SURGICAL MANAGEMENT OF MOYAMOYA DISEASE- RETROSPECTIVE ANALYSIS OF A SINGLE INSTITUTION SERIES

Transcription

1 SURGICAL MANAGEMENT OF MOYAMOYA DISEASE- RETROSPECTIVE ANALYSIS OF A SINGLE INSTITUTION SERIES Submitted for M.Ch Neurosurgery By Dr. Ranjit Devidas Rangnekar October 2016 Department of Neurosurgery Sree Chitra Tirunal Institute for Medical Sciences & Technology Thiruvananthapuram i

2 SURGICAL MANAGEMENT OF MOYAMOYA DISEASE- RETROSPECTIVE ANALYSIS OF A SINGLE INSTITUTION SERIES. Submitted by : Dr.Ranjit Devidas Rangnekar Programme : M.Ch Neurosurgery Month & year of submission : October, 2016 ii

3 CERTIFICATE This is to certify that the thesis entitled SURGICAL MANAGEMENT OF MOYAMOYA DISEASE-RETROSPECTIVE ANALYSIS OF A SINGLE INSTITUTION SERIES is a bonafide work of Dr. Ranjit Devidas Rangnekar and was conducted in the Department of Neurosurgery, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram (SCTIMST), under my guidance and supervision. Dr. Suresh Nair N. Professor and Head Department of Neurosurgery SCTIMST, Thiruvananthapuram. iii

4 DECLARATION This thesis titled Surgical Management of Moyamoya Disease-Retrospective Analysis of a Single Institution Series is a consolidated report based on a bonafide retrospective study of the data for patients managed in a period from January 2003 to April 2014, done by me under the Department of Neurosurgery, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram. This thesis is submitted to SCTIMST in partial fulfilment of rules and regulations of M. Ch Neurosurgery examination. Dr Ranjit Rangnekar SCTIMST, Thiruvananthapuram. iv

5 ACKNOWLEDGEMENT The guidance of Dr. Suresh Nair, Professor and Head of the Department of Neurosurgery, has been invaluable and I am extremely grateful and indebted for his contributions and suggestions, which were of invaluable help during the entire work. He will always be a constant source of inspiration to me. I owe a deep sense of gratitude to Dr. Girish Menon for his invaluable advice, encouragement and guidance, without which this work would not have been possible. The critical remarks, suggestions of Dr. Jayanand Sudhir, helped me in achieving a high standard of work. I am extremely thankful to Dr. Mathew Abraham for his invaluable advice, and for being a constant source of inspiration I am deeply indebted to Dr. Easwer H. V, Dr. Krishnakumar K, Dr. Prakash Nair and colleagues and I thank them for their constant encouragement and support. I am thankful to Dr. Jayadevan, Dr. Santosh for their help in accomplishing the research. Last but not the least, I owe a deep sense of gratitude to all my patients without whom this work would not have been possible. v

6 INDEX INTRODUCTION 1 AIMS AND OBJECTIVES 1 MATERIALS AND METHODS 2 REVIEW OF LITERATURE 4 RESULTS 28 DISCUSSION 55 CONCLUSIONS 64 BIBLIOGRAPHY 65 ANNEXURE I 80 ANNEXURE II 84 vi

7 INTRODUCTION Earlier considered unique to Japan and other oriental countries, Moyamoya disease is being increasingly reported from the Indian subcontinent as a cause for stroke, both among children and elderly. 22,82,96 Coined by Suzuki and Takaku in 1969, the term Moyamoya refers to a puff of smoke like appearance of small collaterals seen traversing the basal ganglia and thalamus, in response to progressive stenosis and occlusion of supraclinoid Internal carotid artery. 16,107 The natural history is generally one of relentless progression if untreated. 96,107 Studies on both adult and paediatric Moyamoya patients have shown that in view of the progression of disease the risk of subsequent ischemic stroke is significantly reduced by revascularization surgeries. 25,55 The role of surgery in haemorrhagic Moyamoya disease is still unclear. AIMS AND OBJECTIVE This study aims to show experience with revascularization for a group of twenty-two patients operated over a period of eleven years. An attempt is also made to study the clinical profile, surgical as well as radiological outcome of paediatric and adult patients operated for Moyamoya disease, using various revascularisation procedures, as well as to differentiate ischemic Moyamoya from haemorrhagic Moyamoya disease. 1

8 MATERIALS AND METHODS All patients with Moyamoya disease treated surgically in the period 2003 to 2014 were included in the study. Patients less than 12 years of age were included in the paediatric group. The demographic details, clinical features and investigations were obtained from retrospective chart review. The imaging and angiographic data were reviewed by a radiologist and neurosurgeon with particular focus on stage of the disease and collateral circulation and post-operative changes. These patients were prospectively followed up and the follow up data was collected during clinical visits. Patients were followed up regularly in the outpatient department at 3 months after the initial event or after revascularization procedure and thereafter every 6 months. During each visits any new neurological event and symptoms are recorded and the functional outcome by Modified Rankin Scale(mRS) was documented. A stable state was defined as the patient remaining event free for 1 year. Radiological follow up was done and was reviewed by a radiologist and a neurosurgeon. The characteristics of both the cohorts were compared using students t test for continuous data. Diagnosis was confirmed using CT, MRI and DSA in all the patients. Cerebro Vascular Reactivity (CVR) studies are done in patients with equivocal clinic radiological correlation to decide on the maximally involved hemisphere and to decide on the need for surgery in an asymptomatic hemisphere. Study protocol was to offer surgery to all hemispheres with clinical involvement and angiographic evidence of Moyamoya Disease. Asymptomatic hemispheres showing angiographic evidence of Moyamoya disease but with no recorded clinical events are also offered surgery. 2

9 The choice of surgery was made based on the calibre of superficial temporal artery assessed on pre-operative angiogram and intraoperative visual observation. If the STA (superficial temporal artery) calibre is found to be small, an indirect procedure in the form of EDAMS was performed. If the STA calibre is found adequate a direct procedure like STMC was performed. In the later stages of the study period there was a preference to do combined procedure in patients with good ST calibre a direct STMC along with an EDAMS. Attempt was always made to perform anastomosis using both the frontal and parietal branch. If one of the branches is found to be too small for direct anastomosis that vessel is incorporated in an arteriosynangiosis. In patients with bilateral involvement we perform bilateral surgeries, first surgery being done on the maximally involved hemisphere followed by the contralateral hemisphere after a gap of 3 to 6 months 3

10 Review of literature Introduction: Moyamoya disease is characterized by chronic progressive stenosis at the apices of the intracranial internal carotid arteries (ICA), including the proximal anterior cerebral arteries and middle cerebral arteries. These collateral vessels, on angiography, have been likened to the appearance of a puff of smoke, which translates to Moyamoya in Japanese. First described in 1957 as hypoplasia of the bilateral internal carotid arteries, 108 the descriptive title of Moyamoya was applied more than a decade later by Suzuki and Takaku in ,16,96 Pathology: Moyamoya disease is characterized by intimal thickening in the walls of the terminal portions of the internal carotid vessels bilaterally. There is a proangiogenic intracranial milieu in the absence of inflammatory or atheromatous involvement. There is an accumulation of smooth muscle cells who have the potential to home in on diseased vessels and differentiate into neointimal smooth muscle cells 1 causing occlusion. The proliferating intima may contain lipid deposits The anterior, middle, and posterior cerebral arteries that arise from the circle of Willis may show varying degrees of stenosis or occlusion. This is associated with fibrocellular thickening of the intima, waving of the internal elastic lamina, and thinning of the media. Disease specific proarteriogenic mechanism that causes diverse intracranial-tointracranial as well as extracranial-to-intracranial collaterals which lead to numerous 4

11 small vascular channels can be seen around the circle of Willis. These are perforators and anastomotic branches. The pia mater may also have reticular conglomerates of small vessels. There may also be formation of micro aneurysms. Etiology Genetic: Although the cause and pathogenesis of Moyamoya disease are poorly understood, genetic factors play a major role. The familial incidence of affected first-degree relatives in Japan is 10%, with a rate of 6% reported in a recent series in the United States. 17,97 Associations with loci on chromosomes 3p24.2-p26, 6q25, 8q23,12p12,17q25, (MYMY1, MYMY2, MYMY3) as well as specific human leukocyte antigen haplotypes have been described. 29,35,40,41,84,94 However, despite evidence supporting a genetic basis of Moyamoya, important caveats remain. Reports exist of identical twins with only 1 affected sibling. 97,113 These data support the premise that environmental factors precipitate the syndrome s clinical emergence in susceptible patients. Mineharu suggested that familial Moyamoya disease is autosomal dominant with incomplete penetrance that depends on age and genomic imprinting factors. Mineharu et al have found a specific gene locus, q25.3, on chromosome A genome-wide association study identified RNF213 as the first gene associated with Moyamoya. 48 One meta-analysis demonstrated that there are strong associations between p. R4859K and p. R4810K polymorphisms of the RNF213 gene and Moyamoya disease. 71 Other variants of RNF213were found in Caucasian and East and South Asian patients with Moyamoya disease. The p. R4810K RNF213 variant 5

12 was reportedly related to the ischemic type of Moyamoya disease, while the non-p. R4810K RNF213 variants, particularly A4399T, were associated with the haemorrhagic-type of Moyamoya disease. 119 People with Moyamoya disease have been found to have a higher incidence of elevated thyroid antibodies. 61 Associated diseases Immunologic - Graves disease/thyrotoxicosis Infections - Leptospirosis and tuberculosis Hematologic disorders - Aplastic anaemia, Fanconi anaemia, sickle cell anaemia, and lupus anticoagulant Congenital syndromes - Apert syndrome, Down syndrome, Marfan syndrome, tuberous sclerosis, Turner syndrome, von Recklinghausen disease (Neurofibromatosis Type 1), and Hirschsprung disease Vascular diseases - Atherosclerotic disease, coarctation of the aorta and fibromuscular dysplasia, cranial trauma, radiation injury, parasellar tumors, and hypertension These associated conditions may not be causative, but they warrant consideration due to their impact on treatment. In the presence of these risk factors, the condition is referred to as Moyamoya syndrome. 6

13 Epidemiology Moyamoya disease was first described in Japan and was originally considered a disease that predominantly affected individuals of Asian heritage where the prevalence and incidence of the disorder there has been reported to be 3.16 cases and 0.35 case per 100,000 people, respectively. 59 Moyamoya disease has now been observed throughout the world and affects individuals of many ethnic backgrounds, with increasing detection of this disease in American and European populations. 55,106,115 Moyamoya disease is the most common paediatric cerebrovascular disease in Japan with a prevalence of approximately 3/100,000. 2,82,117 A recent European study cited an incidence about 1/10th of that in Japan. 93 Studies in the United States suggest an incidence of 0.086/100,000 persons (about 1 in a million). Ages for patients with Moyamoya disease range from 6 months to 67 years There are 2 peak age groups in Moyamoya disease: children at 5 years of age and adults in their mid-40s, 2,27,28 while another study states the highest peak to be in the first decade and smaller peaks in the third and fourth decades. 59 There is also a gender predominance with females affected nearly twice as often as males. 2,97,117 Natural History and prognosis The prognosis of Moyamoya syndrome is difficult to predict as the natural history of this disorder is not well known. The progression of disease can be slow with rare intermittent events, or can be fulminant with rapid neurologic decline. 19,97 The symptoms and clinical course vary widely, with the disease ranging from being 7

14 asymptomatic to manifesting as transient events to causing severe neurologic deficits. Adults experience haemorrhage more commonly while cerebral ischemic events are more common in children. Children may have hemiparesis, monoparesis, sensory impairment, involuntary movements, headaches, dizziness, or seizures. Mental retardation or persistent neurologic deficits may be present. Adults may have symptoms and signs similar to those in children, but intraventricular, subarachnoid, or intracerebral haemorrhage of sudden onset is more in adults However, regardless of the course, Moyamoya syndrome, in terms of arteriopathy and clinical symptoms, inevitably progresses in untreated patients. 5,39 Studies reveal that the rate of disease progression is high even in asymptomatic patients and that medical therapy alone does not halt disease progression. 66 It has been estimated that up to 66% of patients with Moyamoya have symptomatic progression in a 5-year period with poor outcomes if left untreated. 9,12,67 This number contrasts strikingly to an estimated rate of only 2.6% of symptomatic progression following surgical treatment in a recent meta-analysis of 1156 patients. 19 The single greatest predictor of overall outcome for patients with Moyamoya is the neurologic status at time of treatment. 18,97,86 Other factors that influence outcome include the speed and degree of arterial narrowing, the patient s ability to develop functional collateral vessels, the age at diagnosis, and the extent of infarction as demonstrated radiographically at the time of initial presentation. 121 Because neurologic status at the time of treatment is of 8

15 paramount importance to outcome, early diagnosis is imperative and needs to be coupled with the timely delivery of therapy. If surgical revascularization is performed before disabling infarction in Moyamoya syndrome, even if severe angiographic changes are present, the prognosis tends to be excellent. 97 Presentation Patients with Moyamoya disease present with signs and symptoms resulting from changes in flow to the ICAs. These signs and symptoms can be categorized into 2 groups: (1) ischemic injury, producing transient ischemic attacks (TIAs), seizures, and strokes; 51,70,72,80,96 (2) deleterious consequences of compensatory mechanisms responding to this ischemia including haemorrhage from fragile collateral vessels, flow-related aneurysms, or headache from dilated transdural collaterals. 25,27,28,38,121 Individual variation in degrees of arterial involvement, rates of progression, regions of ischemic cortex, and response to the reduction in blood supply helps to explain the wide range of presentations seen in practice. In the United States, most adults and children present with ischemic symptoms, although the rate of haemorrhage is approximately 7 times greater in adults (20% vs 2. 8%). 25,97 Some degree of geographic variability exists; reports from Asian populations indicate adults have much higher rates of haemorrhage as a presenting symptom (42%) compared with US populations (20%). 25,27,28,38,97 In contrast, it is extremely rare for children to present with haemorrhage (2.8%); they predominantly present with TIAs or ischemic strokes (68%) as shown in the largest current report of paediatric Moyamoya patients 9

16 Screening Although there are neither broad-based initiatives nor any class I data supporting screening protocols for Moyamoya syndrome, particular note should be made of the association of Moyamoya with NF1, Down syndrome, and sickle cell disease. These diseases are relatively common in paediatric practice and class III data support the premise of prospective non-invasive screening for Moyamoya syndrome in these selected populations. 45,63,89,92 Recent literature reviewing the treatment of patients with sickle cell disease and Moyamoya may provide additional evidence favouring screening of patients with sickle cell disease who fail transfusion therapy for Moyamoya. 101 The familial incidence of affected first-degree relatives in Japan is 7% to 12% and a similar rate of approximately 6% was found in the Children s Hospital Boston series. 26,32,64,97 Despite these relatively small percentages, the compelling association between neurologic status at presentation and long-term outcome after treatment may support a more aggressive posture toward screening in this population. 97 Terminology Moyamoya disease Idiopathic, bilateral steno occlusive carotid disease in the supraclinoid division of the carotid artery Moyamoya syndrome 10

17 Bilateral or unilateral Moyamoya vessels in the setting of an associated, underlying disease state Atypical Moyamoya Moyamoya vessel formation related to non-carotid steno-occlusive disease or in cases with associated aneurysms or pseudo aneurysms Unilateral: Even though it contradicts the original definition of Moyamoya disease, Children with unilateral changes of Moyamoya disease often progress to typical bilateral Moyamoya disease

18 Diagnosis The diagnosis of Moyamoya is made based on characteristic radiographic findings involving narrowing of the terminal segments of the ICA, often with the associated development of collateral vessels. Consideration of Moyamoya syndrome should be given to any patient, particularly those in the paediatric age group who present with clinical findings suggestive of stroke or TIA. The workup of a patient in whom the diagnosis of Moyamoya syndrome is suspected typically begins with an either a magnetic resonance imaging (MRI) study or computerized tomography (CT) of the brain. On CT, small areas of hypo density suggestive of stroke are commonly observed in cortical watershed zones, basal ganglia, deep white matter, or periventricular regions. 13,98 Although rare in children, haemorrhage from Moyamoya vessels can be readily diagnosed on head CT with the most common sites of haemorrhage being the basal ganglia, ventricular system, medial temporal lobes, and thalamus. Patients with these findings on CT are often subsequently evaluated with MRI/magnetic resonance angiography (MRA). Acute infarcts are well seen using diffusion-weighted imaging (DWI) (Fig A), chronic infarcts are better delineated with T1 and T2 imaging and cortical ischemia may be inferred from fluid attenuated inversion recovery (FLAIR) sequences, which demonstrate linear high signal following a sulcal pattern, felt to represent slow flow in poorly perfused cortical circulation. 7,14 Most suggestive of Moyamoya on MRI is the finding of diminished flow voids in the internal carotid and middle and anterior cerebral arteries coupled with prominent 12

19 collateral flow voids in the basal ganglia and thalamus. These imaging findings are virtually diagnostic of Moyamoya syndrome. 13,26,32,64,98 Because of the excellent diagnostic yield and non-invasive nature of MRI, it has been proposed that MRA be used as the primary diagnostic imaging modality for Moyamoya syndrome instead of conventional cerebral angiography. 5,6,64,91,105,120 Although MRA can detect stenosis of the major intracranial vessels, visualization of basal Moyamoya collateral vessels and smaller vessel occlusions is frequently subject to artefact. Therefore, to confirm the diagnosis of Moyamoya syndrome and to visualize the anatomy of the vessels involved and the patterns of flow through the hemispheres, conventional cerebral angiography is typically required. Definitive diagnosis is based on a distinct arteriographic appearance characterized by bilateral stenosis of the distal intracranial ICA extending to the proximal anterior (ACA) and middle (MCA) arteries, bilaterally and collateral networks. Disease severity is frequently classified into 1 of 6 progressive stages originally defined by Suzuki and Takaku (107) (Table A). Development of an extensive collateral network at the base of the brain along with the classic puff of smoke appearance on angiography is seen during the intermediate stages of the Suzuki grading system (Fig C.1, C.2). Angiography should consist of a full 6-vessel series, including selective injection of the external carotid systems (both internal carotid arteries, external carotid arteries, and vertebral arteries). External carotid imaging is essential to identify pre-existing collateral vessels so that surgery, if performed, will not disrupt them. Aneurysms or 13

20 AVMs, known to be associated with some cases of Moyamoya, can also be best detected by conventional angiography. There is no increased risk of angiography in children with Moyamoya. 90 Cerebral blood flow studies (Fig B), using techniques such as transcranial Doppler ultrasonography (TCD), xenon-enhanced CT, positron emission tomography (PET), and single photon emission computed tomography (SPECT) with acetazolamide challenge, can also be helpful in the diagnostic evaluation of patients with Moyamoya syndrome as well as assisting in treatment decisions. Transcranial Doppler examination provides a non-invasive way to follow changes in blood flow patterns with time in larger cerebral vessels. 81 Xenon CT, PET, and SPECT can be used to detect regional perfusion instability before treatment and to determine the extent of improvement of functional perfusion after therapy. 68,99 The role of SPECT and PET scans in the evaluation and management of Moyamoya syndrome has been increasing in the past decades. 37,56 There is compelling class I data to support the use of TCD as an initial screening study for stroke in the sickle cell population. 21 Another diagnostic evaluation that has been used in the workup of patients with Moyamoya syndrome includes electroencephalography (EEG). Specific alterations of EEG recordings are usually observed only in paediatric patients and include posterior or Centro temporal slowing, a hyperventilation-induced diffuse pattern of monophasic slow waves, and a characteristic re-build-up phenomenon. 65 The rebuild up phenomenon looks identical to the build-up slow waves seen in Moyamoya 14

21 patients, but differs from build-up in timing of presentation; build-up occurs during hyperventilation and rebuild up occurs after the hyperventilation is completed and indicates diminished cerebral perfusion reserve. MRI/MRA and conventional angiography are the standard diagnostic tools used for most patients with Moyamoya. Following surgical treatment, an angiogram and/or MRI/MRA are often obtained 1 year after operation and, depending on the age of the patient, subsequent yearly MRI. DSA is also used for follow up along with MRA. Angiographic classification (according to Suzuki and Takaku) Stage 1. Stenosis of the carotid artery at its suprasellar portion, usually bilateral. Stage 2. Moyamoya vessels begin to develop at the base of the brain Stage 3. Moyamoya vessels become more prominent as major trunks in the anterior circulation become severely stenotic or occluded. Stage 4. Posterior cerebral arteries are occluded, moyamoya vessels begin to diminish and collateral pathways from extracranial circulation develop Stage 5. Moyamoya vessels are diminishing and extracranial circulation progresses. Stage 6. Moyamoya vessels and the major cerebral arteries completely disappear, the cerebral hemispheres receive blood supply through abnormal intra cranialextra cranial anastomosis. Table A. 15

22 Fig A: MR-DWI showing multiple areas of old infarcts. Fig B: MR perfusion showing hypo-perfusion to the bifrontal and right parietal cortex. 16

23 Fig C.1: Suzuki grade 4 collaterals in Lateral view of digital subtraction angiography in a 5-year female child. Fig C.2: Posterior circulation injection in the same patient showing collaterals near PCA. 17

24 Surgical techniques: The arteriopathy of Moyamoya affects the internal carotid artery while sparing the external carotid artery. Surgical treatment of patients with Moyamoya typically uses the external carotid artery as a source of new blood flow to the ischemic hemisphere. Two general methods of revascularization are used: direct and indirect. Indirect: Cervical sympathectomy (CS) Developed by Suzuki and Takaku in which theorized that this would promote dilation of cerebral arteries and thus improve the collateral circulation by altering sympathetic flow. Omental transplantation (OT) A segment of omentum containing perforating vessels of the gastroepiploic artery and vein are isolated. An end-to-end anastomosis between the superficial temporal artery and vein to the gastroepiploic artery and vein, respectively, is performed and laid on cerebral cortex. 50 Multiple burr holes (MBH) Endo and colleagues 11 described the technique in which the dura is opened through each burr and periosteal flap is placed in contact with the exposed parenchyma. Encephalo-myo-synangiosis (EMS) developed by karasawa and colleagues, 49 Involves direct placement of the temporalis muscle on the cerebral cortex. The clinical and experimental basis for using EMS in Moyamoya was based on the reports of Henschen 31 and Tsubokawa et al. 18

25 Encephalo-arterio-synangiosis (EAS) Developed by Touho 114 Encephaloarteriosynangiosis (EAS) is mainly an intermediate procedure most often used as part of an EDAS or EDAMS. It, however, has been described as a single procedure in the past when a direct anastomosis between the STA and the MCA cannot be achieved due to MCA insufficiency, especially in posthemorrhagic presentation of Moyamoya disease. 76 Encephalo-duro-synangiosis (EDS)Intermediate which is used as a part of EDAMS. Encephalo-myo-arterio-synangiosis (EMAS) 76 The temporalis muscle flap with the STA branch attached is sutured to the dural edge to make contact with the frontal cortical surface. This technique can be applied to posterior and middle cerebral circulation as well using the posterior branch of the superficial temporal artery and the posterior auricular or the occipital artery as needed. Encephalo-duro-arterio-synangiosis (EDAS) Matsushima 74 and colleagues developed EDAS with the assumption that the operation would cause the formation of spontaneous anastomoses between the arteries of the cerebral cortex, dura mater and scalp to treat Moyamoya disease. The STA is mobilised and placed directly on the cortex. The free artery with a cuff of surrounding soft tissue is simply sutured to the dura. there are many variants and adjuncts put onto the technique by individual surgeons for additional support for revascularization. This includes most commonly the following combinations: EDAS + pial synangiosis 19

26 EDAS + dural inversion EDAS + split dura technique 52 Encephalo-duro-galeo (periosteal)-synangiosis (EDGS) It incorporates multiple incisions and has been shown to be beneficial mainly for ACA territory ischemia by Kawamoto and colleagues 53 and is used as an adjunct with EDAMS. ENCEPHALODUROARTERIOMYOSYNANGIOSIS EDAMS is an extended technique from the EDAS and the EMS that uses the temporalis muscle s deep temporal artery (DTA), the STA, and the Middle meningeal artery (MMA) to act as adjuncts to facilitate neovascularization. It was proposed and developed in 1984 by Kinugasa and colleagues 57,62 (Fig D) A skin incision is made along the parietal STA branch and the distal frontal branch of the STA in question mark shape in the fronto-parieto-temporal (FPT) region. After reflecting the skin flap anteriorly, both branches of the STA with attached strip of galea of 10 to 15 mm are carefully dissected from the pericranium and the fascia below. The underlying temporalis fascia and muscle and frontal pericranium are incised in a T-shape and elevated from the skull so that the temporalis has a posterior and an anterior cuff. A wide craniotomy is made in the fronto-parietal temporal region while protecting the middle meningeal artery and other dural vessels as well as the dissected STA branches. The dura is opened in both the frontal and temporo parietal regions alongside the MMA, creating two flaps with the MMA free-floating in the center. The stripped frontal STA branch is placed on the surface of the frontal region, and only the proximal and the distal portions of its galea are roughly sutured 20

27 with one or two stitches to the opened dural margin. The parietal branch of the STA, however, is anastomosed near the largest cortical branch of the MCA on the temporo parietal region. This posterior opened dural edge is multiply incised and folded inward into the subdural space to lay on the exposed brain surface. The split temporalis muscles are placed on the intact arachnoid membrane of the frontal and temporo parietal cortex, respectively and sutured to the adjacent dura to facilitate CSF permeation. After rongeuring the lower parts of the squamous temporal bone as well as the bone flap itself to prevent compression of the temporalis muscle pedicle, the bone flap is replaced and secured to the cranium and the scalp is closed. The results for the EDAMS technique have demonstrated on average 85% revascularization rate over 2 years. 85 In 2006, Ozgur developed a slightly modified version. 87 This version involves complete excision of the remaining dural flaps, incising the pia arachnoid surface and adding several small incisions overlying and parallel to the sulci. 21

28 Fig D: Stages of EDAMS procedure. (Barrow Neurological Institute) Multiple combined indirect procedures (MCI) Multiple combined indirect procedures use many of the previously mentioned techniques to obtain the widest and safest coverage and allow revascularization of oligemic cerebrum. These techniques have included many different combinations, but the more commonly described are EDAS plus bifrontal EGDS, 60 bilateral or unilateral concomitant EDAS, 116 EDAS plus EMS 22

29 plus EMAS, 79 EDAS plus EMS only, 43,76,77 parietal EMAS with a frontotemporal EDAMS, 95 MBH with EMS, and EDAS and pial synangiosis. 100 Indirect combined with direct procedures Indirect combined with direct procedures are performed more commonly in adults with Moyamoya disease mainly because of the difficulty in obtaining adequate vessel calibre for paediatric patients for direct anastomosis, as well as frequent complications in paediatric patients as opposed to adults. Direct Bypass: Types: 1) STA-MCA bypass 2) STA ACA bypass 3) STA-PCA bypass 4) Occipital artery-pca bypass ST-MCA bypass: Procedure: After induction of general anaesthesia, both the frontal and parietal divisions of the superficial temporal artery (STA) are mapped with Doppler ultrasound. A Y shaped incision is made along the trunk of the ST and its two divisions. The larger of the 2 divisions which is usually the parietal branch is then dissected first under the operative microscope followed by the smaller division. The vessels are dissected out along with a small galeal cuff. The small branches are meticulously isolated, cauterized and divided. Once an adequate length is obtained, the distal end is ligated and divided. The distal end of the STA is dissected bare of the galea and adventitia and the lumen is flushed with heparin and then clamped using a temporary clip. The temporalis muscle is incised in a T and reflected inferiorly. A circular craniotomy is performed taking care not to injure the ST divisions. The dura is opened in a cruciate manner and the leaflets are cauterized inverted under the 23

30 bone edges. A suitable parietal cortical branch of M 4 segment of MCA is identified and dissected out from the arachnoid. The artery is occluded with 2 mini clips and then incised. An end to side anastomosis is performed using the terminal end of the ST to the side of the middle cerebral artery (MCA) donor branch with multiple interrupted 10-0 monofilament sutures. The procedure is repeated with the frontal division of the ST also. The dural defect is closed using the temporalis muscle and the galeal cuff around the proximal ST. The inferior portion of the bone flap is partially mongered off to allow passage of the STA and muscle and then secured to the skull with the temporalis muscle underneath the bone flap. Care is taken to avoid hypotension during the procedure and adequate propofol protection is given during clamp time. In cases of indirect procedure EDAMS, the initial steps are the same except that the STA branches are not divided. The STA branches with a cuff of galea are tacked to an avascular section of pia with two 10-0 sutures. Dural closure is achieved using temporalis and the galeal cuff around STA (Fig E). Historically, direct procedures have been used in adults for whom an immediate increase of blood flow to the ischemic brain is a major benefit. Augmentation of cerebral blood flow usually does not occur for several weeks with indirect techniques. However, direct bypass is often technically difficult to perform in children because of the small size of both donor and recipient vessels, making indirect techniques appealing. Nonetheless, direct operations have been successful in some children, and indirect procedures have been successful in some adults. 102,116,118 There is considerable debate about the relative merits and shortcomings of 24

31 the two approaches; in fact, some centers advocate a combination of direct and indirect approaches. 36,75,114 Fig E: Anastomosis between STA and M4 cortical branch. (Figure from Direct Bypass Techniques for the treatment of Paediatric Moyamoya Disease Raphael Guzman, Gary K. Steinberg). Medical management: Medical therapy has been used in patients with Moyamoya, particularly when surgery has been considered to present a high risk or the patient has had relatively mild disease, but there are few data showing either its short-term or long-term 25

32 efficacy. A large survey from Japan showed no significant differences in outcome between medically and surgically treated patients with Moyamoya, although a more recent review revealed that 38% of 651 patients with Moyamoya who were initially treated medically ultimately underwent surgery because of progressive symptoms. 16,36 Antiplatelet agents have been used to prevent emboli from micro thrombi formed at sites of arterial stenosis a possible cause of ischemic symptoms in patients with Moyamoya and these agents, although not used universally, are used routinely in patients in many operative series. 97 Anticoagulants such as warfarin are rarely used, although there has been some experience with low-molecularweight heparin. 4,95 Calcium-channel blockers may be useful in ameliorating intractable headaches or migraines, which are commonly seen in patients with Moyamoya, and these agents may be effective in reducing both the frequency and the severity of refractory TIA. Because calcium channel blockers may cause hypotension, they must be used with caution in this patient population. Neuropsychological assessment: Moyamoya disease leads to a drastic decline in neurocognitive functions indicating a role for early surgery to save the intellectual abilities of patients. 118 Hence a preoperative neuropsychological assessment can be added to initial evaluation Moyamoya disease: functional and neurocognitive outcomes in the paediatric and adult populations

33 Endovascular therapy: Angioplasty and/or stenting have been proposed as an alternative treatment for Moyamoya Disease. However, reported failure of these endovascular techniques suggests surgical revascularization is the preferred procedure. In rare cases when initial surgical revascularization is ineffective, repeat revascularization may achieve excellent outcomes. 54,88 Rehabilitation: Rehabilitation with physical therapy, occupational therapy, and speech therapy should be considered, depending on the neurologic impairment. The extent of therapy can range from bedside treatment too full, comprehensive inpatient rehabilitation. The latter would include physical, occupational, speech, and cognitive therapy. 27

34 RESULTS Demographic data: A total of 22 patients were included in the study who underwent cerebral revascularisation procedure over a period of eleven years. There were 13 paediatric and 9 adult patients in the cohort (Fig 1). The mean age at onset of symptoms for the paediatric patients was 3.24± years and 32 ± years for adults. Age distribution showed a bimodal peak in the first decade and in the Mid-40s range. (Fig2) Out of these 22, there were 12 females and 10 male patients. (Fig 3). The male to female sex ratio was 5:4 in adults and a 5:8 in paediatric age group. None of the patients in this cohort had a positive family history. Associated medical conditions which could probably be responsible for a Moyamoya syndrome were seen in 2 patients who had Downs syndrome (Fig 4). The secondary conditions included hypertension, which was present in one adult. 28

35 Fig 1. Age Distribution Adult 41 % [ CATEGORY NAME ] [ PERCENTAGE ] Adult Pediatric Fig Age distribution. Nu 12 m be 10 r of 8 pa tie 6 nts 4 No. of patients to to to to and above Age in years 29

36 Fig 3. Gender distribution Female 54% Male 46% male female Fig 4. Distribution of syndromic vs non syndromic moyamoya 2 20 Syndromic Non syndromic 30

37 Presentation: The presenting complaint in adults was predominantly ischemia in 7(77%) and haemorrhage in 2 (22.2%). All 13 paediatric patients presented with ischemic events as the primary symptomatology (Fig 5). This indicated a higher prevalence of ischemic symptoms in the paediatric age group. In the adult subgroup, 4 (44.44%) patients presented with TIA (transient ischemic attack),2 (22.22%) with minor stroke and 3(33.33%) with major stroke. In the paediatric subgroup, 6(46.15%) presented with major stroke, 5(38.46%) patients presented with TIA,2(15.38%) with minor and (Fig 6). Out of all patients, 19 (86.36%) patients presented with multiple episodes and of these 18/19(94.73%) patients had bilateral involvement. Fig 5. Presentation adult Peaditric Ischemic hemorraghic I 31

38 Fig 6. Events adult pediatric TIA Minor stroke major stroke Side of involvement: Even though the symptoms in some might have been unihemispheric as the time of admission, 19 (86.3%) had bilateral involvement and 3 (13.6%) patients had a unilateral involvement (Table 1) (Fig 7). The paediatric group had a higher proportion of bilaterally, but was statistically non-significant (P 0.54) (fisher extract test) as compared to adult group at the time of diagnosis. Table 1. Side of involvement Adult Paediatric Unilateral 2(22.2%) 1(7.6%) Bilateral 7(77.7%) 12(92.3 %) 32

39 Fig 7 Adult hemispheric distribution Paediatric hemispheric distribution 2 unilateral 1 unilateral 7 bilateral 12 bilateral Pre-operative functional status: The preoperative mean MRS was 2±1.73 in adult and 2.15±1.34 in paediatric group. (Fig 8) shows the distribution of patients across mrs scores with 9 (40%) patients having poor mrs outcome score pre-operatively. The Mean NIHSS score was 3.56±4.25 in adult and 3.54±2.82 in paediatric group at the time of admission. Regarding motor deficits, 6 (66%) patients in adult subgroup and 10 (76.9%) patients in the paediatric subgroup presented with some form of weakness preoperatively. Cognitive decline is a commonly associated phenomenon with Moyamoya disease. In this cohort, no adult patients presented with clinically observable gross cognitive decline, whereas it was present in 3(23%) patient of the 33

40 paediatric group. However, a formal neuropsychiatric evaluation was not done in any subgroup. Fig 8. mrs distribution 6 No 5 of pat4 ien 3 ts mrs score 1 0 Pre-operative Imaging data: Pre-operative imaging evaluation in adult and paediatric patients was distributed as follows. Table 2. Pre-operative imaging distribution. Imaging Adult Paediatric MRA 6(66/66%) 12(92.3%) CT Angiography 5(55.55%) DSA 8(88.88%) 12(92.3%) 34

41 Even though the study did not have a policy for angiography, it was done whenever possible during pre-operative evaluation. DSA was done to assess the stage of the disease and to decide on operative approach. At presentation the Suzuki stage was 4 on an average in adults 4 (44.44%) and as well as paediatric age group - 7 (53.8%) (Fig 9) on digital subtraction angiography. Preoperative perfusion studies were done whenever doubt regarding symptomatic side was present. Using MRI perfusion studies CVR was calculated and preoperative CVR was reduced in 4 out of 5 adults and in 1 paediatric patients. Ag e Fig 9. Scatter plot of Suzuki stage of Moyamoya with age. Suzuki stage Suzuki stage 35

42 Fig 10: Shows the narrowing of the supraclinoid ICA and stenosis of Foetal PCA along with basal collaterals. Fig 11: Shows collaterals near the posterior circulation on vertebral artery injection of contrast with narrowing of the PCA and basilar tip. 36

43 Type of surgery: A total of 8 adults and 1 paediatric patients underwent Direct vascularization (Table 3) (Fig 12,13) which consisted of ST MC bypass. One adult of the direct revascularization group underwent a combined STMC bypass along with EDAMS. One adult and 12 paediatric patients underwent indirect vascularization. The indirect procedures included EDAMS and EDAS. Also, one adult patient had a smaller superficial temporal artery which was inadequate for anastomosis and was taken up for an indirect procedure. Indirect procedures were chosen mainly for paediatric age group or when the anatomy was unfavourable for STMC bypass. Table 3. Type of revascularization Adult Paediatric Stmc bypass 7(77.77%) 1(7.6%) Combined procedure 1(11.11%) - Indirect revascularization 1(11.11%) 12(92.3) Types of Revascularization in Adults STMC bypass combined Indirect revascularization Fig

44 Types of Revascularization in Peadiatric group 1 12 STMC bypass Indirect revascularization Fig 13. A total of 30 hemispheres underwent surgical procedures in these 22 patients. (Table 4) In the adult subgroup 2(2.22%) patients underwent bilateral procedures while 6 (46.15%) patients in the paediatric age group underwent the same. (Table 5) Type of revascularization. Adult hemispheres Paediatric hemispheres Total Stmc/combined revascularization Indirect revascularization Total Table 4: No. of hemispheres in comparison with types of revascularization. 38

45 Table 5. Side operated. Adult Paediatric Unilateral 7 7 Bilateral 2 6 Fig.14: Intraoperative- Direct anastomosis between STA and M4 cortical branch 39

46 Fig 15: Intraoperative: Isolation of STA in a case of indirect anastomosis Follow up: Mean duration of follow up was 48± months in adults (1-121 months) and 58.62±37.86 months in paediatric patients (9-122months) (Fig 16) Peri operative period: Peri procedurally new events were recorded in 1 paediatric and 2 adult patients. One child had a major stroke peri procedurally. One adult patient suffered from haemorrhage post operatively at day 30 due to platelet dysfunction while one had mild dysarthria at 1-month interval which had gradually improved. (Table 6) Local wound complications: This cohort had 4 paediatric patients wound related complications. All of them were related to scalp ischemia and necrosis which necessitated bone flap removal followed by a skin flap cover (4/22). One paediatric 40

47 patient presented with subdural hygroma which was managed conservatively. One adult had scalp hematoma post ST-MC bypass who later on had an haemorrhagic transformation of infarct necessitating the removal of bone flap 3 month events: (peri-operative events not included) (Table 7) Haemorrhagic events: No patients who presented with haemorrhage preoperatively had any further ischemic or haemorrhagic events after surgery. Ischemic events: One paediatric patient presented with a minor stroke within a 3month interval. Mortality: The only mortality in the cohort was a 60-year-old adult male who underwent direct revascularization. Post operatively he suffered from platelet dysfunction resulting in a scalp flap hematoma for which a bone flap removal was done. This patient had a fatal haemorrhagic stroke day 30 related to the same. The patient had incidentally presented with ischemic symptoms at the onset of the disease rather than haemorrhagic. 41

48 Fig 1 6. Nu 25 m 20 be r 15 of pa 10 tie nts 5 0 Distribution of follow up of patients. < 1 year <2 years <3 years <4 years <5 years >5 years follow up in years Table 6: Perioperative events Peri-operative events. Adult Paediatric Ischemic events. TIA Minor stroke Major stroke Haemorrhagic events 1 - Table 7: Three month new events. 3 month new events Adult Paediatric Ischemic events TIA Minor stroke Major stroke Haemorrhagic events

49 Long term events: (3-month data not included) When patients were evaluated up to last follow up, 7/8 adult patients and 12/13 for paediatric patients had no events. (Table 8). The 2 events included one adult who had a posterior circulation infarct at one year and one paediatric patient with Transient ischemic attack. Kaplan-Meier curve analysis was done which showed higher probability of event free survival with progress of time for both adult and paediatric patients. (Fig 17) Gross clinical cognitive condition showed stability at last follow up with decline being present only in 1/6 adult and 1/12 paediatric patients. Table 8. Event free at 3 months Adult Paediatric Number of patients. 7/8 12/13 43

50 Fig 17: Kaplan Meier curve showing probability of event free period with time (Upper line -paediatric group; Lower line -adult group) 44

51 Revascularization: Statistical analysis Analysis was done using a Paired T test. Preoperative number of ischemic events was compared with number of post-operative ischemic events across all subgroups. 1)In patients with indirect revascularization there was significant reduction in events at 3-month interval (p value 0.001) (Table 9) as compared to pre-operative events. (direct complications of surgery not included) (Peri-operative events were defined as those occurring within 30 days of surgery. Indirect revascularization Pre-operative ischemic events. 3 month ischemic events. Number of patients(n) Mean of all ischemic events (No of events/n) SD (standard deviation) Sem (standard error of means) P value Table 9. 45

52 2)Direct revascularization patients had significant reduction in events at 1-month interval as compared to pre-operative events. (p value 0.002) (Table 10) Direct revascularization. Table 10. Direct revascularization events (pre-operative) 1 month events. Number of patients(n) 9 9 Mean of all ischemic events (No of events/n) SD (standard deviation) Sem (standard error of means) P value )Adult patients had significant reduction in events at 3month interval (p value 0.002) (Table 11) as compared to pre-operative events. (peri-operative events not included) Table 11. Adult revascularization. Pre-operative events. 3 month events Number of patients(n) 8 8 Mean of all ischemic events (No of events/n) SD (standard deviation) Sem (standard error of means) P value

53 4) Paediatric patients also showed significant decrease in 3-month ischemic post op events as compared to pre-operative period. (p ) (Table 12) (peri-operative events not included). Table 12. Paediatric revascularization Pre-operative events 3 month events Number of patients(n) Mean of all ischemic events (No of events/n) SD (standard deviation) Sem (standard error of means) P value )There was significant decrease in number of events at last follow up compared to pre-operative in all patients (Table 13). All sub groups Table 13. All pre-operative ischemic events Events at last follow up Number of patients(n) Mean of all ischemic events (No of events/n) SD (standard deviation) Sem (standard error of means) P value

54 6)Analysis was done using Unpaired T test for efficacy of Direct vascularization in comparison to Indirect revascularization for events at 3 months (peri -operative events not included (Table 14). There was no statistical difference found (p value 0.11). Similarly, no difference was present even at last follow-up (p value 0.86). Hence no difference could be ascertained in the efficacy of one procedure over other. Table 14. Indirect revascularization 3 month events. Direct revascularization 3 month events. Number of patients(n) 13 8 Mean of all ischemic events (No of events/n) (Postoperative) SD (standard deviation) P value ) Similarly no statistical difference was found in comparing adult and paediatric subgroups for events at last follow up (p value 0.6) Post-operative radiology: The radiological follow-up was 2.6 years on and average in adults and 4.7 years in paediatric group. Post operatively imaging such as MRI and CT angiography was obtained (Table 15). Digital subtraction angiography was done on follow-up to study the effectiveness of 48

55 the procedure and ascertain the need for any additional revascularization or additional follow-up. Table 16. Shows the distribution of post-operative imaging across the subgroup. Table 15. Follow up imaging. Adult Paediatric DSA 2 5 CT Angiography 3 - MRI 2 3 Plain CT 1 7 Fig 18: Post-operative CT Angiographic reconstruction of a patent STMC bypass (Blue arrow) Angiographic outcome: Post-operative imaging showed the all revascularization procedures irrespective of being direct or indirect, produced patent bypass channels in 6/6(100%) adult and 5/5(100%) of paediatric patients when imaged post operatively. It also showed that there was reduction in basal collateral as compared 49

56 to pre-operative imaging in 2/6 (33%) adults and 3/5 (60 %) paediatric patients. The reduction in collaterals had no significant relation with mrs score improvement or absence of events (p value 1) (2x2 contingency table). Previous angiographic outcome studies have measured the dilation of Posterior communicating(pcom) and anterior choroidal arteries as an indicator of risk of haemorrhage in adults post-operatively. However, this could not be demonstrated in the current study. DSA revealed the pcom artery was dilated /patent in 2/3 adults and 2/4 paediatric patients. The anterior choroidal on the other hand was visualised in 2 adult patients. Matushima and Inaba grading was done for measuring extent of revascularization in all patients who underwent DSA in 7/22 (31%). Table 16 shows the classification described by Matushima. 75 It is based on percentage of MCA territory revascularization on Antero-Posterior film during external carotid injection. The outcome revealed that majority of the patients were present in grade B perfusion category. (Table 17) while 2 patients fell in grade A perfusion category indicating a positive outcome of revascularization. Grade A Grade B Grade C Table 16: Matushima and Inaba angiographic grade More than 2/3. filling of MCA territory 1/3 rd to 2/3 rd filling of MCA territory Less than 1/3 rd filling of the MCA territory 50

57 Table 17. Matushima grade Adult (2) Paediatric (5) Grade A perfusion 1 1 Grade B perfusion 1 4 Grade C perfusion Fig 19: ECA injection showing filling of the bypass in an indirect revascularization case. Follow-through of the same sequence showing more than 1/3 rd -2/3 rd filling of MCA territory (Grade B perfusion). 51