Revascularization of the Brainstem and Cerebellum (2010)

In Reply: Despite maximal medical therapy, patients with intracranial vertebrobasilar stenosis and occlusion experience significant stroke rates. In well selected patients necessitating revascularization of the posterior circulation, direct bypass revascularization or endovascular therapy has been shown to be beneficial. Rafael reports the clinical improvement in three patients with vertebrobasilar ischemic disease following revascularization with omental transplantation. In certain circumstances indirect bypass with omental transplantation may be beneficial as a last resort, but without angiographic follow-up, the theoretical benefits of posterior fossa omental grafts are difficult to support. Further work is necessary to better define the screening, diagnosis, operative patient selection, and ideal surgical revascularization procedures of patients with brainstem and cerebellar ischemia. Studies have found that patients with intracranial vertebrobasilar stenosis experience stroke rates of 4.5–15% and up to 100% in patients with bilateral steno-occlusive disease.1 Despite maximal medical therapy a number of patients will continue to suffer recurrent cerebrovascular ischemic events.2–6 Advances in bypass surgery7,8 and endovascular treatment9,10 have provided more options for definitive treatment of patients with vertebrobasilar insufficiency. Rafael reports the use of omental transplantation in the treatment of three patients with vertebrobasilar ischemic disease. This technique was first reported in revascularization studies carried out in dogs11,12 and monkeys.13 In 1977, Yonekawa and Yaşargil were the first to carry out this technique for the treatment of cerebral ischemia in humans.14 More recently, Goldsmith reported on the use of omental transplantation in the treatment of with Alzheimer's disease.15 As reported by Rafael for the treatment of brainstem and cerebellar ischemia, omental tissue can be placed directly on the cerebellum and/or on the medulla oblongata, and indirect bypass is possible through end-to-end anastomoses between the occipital vessels and the gastroepiploic vessels of the omentum. Rafael also reports this use of omental transplant in a variety of other diseases which he attributes the specific etiology of the cases to be vascular in nature: Parkinson disease,16 Huntington disease,17 Alzheimer disease,18 essential arterial hypertension,19 Type 2 diabetes mellitus,20 spinal cord injury,21,22 and epilepsy.23,24 In each case, the authors report patient clinical improvement within one day of surgery with greater neurological improvement during the first weeks after surgery than in the following months. In well selected patients necessitating revascularization of the posterior circulation, we believe that direct bypass revascularization is the best option because it provides immediate restoration of blood flow. Patients treated with indirect bypass may be at increased risk of early ischemic injury possibly as a result of delayed revascularization and collateral growth. High flow interposition grafts provide increased blood flow versus traditional direct bypass grafts.7 Although high flow grafts are technically more difficult and provide greater risks to the patient, we have found that advances in surgical applications have made high flow grafts in difficult locations more feasible.8,25–27 Further limitations of indirect bypass specific to omental transplantation are the need for a second abdominal surgery with associated risk. An omental transplant may also place pressure on the posterior fossa post-operatively leading to the theoretical risks of ischemia, edema, and/or hydrocephalus. For these reasons, we would consider the use of omental transplant only as a last resort. In other vascular arenas, the best form of bypass remains uncertain. Some consider direct STA-MCA bypass to be the optimal procedure for adult moyamoya disease patients (DJL), while others prefer indirect bypass (ESC). We have found little evidence to support the notion that there is a superior bypass technique in adults.28 As in vertebrobasilar disease, there have been no randomized trials to assess the efficacy of any single surgical treatment, and case series suffer from inadequate power, selection bias, and inherent differences in patient characteristics. Furthermore, differences in the natural history of ischemic diseases further complicates the assessment of beneficial effects of surgical intervention. Although we support the use of direct bypass as the primary modality in vertebrobasilar disease, in cranial revascularization indirect bypass has a number of distinct advantages; it may be safer, generally less complicated, performed in patients with poor recipient anastomosis vessels, and augment a greater and more specific region of cerebral perfusion without being limited to the vascular network of the recipient vessel. The EC-IC trial found that patients that received direct bypass for symptomatic ICA occlusion and MCA stenosis had a 1.2 (95% CI 1.00–1.59) and 1.6 (95% CI 1.08–2.35) fold increased risk of infarction, respectively, when compared to medically treated patients.29,30 This may be in part due to immediate flow-reversal in critical perforator bearing segments. Patients may also experience symptomatic cerebral hyperpefusion following direct bypass, although these deficits are usually transient.31,32 Indirect bypass might in theory avoid rapid flow reversal while slowly providing additional flow to distal vascular beds at risk. As we have shown in the case reported of a patient with bilateral vertebral artery occlusion, in certain circumstances, flow reversal may be a consequence and a necessity of adequate revascularization.1 Other studies have shown that pre-operative reversal of flow on MRI NOVA imaging is predictive of favorable outcome after bypass surgery in vertebrobasilar disease.33 Rafael uses an indirect, on-lay omental transposition graft. Although the author has observed improved clinical results within 24 hours of surgery, it is unclear how this form of indirect bypass results in immediate improvement and revascularization. Rafael hypothesizes that placing omentum directly upon the nervous tissue promotes the neoformation of blood vessels and, through omental neovessels the brain tissue receives an increase in blood flow, oxygen, neurotransmitters, neurotrophic factors, cytokines and omental stem cells. Rafael also further hypothesizes that in the case of brain stem and cerebellar revascularization, function of neurons and axons in the residual nervous tissue in the ischemic penumbra improve later on as a result of neuronal regeneration and neurogenesis. A number of previous authors34,35 have pointed out that this procedure has been reported by Rafael in letters to journal editors to be an excellent treatment for a wide variety of disease, without an underlying mechanism having been demonstrated.16,34–42 The clinical results observed by Rafael would be strengthened by further studies of omental tissue transplantation in animals, image confirmed alterations in local perfusion with vascular studies such as SPECT scan or angiography, post-mortem pathological investigation, and analysis of local vascular protein expression. Without angiographic follow-up, the theoretical benefits of posterior fossa omental grafts are difficult to rationalize or support. We have found that indirect bypass with pial synangiosis in adult moyamoya patients promotes adequate pial collateral development, increased perfusion, and preserved or improved functional independence.43 In contrast, we have found that indirect bypass does no induce adequate collateral vessel growth or increased perfusion in non-moyamoya patients with symptomatic intracranial athero-occlusive disease.44 Patients with atherosclerotic disease may have impaired angiogenesis secondary to reduced endothelial repair capacity. It is known, for example, that endothelial progenitor cells (EPCs), which have been characterized as (KDR+)/CD133+ cells,45 are reduced in patients with atherosclerotic risk factors and cardiovascular disease.46 Recent studies have found that patients with moyamoya disease have increased circulating EPCs and serum levels of vascular endothelial growth factor versus patients with atherosclerotic cerebrovascular disease patients and healthy controls.47 For this reason we are more skeptical of the use of indirect bypass in brainstem and cerebellar revascularization due to atherosclerosis. Despite these limitations, recent studies have found that omental stem cells showed a high rate of proliferation (Ki67 staining), expressed CD34 marker, and synthesized bFGF and VEGF. This provides some evidence that CD34+ cell population of human omentum could be responsible for the clinical benefit of omental transplantation by promoting angiogenesis and synthesizing angiogenic growth factors to facilitate revascularization of injured tissue.48 A number of researchers have noted that it is particularly difficult to judge outcome following surgery in patients with chronic ischemic vascular disease, as surgery is often a form of palliative care in a disease with poor natural history.49,50 Furthermore, studies have not used standardized outcome measures to assess patients on presentation and on long-term follow-up. Further work is necessary to better define the screening, diagnosis, operative patient selection, and ideal surgical revascularization procedures of patients with brainstem and cerebellar ischemia. Studies that incorporate vascular growth factors and stem cells with or without vascular reconstruction may provide a better means of neuroprotection and revascularization in the future. Robert M. Starke Charlottesville, Virginia Mark Chwajol Daniel Lefton Chandranath Sen E. Sander Connolly Alejandro Berenstein David J. Langer New York, New York