Cerebral cavernous malformation treatment

Cerebral cavernous malformation treatment

Ren et al. demonstrated that cerebral cavernous malformation (CCM) growth requires increased PI3K/AKT/mTOR pathway and loss of CCM protein function. They identified PIK3CA gain of function (GOF) and CCM loss of function (LOF) somatic mutations in the same cells in a majority of human CCMs. Using mouse models, they showed that CCM growth requires both PI3K GOF and CCM LOF in endothelial cells, and that both CCM LOF and increased expression of the transcription factor KLF4, a downstream MEKK3 effector, augment mTOR signalling in endothelial cells. Consistent with these findings, the mTORC1 inhibitor Rapamycin effectively blocks CCM formation in mouse models. They established a three-hit mechanism analogous to cancer in which aggressive vascular malformations arise through the loss of vascular “suppressor genes” that constrain vessel growth and gain of a vascular “oncogene” that stimulates excess vessel growth. These findings suggest that aggressive CCMs may be treated using clinically approved mTORC1 inhibitors 1).

see Intracranial cavernous malformation surgery.


There have been few comparative studys of microsurgical excision vs conservative treatment of cerebral cavernous malformations (CCM) and none of them has reliably demonstrated a statistically and clinically significant difference.

A prospective, population-based study to identify and independently validate definite cerebral cavernous malformation diagnoses first made in 1999-2003 in Scottish adult residents, used multiple sources of prospective follow-up to assess adults’ dependence and to identify and independently validate outcome events.

Moultrie et al., used univariate and multivariable survival analyses to test the influence of CCM excision on outcome, adjusted for prognostic factors and baseline imbalances.

Of 134 adults, 25 underwent CCM excision; these adults were younger (34 vs 43 years at diagnosis, p = 0.004) and more likely to present with symptomatic intracranial hemorrhage or focal neurological deficit than adults managed conservatively (48% vs 26%; odds ratio 2.7, 95% confidence interval [CI] 1.1-6.5). During 5 years of follow-up, CCM excision was associated with a deterioration to an Oxford Handicap Scale score 2-6 sustained over at least 2 successive years (adjusted hazard ratio [HR] 2.2, 95% CI 1.1-4.3) and the occurrence of symptomatic intracranial hemorrhage or new focal neurologic deficit (adjusted HR 3.6, 95% CI 1.3-10.0).

CCM excision was associated with worse outcomes over 5 years compared to conservative management. Long-term follow-up will determine whether this difference is sustained over patients’ lifetimes. Meanwhile, a randomized controlled trial appears justified.

CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CCM excision worsens short-term disability scores and increases the risk of symptomatic intracranial hemorrhage and new focal neurologic deficits 2).


Antithrombotic therapy use is associated with a lower risk of intracranial haemorrhage or focal neurological deficit from cerebral cavernous malformations than avoidance of antithrombotic therapy. These findings provide reassurance about safety for clinical practice and require further investigation in a randomised controlled trial 3).


1)

Ren AA, Snellings DA, Su YS, Hong CC, Castro M, Tang AT, Detter MR, Hobson N, Girard R, Romanos S, Lightle R, Moore T, Shenkar R, Benavides C, Beaman MM, Mueller-Fielitz H, Chen M, Mericko P, Yang J, Sung DC, Lawton MT, Ruppert M, Schwaninger M, Körbelin J, Potente M, Awad IA, Marchuk DA, Kahn ML. PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism. Nature. 2021 Apr 28. doi: 10.1038/s41586-021-03562-8. Epub ahead of print. PMID: 33910229.
2)

Moultrie F, Horne MA, Josephson CB, Hall JM, Counsell CE, Bhattacharya JJ, Papanastassiou V, Sellar RJ, Warlow CP, Murray GD, Al-Shahi Salman R; Scottish Audit of Intracranial Vascular Malformations (SAIVMs) steering committee and collaborators. Outcome after surgical or conservative management of cerebral cavernous malformations. Neurology. 2014 Aug 12;83(7):582-9. doi: 10.1212/WNL.0000000000000684. Epub 2014 Jul 3. PubMed PMID: 24994841.
3)

Zuurbier SM, Hickman CR, Tolias CS, Rinkel LA, Leyrer R, Flemming KD, Bervini D, Lanzino G, Wityk RJ, Schneble HM, Sure U, Al-Shahi Salman R; Scottish Audit of Intracranial Vascular Malformations Steering Committee. Long-term antithrombotic therapy and risk of intracranial haemorrhage from cerebral cavernous malformations: a population-based cohort study, systematic review, and meta-analysis. Lancet Neurol. 2019 Aug 6. pii: S1474-4422(19)30231-5. doi: 10.1016/S1474-4422(19)30231-5. [Epub ahead of print] PubMed PMID: 31401075.

Cerebral arteriovenous malformation (AVM)

Cerebral arteriovenous malformation (AVM)

Intracranial arteriovenous malformation in the brain.

see Cerebral arteriovenous malformation epidemiology.

see Arteriovenous malformation associated aneurysm

Cerebral microarteriovenous malformation

Parafalcine arteriovenous malformation,….

Ruptured cerebral arteriovenous malformation

Unruptured cerebral arteriovenous malformation

AVMs that occur in the coverings of the brain are called dural arteriovenous malformation.

Deep arteriovenous malformation.

Motor area arteriovenous malformation.

Pediatric Cerebral arteriovenous malformation.

Cerebral Arteriovenous Malformation Grading.

Cerebral arteriovenous malformation pathophysiology

Cerebral Arteriovenous Malformation Clinical Features.

Primary lobar hemorrhages (usually due to cerebral amyloid angiopathy) are typically seen in elderly. Younger patients may also develop lobar haemorrhages, but in such cases they usually have an underlying lesion (e.g. cerebral arteriovenous malformation).

see Cerebral arteriovenous malformation treatment.

Cerebral arteriovenous malformation outcome.

Cerebral arteriovenous malformation case series.

Quantitative electroencephalography for delayed cerebral ischemia diagnosis

Quantitative electroencephalography for delayed cerebral ischemia diagnosis

The association between alpha-delta ratio (ADR) on quantitative electroencephalography (EEG) and DCI has been reported in several previous studies, but their results are conflicting 1).


Focal reduction in alpha power may represent a valid, observer-independent, non-invasive and continuous marker for vasospasm/DCI in SAH patients 2).

A prolonged alpha-theta/delta (AT/D) ratio decrease seems to be a reliable biomarker of DCI 3).


In a study, Mueller et al. aimed to compare and analyze the ability of qEEG and transcranial color-coded duplex ultrasonography (TCD/TCCS) to early identify patients who will develop later manifest cerebral infarction.

They analyzed cohorts of two previous qEEG studies. Continuous six-channel-EEG with artifact rejection and a detrending procedure was applied. Alpha power decline of ≥ 40% for ≥ 5 hours compared to a 6-hour-baseline was defined as a significant EEG event. Median reduction and duration of alpha power decrease in each channel were determined. Vasospasm was diagnosed by TCD/TCCS, identifying the maximum frequency and days of vasospasm in each territory.

34 patients were included (17 male, mean age 56 ± 11 years, Hunt and Hess grade: I-V, cerebral infarction: 9). Maximum frequencies in TCD/TCCS and alpha power reduction in qEEG were correlated (r = 0.43; p = 0.015). Patients with and without infarction significantly differed in qEEG parameters (maximum alpha power decrease: 78% vs 64%, p = 0.019; summed hours of alpha power decline: 236 hours vs 39 hours, p = 0.006) but showed no significant differences in TCD/TCCS parameters.

There was a moderate correlation between TCD/TCCS frequencies and qEEG alpha power reduction but only qEEG differentiated between patients with and without cerebral infarction.

Significance: qEEG represents a non-invasive, continuous tool to identify patients at risk of cerebral infarction 4).


1)

Yu Z, Wen D, Zheng J, Guo R, Li H, You C, Ma L. The predictive accuracy of alpha-delta ratio on quantitative electroencephalography for delayed cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage: a meta-analysis. World Neurosurg. 2019 Feb 27. pii: S1878-8750(19)30493-0. doi: 10.1016/j.wneu.2019.02.082. [Epub ahead of print] PubMed PMID: 30825635.
2)

Gollwitzer S, Groemer T, Rampp S, Hagge M, Olmes D, Huttner HB, Schwab S, Madžar D, Hopfengaertner R, Hamer HM. Early prediction of delayed cerebral ischemia in subarachnoid hemorrhage based on quantitative EEG: A prospective study in adults. Clin Neurophysiol. 2015 Aug;126(8):1514-23. doi: 10.1016/j.clinph.2014.10.215. Epub 2014 Nov 14. PMID: 25500193.
3)

Balança B, Dailler F, Boulogne S, Ritzenthaler T, Gobert F, Rheims S, Andre-Obadia N. Diagnostic accuracy of quantitative EEG to detect delayed cerebral ischemia after subarachnoid hemorrhage: A preliminary study. Clin Neurophysiol. 2018 Sep;129(9):1926-1936. doi: 10.1016/j.clinph.2018.06.013. Epub 2018 Jul 5. PMID: 30007892.
4)

Mueller TM, Gollwitzer S, Hopfengärtner R, Rampp S, Lang JD, Stritzelberger J, Madžar D, Reindl C, Sprügel MI, Dogan Onugoren M, Muehlen I, Kuramatsu JB, Schwab S, Huttner HB, Hamer HM. Alpha power decrease in quantitative EEG detects development of cerebral infarction after subarachnoid hemorrhage early. Clin Neurophysiol. 2021 Mar 26:S1388-2457(21)00465-X. doi: 10.1016/j.clinph.2021.03.005. Epub ahead of print. PMID: 33867261.
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