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.

Acute ischemic stroke treatment

Acute ischemic stroke treatment

In the complete absence of blood flowneuronal death occurs within 2–3 minutes from the exhaustion of energy stores. However, in most strokes, there is a salvageable penumbra (tissue at risk) that retains viability for a period of time through suboptimal perfusion from collaterals. Local cerebral edema from the stroke results in a compromise of these collaterals and progression of the ischemic penumbra to infarction if the flow is not restored and maintained. Prevention of this secondary neuronal injury drives the treatment of stroke and has led to the creation of designated Primary Stroke Centers that offer appropriate and timely triage and treatment of all potential stroke patients.

Time delays from initial CTA acquisition to neuroendovascular surgery (NES) team notification can prevent expedient treatment with endovascular thrombectomy (ET). Process improvements and automated stroke detection on imaging with automated notification of the NES team may ultimately improve the time to reperfusion 1).

American Heart Association Guidelines for the Early Management of Patients With Acute Ischemic Stroke

see Endovascular intervention for ischemic stroke treatment..

see Hypothermia for acute ischemic stroke treatment.


Brain ischemia and treatment are one of the important topics in neurological science. Free oxygen radicals and inflammation formed after ischemia are accepted as the most important causes of damage. Currently, there are studies on many chemopreventive agents to prevent cerebral ischemia damage. The aim of Aras et al is to research the preventive effect of the active ingredient in genistein There is currently no promising pharmacotherapy aside from intravenous or intra-arterial thrombolysis. Yet because of the narrow therapeutic time window involved, thrombolytic application is very restricted in clinical settings. Accumulating data suggest that non-pharmaceutical therapies for stroke might provide new opportunities for stroke treatment 2).

Progression of focal stroke symptoms still constitutes a serious clinical problem for which heparin has insufficient effectiveness in clinical practice. New therapies, ideally preventive, are needed 3).

Omega 3 fatty acid enhance cerebral angiogenesis and provide long-term protection after stroke 4).

After cerebral ischemia, revascularization in the ischemic boundary zone provides nutritive blood flow as well as various growth factors to promote the survival and activity of neurons and neural progenitor cells. Enhancement of angiogenesis and the resulting improvement of cerebral microcirculation are key restorative mechanisms and represent an important therapeutic strategy for ischemic stroke.

Improvements in acute ischemic stroke (AIS) outcomes have been achieved with intravenous thrombolytics (IVT) and intra-arterial thrombolytics vs supportive medical therapy. Given its ease of administration, noninvasiveness, and most validated efficacy, IVT is the standard of care in AIS patients without contraindications to systemic fibrinolysis. However, patients with large-vessel occlusions respond poorly to IVT. Recent trials designed to select this population for randomization to IVT vs IVT with adjunctive endovascular therapy have not shown improvement in clinical outcomes with endovascular therapy. This could be due to the lack of utilization of modern thrombectomy devices such as Penumbra aspiration devices, Solitaire stent-trievers, or Trevo stent-trievers, which have shown the best recanalization results. Continued improvement in the techniques with using these devices as well as randomized controlled trials using them is warranted 5).

With the emergence of new technologies in imaging, thrombolysis and endovascular intervention, the treatment modalities of acute ischemic stroke will enter a new era 6).

Within 3 h from symptom onset, the existence of FLAIR-positive lesions on pretreatment MRI is significantly associated with an increased bleeding risk due to systemic thrombolysis. Therefore, considering FLAIR-positive lesions on baseline MRI might guide treatment decisions in ischemic stroke 7).

see Acute ischemic stroke thrombolysis

see Blood Pressure Management


1)

Yaeger KA, Rossitto CP, Marayati NF, Lara-Reyna J, Ladner T, Hardigan T, Shoirah H, Mocco J, Fifi JT. Time from image acquisition to endovascular team notification: a new target for enhancing acute stroke workflow. J Neurointerv Surg. 2021 Apr 8:neurintsurg-2021-017297. doi: 10.1136/neurintsurg-2021-017297. Epub ahead of print. PMID: 33832969.
2)

Chen F, Qi Z, Luo Y, Hinchliffe T, Ding G, Xia Y, Ji X. Non-pharmaceutical therapies for stroke: Mechanisms and clinical implications. Prog Neurobiol. 2014 Jan 6. pii: S0301-0082(13)00147-0. doi: 10.1016/j.pneurobio.2013.12.007. [Epub ahead of print] PubMed PMID: 24407111.
3)

Rödén-Jüllig A, Britton M. Effectiveness of heparin treatment for progressing ischaemic stroke: before and after study. J Intern Med. 2000 Oct;248(4):287-91. PubMed PMID: 11086638.
4)

Wang J, Shi Y, Zhang L, Zhang F, Hu X, Zhang W, Leak RK, Gao Y, Chen L, Chen J. Omega-3 polyunsaturated fatty acids enhance cerebral angiogenesis and provide long-term protection after stroke. Neurobiol Dis. 2014 Apr 29. pii: S0969-9961(14)00103-X. doi: 10.1016/j.nbd.2014.04.014. [Epub ahead of print] PubMed PMID: 24794156.
5)

Serrone JC, Jimenez L, Ringer AJ. The role of endovascular therapy in the treatment of acute ischemic stroke. Neurosurgery. 2014 Feb;74 Suppl 1:S133-41. doi: 10.1227/NEU.0000000000000224. PubMed PMID: 24402482.
6)

Lu AY, Ansari SA, Nyström KV, Damisah EC, Amin HP, Matouk CC, Pashankar RD,Bulsara KR. Intra-arterial treatment of acute ischemic stroke: the continued evolution. Curr Treat Options Cardiovasc Med. 2014 Feb;16(2):281. doi:10.1007/s11936-013-0281-2. PubMed PMID: 24398801.
7)

Hobohm C, Fritzsch D, Budig S, Classen J, Hoffmann KT, Michalski D. Predicting intracerebral hemorrhage by baseline magnetic resonance imaging in stroke patients undergoing systemic thrombolysis. Acta Neurol Scand. 2014 Jul 18. doi: 10.1111/ane.12272. [Epub ahead of print] PubMed PMID: 25040041.

Sinus pericranii treatment

Sinus pericranii treatment

Accepted guidelines or recommendations concerning the managementdiagnosis, and treatment of sinus pericranii are still lacking.

Angiography plays a crucial role in the classification of SP and choice of the optimal treatment. Only accessory SP is amenable to treatment, whereas dominant SP must be preserved.

Ellis et al describe a simple and unique method for determining whether intracranial venous outflow may be compromised by sinus pericranii treatment. This involves performing catheter angiography while the lesion is temporarily obliterated by external compression. Analysis of intracranial venous outflow in this setting allows visualization of angiographic changes that will occur once the sinus pericranii is permanently obliterated. Thus, the safety of surgical intervention can be more fully appraised using this technique 1).


There were notable improvements following surgical resection for the abnormal venous lesions and several sclerotherapies 2)


Intraoperative hemostasis is essential while sinus pericranii is detached from the craniumHemostatic agents such as bone wax or absorbable gelatin and heat coagulation seem to be useful. However, complicative hemorrhage concerning to the preceded technique has been also reported. To detect minor shunting points between the sinus pericranii and the intracranial veins, the major venous connection can be manually compressed. Intraoperative manual compression of a major venous connection of sinus pericranii can be an option to manage intraoperative bleeding 3).

The endovascular approach is becoming increasingly relevant and has proven to be safe and effective 4).

The surgical treatment involves the resection of the extracranial venous package and ligation of the emissary communicating vein. In some cases of SP, surgical excision is performed for cosmetic reasons. The endovascular technique has been described by transvenous approach combined with direct puncture and the recently endovascular embolization with Onyx 5).


1)

Ellis JA, Mejia Munne JC, Feldstein NA, Meyers PM. Determination of sinus pericranii resectability by external compression during angiography: technical note. J Neurosurg Pediatr. 2015 Oct 16:1-5. [Epub ahead of print] PubMed PMID: 26474103.
2)

Ryu JY, Lee JH, Lee JS, Lee JW, Lee SJ, Lee JM, Lee SY, Huh S, Kim JY, Hwang SK, Chung HY. Combined treatment of surgery and sclerotherapy for sinus pericranii. Arch Craniofac Surg. 2020 Apr;21(2):109-113. doi: 10.7181/acfs.2019.00521. Epub 2020 Apr 20. PMID: 32380811; PMCID: PMC7206457.
3)

Fujimoto Y, Ishibashi R, Maki Y, Kitagawa M, Kinosada M, Kurosaki Y, Ikeda H, Chin M. A Simple Surgical Technique for Pediatric Sinus Pericranii: Intraoperative Manual Compression of a Major Shunting Point. Pediatr Neurosurg. 2021 Mar 29:1-6. doi: 10.1159/000514478. Epub ahead of print. PMID: 33780955.
4)

Pavanello M, Melloni I, Antichi E, Severino M, Ravegnani M, Piatelli G, Cama A, Rossi A, Gandolfo C. Sinus pericranii: diagnosis and management in 21 pediatric patients. J Neurosurg Pediatr. 2015 Jan;15(1):60-70. doi: 10.3171/2014.9.PEDS13641. PubMed PMID: 25360854.
5)

Rangel-Castilla L, Krishna C, Klucznik R, Diaz O. Endovascular embolization with Onyx in the management of sinus pericranii: a case report. Neurosurg Focus. 2009 Nov;27(5):E13. doi: 10.3171/2009.8.FOCUS09170. PubMed PMID: 19877791.
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