, presented with the complaints of fever, headache, and vomiting followed by altered behavior for 1 day. Later, he developed diplopia and acute vision loss. He had a history of right and left hemiparesis (at 5 and 6 years of age, respectively), received some Ayurvedic medications, and did not undergo any investigations for the illness. On admission, he was noted to have vision as finger counting at 1 m. Rest of the general and systemic examination was normal. MRI brain revealed acute infarcts at bilateral parieto-occipital region and tiny focal infarct at the left frontal precentral subcortical white matter. MR angiography showed occlusion of bilateral ICA, ACA, MCA, basilar artery, and PCA with distal reformation via collaterals (moyamoya formation). Detailed vasculitis and prothrombotic workup were negative. Indirect revascularization procedure in the form of multiple burr-hole surgery was performed after 6 months. He withstood the procedure well without any postoperative complications. His vision improved completely on follow-up within 3 months. He had no residual neurological deficit and ischemic events on follow-up 1½ years later.

DISCUSSION

Moyamoya vasculopathy has been frequently reported in the Japanese population, the incidence being about 3–10/100,000. As highlighted in the recent studies, the data from Indian patients, especially children with MMD, are still lacking.[7] Our study adds further to this information. A brief comparison with selected Indian studies is shown in Table 4.[716172122]

Table 4

Comparison with selected Indian studies

We agree with earlier Indian studies that our patients have a relatively benign course and no familial predisposition contrary to their counterparts from other Asian countries.[110111516171819202122232425] We have found a male preponderance (M:F =1.15:1) as against female preponderance noted in previous studies.[11421232425] Among our cohort, 9.7% patients had a history of consanguinity.

A genetic predisposition has been observed. This is especially incurred from the fact that moyamoya vasculopathy was noted in about 10% and 6% of first-degree relatives of patients among the Japanese and the US population, respectively.[10] Besides the major gene locus identified on chromosome 17q25, mutations in the tissue inhibitor of matrix metalloprotein type 2 and caspase-3-dependent apoptosis pathway are found to be related to MMD.[2627] It is also important to mention at this point that genetic studies have not been performed in Indian patients with moyamoya vasculopathy, especially MMD, which is an important point for research in the future.

Moyamoya vasculopathy in children differs from that in adults in terms of features such as headache, cognitive decline, hypertension, and temporary or permanent blindness; hemorrhages tend to be more common in adults.[28] Majority of our patients presented with ischemic events which relate to the earlier onset of occlusive arteriopathy in children as compared to adult patients. Traditionally, DSA is the gold standard for diagnosis. However, MRI and MRA have become more reliable and accepted diagnostic modalities owing to their noninvasive nature.[1] The overall sensitivity and specificity have been found to be 100% and 93%, respectively, for MRA as compared to the conventional angiography.[29]

Studies on the outcome of conservatively managed patients have shown that neurological symptoms or deficit may develop in 37% of patients, while 3% of patients may die if left untreated.[2830] This suggests the necessity of active surgical treatment in children with MMD.

The common revascularization surgeries performed are direct procedures (superficial temporal artery to middle cerebral artery [STA-MCA] bypass) or indirect procedures (EDAS, encephalo-myo-synangiosis [EMS], encephalo-duro-arterio-myo-synangiosis [EDAMS]), and various combinations of these.[1516] Other indirect procedures include multiple burr holes, dural inversion, galeal apposition, and omental transplants.[15313233] The rationale behind a revascularization surgery is to prevent future strokes and thereby limit disease progression.[516] A meta-analysis on patients with MMD has shown that 87% patients (1003/1156) benefit from surgical revascularization irrespective of the technique used (direct, indirect, or combined).[12]

Direct STA-MCA bypass procedure is technically more difficult in children as cerebral vessels are slender and fragile.[528] Children with MMD who underwent direct procedures have shown good control of ischemic symptoms; however, mental disorders may be exacerbated.[28] EDAS has been found as an effective therapeutic alternative for surgical treatment of pediatric MMD.[34] Comparison between patients undergoing EDAS versus EDAMS (regardless of the combined STA-MCA anastomosis) has shown EDAMS to be significantly effective for good postoperative angiographic revascularization.[35] Multiple burr-hole surgery as an option for revascularization has been found to give relatively good results and no exacerbated ischemic outcomes both in adults and children.[313233] As regard to effective revascularization postsurgery, direct/combined bypass was more often associated with better results than that of indirect bypass.[36] However, another study analyzed the effectiveness of various revascularization procedures in both adult and pediatric patients with MMD and concluded that indirect and combination procedures may offer optimal results at long-term follow-up as compared to direct procedures.[12] The surgical risk of revascularization procedures is about 8%–13%.[3738] The complications include stroke, infection, and hemorrhage.

Our study, too, has shown that revascularization, especially indirect procedures (EDAS, EDAMS, and multiple burr-hole surgery) is safe and effective in preventing further strokes in children with moyamoya vasculopathy. However, two of our operated patients (who underwent EDAS procedure) had significant postsurgery strokes. One of these two patients had been operated early (within 3 months of clinical presentation, due to repetitive TIAs) and developed severe brain swelling postoperatively requiring a decompression craniotomy. She was left with significant neurological deficit. The outcome of patients managed conservatively has been obtained on those who are either reluctant for surgery or those who remained asymptomatic for longer duration. These data, however, remain inadequate due to a small number of patients who were lost to follow-up. Our patients have shown good postsurgery revascularization and definite reduction of stroke recurrence postsurgery.

Our study has its limitations. The main shortcomings being its retrospective nature, small sample size, and referral bias to the hospital as ours is a tertiary care center. Our patient population comprised both MMD and MMS; those with an underlying predisposing factor generally have a different course, sometimes severe; for instance, in patients with sickle cell disease. The absolute numbers in both the operated versus nonoperated groups were not comparable. The availability of a trained team of neurosurgical faculty with excellent postoperative outcome in various studies prompted us to opt for surgical option in our cases.

CONCLUSION

Our study adds further to the data on children with moyamoya vasculopathy in India. We agree with previous studies that Indian patients differ from their Asian as well as European counterparts. The availability of expertise in revascularization surgeries in various centers should prompt surgery as an efficient and safe treatment option. The candidates for early surgery should be those with early onset of disease, catastrophic events at presentation, and frequent ischemic events.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.