Cerebral cavernous malformation treatment

Cerebral cavernous malformation treatment

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 1).


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 2).

References

1)

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.
2)

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.

Oral anticoagulant

Oral anticoagulant

Oral anticoagulation was first established in 1941 by Karl Paul Link, who discovered dicumarol 1).

Novel oral anticoagulants (NOAs) which directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban and apixaban) have recently been developed.

The purpose of a study was the evaluation of the reporting quality of RCTs for novel oral anticoagulants (NOACs) in venous thromboembolism (VTE) based on the CONSORT statement. MEDLINE was meticulously searched, while quoted references by retrieved RCTs were manually screened. The primary objective was to establish the mean CONSORT compliance of RCTs for NOACs in VTE. Secondary objectives were the calculation of compliance per CONSORT item and the investigation for probable determining factors with regards to the reporting quality of RCTs. Reporting above 70% of the items was defined as adequate compliance to the CONSORT statement. A total of 83 articles were considered eligible. Mean adherence to the CONSORT statement was 61.84%, standard deviation (SD) = 18.72. Among retrieved studies, 35 (42.17%) reported above 70% of the items, while 48 (57.83%) described less than 70% of the items. Inter-rater agreement was satisfactory (Cohen’s kappa ≥ 0.75). Items with respect to randomization and blinding were principally underreported, whereas the rest of the methodological features and results were more sufficiently reported. Logistic regression failed to demonstrate significant effect for any of the factors investigated. Impact factor [odds ratio (OR) = 1.347, 95% confidence interval (CI) (0.994, 1.826), p = 0.055], number of authors [OR = 1.277, 95% CI (0.975, 1.672), p = 0.076] and presentation of participant flow-diagram [OR = 55.358, 95% CI (0.914, 3351.765), p = 0.055], came closer to significance. Exploratory analysis revealed significant, strong, positive correlation between abstract and article adherence to the CONSORT guidelines (r = 0.851, p < 0.001). Reporting quality of RCTs for NOACs in VTE is moderate. A superior reporting quality is desirable, especially relating to randomization and blinding 2)

Vitamin K oral anticoagulant

Non vitamin K oral anticoagulant

Complications

Patients with minor and moderate associated bleeding can be treated with supportive care and general hemostatic measures. Nonspecific reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate) are of unproven benefit, carry a risk of thrombosis, and should be reserved for severe bleeding. Specific reversal agents, such as idarucizumab (a monoclonal antibody fragment that binds dabigatran) and andexanet alfa (a recombinant factor Xa variant that binds factor Xa inhibitors but lacks coagulant activity), are in clinical development 3).

References

1)

Campbell HA, Roberts WL, Smith WK, Link KP. Studies of the hemorrhagic sweet clover disease. I. The preparation of hemorrhagic concentrates. J Biol Chem. 1940;136:47–55.
2)

Liampas I, Chlinos A, Siokas V, Brotis A, Dardiotis E. Assessment of the reporting quality of RCTs for novel oral anticoagulants in venous thromboembolic disease based on the CONSORT statement. J Thromb Thrombolysis. 2019 Aug 10. doi: 10.1007/s11239-019-01931-9. [Epub ahead of print] Review. PubMed PMID: 31401718.
3)

Cuker A, Siegal D. Monitoring and reversal of direct oral anticoagulants. Hematology Am Soc Hematol Educ Program. 2015 Dec 5;2015(1):117-24. doi: 10.1182/asheducation-2015.1.117. PubMed PMID: 26637710.

ABC/2

ABC/2

A is the greatest diameter by CT, B is the diameter 90 degrees to A, and C is the approximate number of CT slices with hemorrhage multiplied by the slice thickness.

Intracerebral hemorrhage

The ABC/2 method for calculating intracerebral hemorrhage (ICH) volume has been well validated. However, the formula, derived from the volume of an ellipse, assumes the shape of ICH is elliptical.

Although the ABC/2 formula for calculating elliptical ICH is well validated, it must be used with caution in ICH scans where the elliptical shape of ICH is a false assumption.

Haley et al., validated the adjustment of the ABC/2.4 method in randomization, antithrombotic-associated, heterogeneous-density, and irregular-shape ICH 1).


The ICH volumes for 118 patients were evaluated in a mean of 38 seconds and correlated with planimetric measurements (R2 = 9.6). Interrater and intrarater reliability were excellent, with an intraclass correlation of .99 for both.

Kothari et al., conclude that ICH volume can be accurately estimated in less than 1 minute with the simple formula ABC/2 2).

Rapid calculation of ICH volume at the time of initial patient presentation has clinical utility. For prognosis, a model of 30-day mortality that used the Glasgow Coma Scale and hemorrhage volume in patients with ICH correctly predicted outcome with a sensitivity and specificity of 97%.

The ABC/2 technique may also be used to identify appropriate patients with ICH suitable for randomization into therapeutic trials.

For example, the technique is the measurement method used for patient eligibility assessment in the multicenter Surgical Trial of Intracerebral Hemorrhage (J. Grotta, unpublished data, 1996). In this trial, patients with ICH and anticipated good outcome are not eligible for surgery. Thus, patients with hemorrhage volumes of less than 10 cm3 and patients with lobar hemorrhage volumes of 10 to 20 cm3 with minimal or no neurological deficits are excluded.


Lisk and colleagues demonstrated the ease and power of the ABC/2 method of volume measurement in a model of outcome after ICH but did not correlate this technique with other methods of volume measurement. The ABC/2 formula can be adjusted for CT slices of varying thickness by multiplying the number of slices of the different thicknesses on which the hematoma is seen (C of ABC/2) by the slice thickness in centimeters. Other authors have estimated hematoma volume by assuming it to approximate the volume of a sphere, an ellipsoid, or a rectangulopiped.

Only estimates of volume that use the formula for an ellipsoid have been shown to correlate with planimetric techniques.

This rapid method of measuring hemorrhage volume may allow physicians to quickly select and stratify patients in future treatment trials 3).

Meningioma

Measurement of tumor growth rates over time for patients with meningiomas has important prognostic and therapeutic implications. The objective of Opalak et al. was to compare two methods of measuring meningioma volume: (1) the simplified ellipsoid (ABC/2) method; and (2) perimetric volume measurements using imaging software modules.

Patients with conservatively managed meningiomas for at least 1.5 years were retrospectively identified from the VCU Brain and Spine Tumor Registry over a 10-year period (2005-2015). Tumor volumes were independently measured using the simplified ellipsoid and computerized perimetric methods. Intra class correlations (CC) and Bland-Altman analyses were performed.

A total of 26 patients representing 29 tumors were identified. Across 146 images, there were 24 (16%) images that were non-measurable using standard application commands with the computerized perimetric method. The mean volume obtained using the ABC/2 and computerized perimetric methods were 3.2 ± 3.4 cm3 and 3.4 ± 3.5 cm3, respectively. The mean volume difference was 0.2 cm3 (SE = 0.12; p = 0.10) across measurement methods. The concordance correlation coefficient (CCC) between methods was 0.95 (95% CI 0.91, 0.98).

There is excellent correlation between the simplified ellipsoid and computerized perimetric methods of volumetric analysis for conservatively managed meningiomas. The simplified ellipsoid method remains an excellent method for meningioma volume assessment and had an advantage over the perimetric method which failed to allow measurement of roughly one in six tumors on imaging 4).

Vestibular schwannoma

Epidural hematoma

The ABC/2 method could be used for epidural hematoma volume EDHV measurement, which would contribute to treatment decision making as well as clinical outcome prediction. However, clinicians should be aware that the ABC/2 method results in a general volume overestimation. Future studies focusing on justification of the technique to improve its accuracy would be of practical value 5).

References

1)

Haley MD, Gregson BA, Mould WA, Hanley DF, Mendelow AD. Retrospective Methods Analysis of Semiautomated Intracerebral Hemorrhage Volume Quantification From a Selection of the STICH II Cohort (Early Surgery Versus Initial Conservative Treatment in Patients With Spontaneous Supratentorial Lobar Intracerebral Haematomas). Stroke. 2018 Feb;49(2):325-332. doi: 10.1161/STROKEAHA.117.016677. Epub 2018 Jan 10. PubMed PMID: 29321340.
2) , 3)

Kothari RU, Brott T, Broderick JP, Barsan WG, Sauerbeck LR, Zuccarello M, Khoury J. The ABCs of measuring intracerebral hemorrhage volumes. Stroke. 1996 Aug;27(8):1304-5. PubMed PMID: 8711791.
4)

Opalak CF, Parry M, Rock AK, Sima AP, Carr MT, Chandra V, Workman KG, Somasundaram A, Broaddus WC. Comparison of ABC/2 estimation and a volumetric computerized method for measurement of meningiomas using magnetic resonance imaging. J Neurooncol. 2019 Aug 10. doi: 10.1007/s11060-019-03205-z. [Epub ahead of print] PubMed PMID: 31401721.
5)

Hu TT, Yan L, Yan PF, Wang X, Yue GF. Assessment of the ABC/2 Method of Epidural Hematoma Volume Measurement as Compared to Computer-Assisted Planimetric Analysis. Biol Res Nurs. 2015 Mar 23. pii: 1099800415577634. [Epub ahead of print] PubMed PMID: 25802386.
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