Cerebellar Arteriovenous Malformation Grading

Cerebellar Arteriovenous Malformation Grading

Anatomic diversity among cerebellar arteriovenous malformations (AVMs) calls for a classification that is intuitive and surgically informative. Selection tools like the Spetzler-Martin grading system are designed to work best with cerebral AVMs but have shortcomings with cerebellar AVMs 1)

The objective of a study from the Department of Neurosurgery, University of California, San FranciscoBanner-University Medical Center TucsonArizona and Barrow Neurological Institute, Phoenix, was to evaluate the existing Spetzler-Martin AVM grading system (SM), Spetzler Ponce classification (SP), and Lawton-Young Grading System (LY) for cerebellar arteriovenous malformations (AVMs) and to propose a new grading system to estimate the risks associated with these lesions.

Data for patients with cerebellar AVMs treated microsurgically in two tertiary medical centers were retrospectively reviewed. Data from patients at institution 1 were collected from September 1999 to February 2013, and at institution 2 from October 2008 to October 2015. Patient outcomes were classified as favorable (modified Rankin Scale [mRS] score 0-2) or poor (mRS score 3-6) at the time of discharge. Using chi-square and logistic regression analysis, variables associated with poor outcomes were assigned risk points to design the proposed grading system. The proposed system included neurological status prior to treatment (poor, +2 points), emergency surgery (+1 point), age > 60 years (+1 point), and deep venous drainage (deep, +1 point). Risk point totals of 0-1 comprised grade 1, 2-3 grade 2, and 4-5 grade 3.

A total of 125 cerebellar AVMs of 1328 brain AVMs were reviewed in 125 patients, 120 of which were treated microsurgically and included in the study. With our proposed grading system, we found poor outcomes differed significantly between each grade (p < 0.001), while with the SM, SP, and LY grading systems they did not (p = 0.22, p = 0.25, and p = 1, respectively). Logistic regression revealed grade 2 had 3.3 times the risk of experiencing a poor outcome (p = 0.008), while grade 3 had 9.9 times the risk (p < 0.001). The proposed grading system demonstrated a superior level of predictive accuracy (area under the receiver operating characteristic curve [AUROC] of 0.72) compared with the SM, SP, and LY grading systems (AUROC of 0.61, 0.57, and 0.51, respectively).

Nisson et al., propose a novel grading system for cerebellar AVMs based on emergency surgery, venous drainage, preoperative neurological status, and age that provides a superior prognostication power than the formerly proposed SM, SP, and LY grading systems. This grading system is clinically predictive of patient outcomes and can be used to better guide vascular neurosurgeons in clinical decision-making 2).


Rodriguez-Hernandez et al. hypothesized that the predictive capability of the supplementary grading scale was superior to that of the Spetzler Martin grading scale for assessment of outcomes following microsurgical resection of cerebellar AVMs 3).

Deep venous drainage is a better indicator of the depth of the nidus for cerebral AVMs than for cerebellar AVMs. Cerebellar anatomy is altered by AVMs in a different manner than cerebral anatomy such that the supplementary grading scale may be better than the Spetzler-Martin grade for prediction of surgical outcomes. In comparison with ruptured cerebral AVMs, which may be managed conservatively followed by radiosurgery for achievement of obliteration, ruptured cerebellar AVMs may be better treated by surgical resection, especially when the associated hemorrhage results in symptomatic compression of surrounding neural structures.

In conclusion, the surgical risk for cerebellar AVMs may be predicted by either the Spetzler-Martin or supplementary grading scales, although the supplementary scale may show better correlation with outcomes 4) 5) 6). However, neither grading system can substitute for experienced clinical and surgical judgment 7).

References

1) , 3) , 5)

Rodríguez-Hernández A, Kim H, Pourmohamad T, Young WL, Lawton MT. University of California, San Francisco Arteriovenous Malformation Study Project. Cerebellar arteriovenous malformations: Anatomic subtypes, surgical results, and increased predictive accuracy of the supplementary grading system. Neurosurgery. 2012 Dec;71(6):1111–1124.
2)

Nisson PL, Fard SA, Walter CM, Johnstone CM, Mooney MA, Tayebi Meybodi A, Lang M, Kim H, Jahnke H, Roe DJ, Dumont TM, Lemole GM, Spetzler RF, Lawton MT. A novel proposed grading system for cerebellar arteriovenous malformations. J Neurosurg. 2019 Mar 8:1-11. doi: 10.3171/2018.12.JNS181677. [Epub ahead of print] PubMed PMID: 30849761.
4)

Lawton MT, Kim H, McCulloch CE, Mikhak B, Young WL. A supplementary grading scale for selecting patients with brain arteriovenous malformations for surgery. Neurosurgery. 2010 Apr;66(4):702–713. discussion 713.
6)

Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986 Oct;65(4):476–483.
7)

Ding D, Liu KC. Predictive Capability of the Spetzler-Martin versus Supplementary Grading Scale for Microsurgical Outcomes of Cerebellar Arteriovenous Malformations. J Cerebrovasc Endovasc Neurosurg. 2013 Dec;15(4):307-10. doi: 10.7461/jcen.2013.15.4.307. Epub 2013 Dec 31. PubMed PMID: 24729957; PubMed Central PMCID: PMC3983531.

Cerebral arteriovenous malformation epidemiology

Cerebral arteriovenous malformation epidemiology

There has been increased detection of incidental Cerebral arteriovenous malformations (CAVM)s as result of the frequent use of advanced imaging techniques 1).

Common estimates of the prevalence rate vary widely, and their accuracy is questionable and are unfounded.

The prevalence of cerebral arteriovenous malformation (CAVM) in first-degree relatives (FDRs) of patients with a CAVM was increased but did not meet a prespecified criterion for a shared familial risk factor. In combination with the low absolute risk of a CAVM in FDRs, the results do not support screening of FDRs for CAVMs 2).

Since the most severe complication of an AVM is hemorrhagic stroke, most epidemiologic studies have concentrated on the hemorrhage risk and its risk factors 3).

Because of the rarity of the disease and the existence of asymptomatic patients, establishing a true prevalence rate is not feasible. Owing to variation in the detection rate of asymptomatic AVMs, the most reliable estimate for the occurrence of the disease is the detection rate for symptomatic lesions: 0.94 per 100,000 person-years (95% confidence interval, 0.57-1.30/100,000 person-years). This figure is derived from a single population-based study, but it is supported by a reanalysis of other data sources. The prevalence of detected, active (at risk) AVM disease is unknown, but it can be inferred from incidence data to be lower than 10.3 per 100,000 population. 4).

AVMs account for between 1 and 2% of all strokes, 3% of strokes in young adults, 9% of subarachnoid haemorrhages and, of all primary intracerebral haemorrhages, they are responsible for 4% overall, but for as much as one-third in young adults. AVMs are far less common causes of first presentations with unprovoked seizures (1%), and of people presenting with headaches in the absence of neurological signs (0.3%). At the time of detection, at least 15% of people affected by AVMs are asymptomatic, about one-fifth present with seizures and for approximately two-thirds of them the dominant mode of presentation is with intracranial haemorrhage. The limited high quality data available on prognosis suggest that long-term crude annual case fatality is 1-1.5%, the crude annual risk of first occurrence of haemorrhage from an unruptured AVM is approximately 2%, but the risk of recurrent haemorrhage may be as high as 18% in the first year, with uncertainty about the risk thereafter. For untreated AVMs, the annual risk of developing de novo seizures is 1%. There is a pressing need for large, prospective studies of the frequency and clinical course of AVMs in well-defined, stable populations, taking account of their prognostic heterogeneity 5).

According to reports, 0.1% of the population harbors an AVM 6) 7).

Both sexes are affected equally. AVMs are the leading cause of nontraumatic intracerebral hemorrhage in people less than 35 years old 8).

Most lesions reach attention in patients in their 40’s and 75% of the hemorrhagic presentations occur before the age of 50 years 9)

According to autopsy studies, only 12% of AVMs become symptomatic during life 10).


They are the most frequently encountered structural cause of spontaneous intracerebral hemorrhage in childhood, excluding hemorrhages of prematurity.

AVMs are seen more frequently on MRI with advancing age in children and young adults 11).

References

1) Ajiboye N, Chalouhi N, Starke RM, Zanaty M, Bell R. Cerebral arteriovenous malformations: evaluation and management. ScientificWorldJournal. 2014;2014:649036. doi: 10.1155/2014/649036. Epub 2014 Oct 15. Review. PubMed PMID: 25386610; PubMed Central PMCID: PMC4216697. 2) van Beijnum J, van der Worp HB, Algra A, Vandertop WP, van den Berg R, Brouwer PA, van der Sprenkel JW, Kappelle LJ, Rinkel GJ, Klijn CJ. Prevalence of brain arteriovenous malformations in first-degree relatives of patients with a brain arteriovenous malformation. Stroke. 2014 Nov;45(11):3231-5. doi: 10.1161/STROKEAHA.114.005442. Epub 2014 Sep 18. PubMed PMID: 25236872. 3) Laakso A, Hernesniemi J. Arteriovenous malformations: epidemiology and clinical presentation. Neurosurg Clin N Am. 2012 Jan;23(1):1-6. doi: 10.1016/j.nec.2011.09.012. Review. PubMed PMID: 22107853. 4) Berman MF, Sciacca RR, Pile-Spellman J, Stapf C, Connolly ES Jr, Mohr JP, Young WL. The epidemiology of brain arteriovenous malformations. Neurosurgery. 2000 Aug;47(2):389-96; discussion 397. Review. PubMed PMID: 10942012. 5) Al-Shahi R, Warlow C. A systematic review of the frequency and prognosis of arteriovenous malformations of the brain in adults. Brain. 2001 Oct;124(Pt 10):1900-26. Review. PubMed PMID: 11571210. 6) , 9) Brown R. D., Jr., Wiebers D. O., Torner J. C., O’Fallon W. M. Frequency of intracranial hemorrhage as a presenting symptom and subtype analysis: a population-based study of intracranial vascular malformations in Olmsted County, Minnesota. Journal of Neurosurgery. 1996;85(1):29–32. doi: 10.3171/jns.1996.85.1.0029. 7) The Arteriovenous Malformation Study Group Arteriovenous malformations of the brain in adults. The New England Journal of Medicine. 1999;340(23):1812–1818. doi: 10.1056/NEJM199906103402307. 8) Ruíz-Sandoval J. L., Cantú C., Barinagarrementeria F. Intracerebral hemorrhage in young people: analysis of risk factors, location, causes, and prognosis. Stroke. 1999;30(3):537–541. doi: 10.1161/01.STR.30.3.537. 10) McCormick W. E. Classification, pathology and natural history of angiomas of the central nervous system. Weekly Update: Neurology and Neurosurgery. 1978;14:2–7. 11) O’Lynnger TM, Al-Holou WN, Gemmete JJ, Pandey AS, Thompson BG, Garton HJ, Maher CO. The effect of age on arteriovenous malformations in children and young adults undergoing magnetic resonance imaging. Childs Nerv Syst. 2011 Aug;27(8):1273-9. doi: 10.1007/s00381-011-1434-9. Epub 2011 Mar 26. PubMed PMID: 21442267.

Update: Cerebral cavernous malformation pathogenesis

Cerebral cavernous malformation pathogenesis

Genes mutated in cerebral cavernous malformation (CCM) encode proteins that modulate junction formation between vascular endothelial cells.

Most cerebral cavernous malformations are linked to loss-of-function mutations in 1 of 3 genes, namely CCM1 (originally called KRIT1), CCM2(MGC4607), or CCM3 (PDCD10).

How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/β-catenin) and processes such as endothelial mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 1).

Although a role for these three genes in the formation of these intracranial vascular lesions has been established since the 1990s, additional works have further elucidated the molecular mechanisms by which mutations in these genes and the resultant aberrant proteins interact, leading to the formation of CCMs.

Therefore, it is reasonable to assume that a molecular pathway exists that requires all three proteins to function together correctly for proper cellular function. Moreover, research is demonstrating how each component protein is capable of interacting with numerous other signaling and cytoskeletal molecules allowing for a diverse range of functions in molecular signaling pathways via unique protein–protein interactions.

Significant research findings from 2000 to 2015 have further enhanced our understanding of the pathogenesis of CCM formation. The use of advanced sequencing technologies to characterize genomic mutations and the identification of new signaling pathways and protein–protein interactions have led to great strides in understanding the molecular genetics involved in the development of CCMs. However, many unanswered questions remain, and future studies are clearly needed to improve our understanding of CCM pathogenesis. “Gene to protein to disease” mechanisms involved in the pathogenesis of CCMs should shed further light on potential therapeutic targets. 2).

The Phosphoinositide 3 kinase (PI3K)/Akt pathway is known to play a major role in angiogenesis. Studies have shown that the phosphatase and tensin homologue deleted on chromosome ten (PTEN), a tumor suppressor, is an antagonist regulator of the PI3K/Akt pathway and mediates angiogenesis by activating vascular endothelial growth factor (VEGF) expression.

Understanding the biology of these proteins with respect to their signaling counterpart will help to guide future research towards new therapeutic targets applicable for CCM treatment 3).


Studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics 4).

CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified.


Tang et al. identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of cerebral cavernous malformationformation. Activation of TLR4 by Gram negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment 5).


In this scenario, the lack of effective pharmacologic options remains a critical barrier that poses an unfulfilled and urgent medical need 6).

References

1) , 4)

Zhou Z, Tang AT, Wong WY, Bamezai S, Goddard LM, Shenkar R, Zhou S, Yang J, Wright AC, Foley M, Arthur JS, Whitehead KJ, Awad IA, Li DY, Zheng X, Kahn ML. Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature. 2016 Apr 7;532(7597):122-6. doi: 10.1038/nature17178. Epub 2016 Mar 30. Erratum in: Nature. 2016 May 25;536(7617):488. PubMed PMID: 27027284; PubMed Central PMCID: PMC4864035.
2)

Baranoski JF, Kalani MY, Przybylowski CJ, Zabramski JM. Cerebral Cavernous Malformations: Review of the Genetic and Protein-Protein Interactions Resulting in Disease Pathogenesis. Front Surg. 2016 Nov 14;3:60. Review. PubMed PMID: 27896269.
3)

Kar S, Samii A, Bertalanffy H. PTEN/PI3K/Akt/VEGF signaling and the cross talk to KRIT1, CCM2, and PDCD10 proteins in cerebral cavernous malformations. Neurosurg Rev. 2015 Apr;38(2):229-36; discussion 236-7. doi: 10.1007/s10143-014-0597-8. Epub 2014 Nov 19. PubMed PMID: 25403688.
5)

Tang AT, Choi JP, Kotzin JJ, Yang Y, Hong CC, Hobson N, Girard R, Zeineddine HA, Lightle R, Moore T, Cao Y, Shenkar R, Chen M, Mericko P, Yang J, Li L, Tanes C, Kobuley D, Võsa U, Whitehead KJ, Li DY, Franke L, Hart B, Schwaninger M, Henao-Mejia J, Morrison L, Kim H, Awad IA, Zheng X, Kahn ML. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature. 2017 May 10. doi: 10.1038/nature22075. [Epub ahead of print] PubMed PMID: 28489816.
6)

Chohan MO, Marchiò S, Morrison LA, Sidman RL, Cavenee WK, Dejana E, Yonas H, Pasqualini R, Arap W. Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease: A Review. JAMA Neurol. 2018 Nov 26. doi: 10.1001/jamaneurol.2018.3634. [Epub ahead of print] PubMed PMID: 30476961.
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