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Advanced Neurology Targets and medications for AVM of CNS

BAVMs have an incidence of 1.3/100,000 patient- widely recognized that angiogenesis plays a key role in
years, while the incidence of SAVMs has been reported to AVM pathogenesis.
be 1/10 that of BAVMs . These lesions are a significant The process of angiogenesis is regulated by pro- and
[5]
th
cause of hemorrhagic stroke in young patients. Natural antiangiogenic factors, and an imbalance between them
history studies have shown that the annual hemorrhagic would drive the sprouting of endothelial cells and newly
rate of an unselected BAVM cohort is 1%–4% and formed vasculature [20,21] . Compelling studies have indicated
approximately 5% for patients with a rupture history [6-11] . that vascular endothelial growth factor (VEGF) is a vital
Considering that BAVMs are commonly observed in and essential pro-angiogenic molecule that stimulates
young patients aged 20 – 40 years, patients with BAVMs and regulates angiogenesis. The previous investigations
may harbor a significantly higher mortality risk than have shown that patients with BAVMs have higher plasma
healthy populations . Compared to BAVMs, SAVMs are VEGF levels and significantly elevated expression of VEGF
[12]
characterized by a greater clinical risk . They usually and VEGF receptors [22-24] . A series of animal model-based
[13]
lead to neurological deficits, resulting from hemorrhage studies have confirmed that the elevation of VEGF is a
and venous hypertension of the spinal cord. The average prerequisite for AVM formation and the inhibition of this
age of onset of SAVM is 25 years, and its pre-treatment pathway can restrict AVM occurrence [22-26] . Therefore, the
annual neurological deficit deterioration rate is over VEGF signaling pathway is expected to be a promising
30% . The largest cohort study has shown that the target for AVM pharmacotherapy.
[13]
annual hemorrhagic rate is 10% and the cumulative
spinal hemorrhagic rate 4 years after the initial onset of Bevacizumab, a humanized monoclonal VEGF
symptoms is 32% . antibody, has been shown to effectively restrict tumor
[13]
growth through its antiangiogenic effect. It was approved
Several interventional approaches, including by the Food and Drug Administration (FDA) for the
microsurgery, endovascular embolization, and stereotactic treatment of several solid cancers [27,28] . The preliminary
radiotherapy, are used alone or in combination to clinical outcomes of patients with HHT who are treated
obliterate AVM lesions. However, due to their complex with bevacizumab are seemingly promising [29,30] . Published
angioarchitecture and their close anatomical relationship Phase 1 and Phase 2 clinical trials of bevacizumab did
with brain or spinal cord tissue, the outcomes of current not show any convincing anti-epistaxis effect in HHT
treatment strategies are unsatisfactory. It has been patients [31,32] . In another study conducted by Olsen et al.,
indicated that the complete obliteration rate in published bevacizumab significantly reduced cardiac output and
BAVM cases was <50%, with a permanent treatment- relieved heart failure in HHT patients with liver AVMs .
[33]
related neurological deficit rate of 4 – 7% [14,15] . The invasive In addition, preclinical studies have shown that this drug
interventions for SAVMs are even more challenging; the could reduce the number of dysplastic vessels, as indicated
permanent treatment-related clinical deterioration rate by a 54% reduction in the dysplasia index in a HHT-based
reported in literature varies between 4% and 25% [13,16,17] , BAVM mouse model . Pazopanib (Votrient), another
[34]
and <40% of patients can be cured. In addition, prospective VEGF inhibitor, shows a convincing anti-epistaxis effect in
clinical trials, such as a randomized trial of unruptured HHT patients . Table 1 shows the different clinical studies
[35]
BAVMs (ARUBA), have shown that interventional of bevacizumab and pazopanib according to timeline.
therapy increases the risk of stroke or death in patients
with unruptured BAVMs . The lack of pharmacotherapy The above favorable results have prompted the
[6]
for AVMs represents a compelling unmet clinical need investigation of the use of bevacizumab to reduce the
and has thus prompted a series of laboratory-based and risk of hemorrhage in CNS AVMs. However, a recently
clinical investigations in the past two decades. The aim of published proof-of-concept pilot study of bevacizumab in
[36]
this review is to summarize the potential pharmacotherapy BAVMs has shown a negative result . As the first clinical
targets and their clinical outcomes in the treatment of investigation to evaluate bevacizumab as a treatment
AVMs of the central nervous system. for sporadic BAVMs, the study recruited two patients
with large (Spetzler‒Martin Grade IV/V) brain AVMs
2. Targets and medications who denied a history of intracranial hemorrhage (ICH).
The participants received 5 mg/kg of bevacizumab every
2.1. Angiogenesis 2 weeks for 12 weeks; however, the AVM volumes observed
Although the detailed molecular pathobiology of AVM 26 and 52 weeks after the treatment did not change
formation and progression is unclear, the growth and compared to the baseline. Although the symptoms were
enlargement of AVM lesions are inevitably associated stable and the patients’ serum VEGF levels reduced, the
with the proliferation of vessels [18,19] . Therefore, it has been results were still discouraging.

Volume 1 Issue 3 (2022) 2 https://doi.org/10.36922/an.v1i3.211