Clinical course of untreated thalamic cavernous malformations: hemorrhage risk and neurological outcomes

Restricted access

 

OBJECTIVE

The natural history of cerebral cavernous malformations (CMs) has been widely studied, but the clinical course of untreated thalamic CMs is largely unknown. Hemorrhage of these lesions can be devastating. The authors undertook this study to obtain a prospective hemorrhage rate and provide a better understanding of the prognosis of untreated thalamic CMs.

METHODS

This longitudinal cohort study included patients with thalamic CMs who were diagnosed between 2000 and 2015. Clinical data were recorded, radiological studies were extensively reviewed, and follow-up evaluations were performed.

RESULTS

A total of 121 patients were included in the study (56.2% female), with a mean follow-up duration of 3.6 years. The overall annual hemorrhage rate (subsequent to the initial presentation) was calculated to be 9.7% based on the occurrence of 42 hemorrhages over 433.1 patient-years. This rate was highest in patients (n = 87) who initially presented with hemorrhage and focal neurological deficits (FNDs) (14.1%) (χ2 = 15.358, p < 0.001), followed by patients (n = 19) with hemorrhage but without FND (4.5%) and patients (n = 15) without hemorrhage regardless of symptoms (1.2%). The initial patient presentations of hemorrhage with FND (hazard ratio [HR] 2.767, 95% CI 1.336–5.731, p = 0.006) and associated developmental venous anomaly (DVA) (HR 2.510, 95% CI 1.275–4.942, p = 0.008) were identified as independent hemorrhage risk factors. The annual hemorrhage rate was significantly higher in patients with hemorrhagic pres entation at diagnosis (11.7%, p = 0.004) or DVA (15.7%, p = 0.002). Compared with the modified Rankin Scale (mRS) score at diagnosis (mean 2.2), the final mRS score (mean 2.0) was improved in 37 patients (30.6%), stable in 59 patients (48.8%), and worse in 25 patients (20.7%). Lesion size (odds ratio [OR] per 0.1 cm increase 3.410, 95% CI 1.272–9.146, p = 0.015) and mRS score at diagnosis (OR per 1 point increase 3.548, 95% CI 1.815–6.937, p < 0.001) were independent adverse risk factors for poor neurological outcome (mRS score ≥ 2). Patients experiencing hemorrhage after the initial ictus (OR per 1 ictus increase 6.923, 95% CI 3.023–15.855, p < 0.001) had a greater chance of worsened neurological status.

CONCLUSIONS

This study verified the adverse predictors for hemorrhage and functional outcomes of thalamic CMs and demonstrated an overall annual symptomatic hemorrhage rate of 9.7% after the initial presentation. These findings and the mode of initial presentation are useful for clinicians and patients when selecting an appropriate treatment, although the tertiary referral bias of the series should be taken into account.

ABBREVIATIONS CCM = cerebral cavernous malformation; CM = cavernous malformation; DVA = developmental venous anomaly; FND = focal neurological deficit; GK = Gamma Knife; HR = hazard ratio; mRS = modified Rankin Scale; OR = odds ratio.

Article Information

Correspondence Da Li, Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantan Xili 6, Dongcheng District, Beijing 100050, People's Republic of China. email: lidaatlas@aliyun.com.

INCLUDE WHEN CITING Published online November 11, 2016; DOI: 10.3171/2016.8.JNS16934.

Drs. Tian, Zheng, and Ma contributed equally to this work.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Flow chart of participants with untreated thalamic CMs. *Eight patients were lost to follow-up before the end of the designated follow-up period, but their most recent follow-up data were obtained and included in analysis. Pts = patients.

  • View in gallery

    Case 1. Axial MR images obtained in an untreated patient with a vanishing hematoma. This 17-year-old male patient with an mRS score of 3 at diagnosis suffered a single hemorrhage of a right thalamic CM according to the results of an MRI scan (T1- weighted image, A). At the follow-up evaluation 3 months later, the hematoma had disappeared, and the lesion had decreased in size (T1-weighted image, B) with hemosiderin evident on T2-weighted (C) and gradient-echo images (D). After a follow-up duration of 63.9 months, the patient's mRS score had decreased to 0, and he was symptom free.

  • View in gallery

    Case 2. Axial MR images obtained in an untreated patient who suffered multiple hemorrhages. This 37-year-old woman presented with a medical history of hydrocephalus for which she had undergone ventriculoperitoneal shunt placement 7 years previously at another medical facility; evidence of a CM was absent except for an enhancing venous anomaly detected on the T1-weighted contrast-enhanced MRI (A). At the patient's initial visit to our institution, a left thalamic CM was identified on the T1-weighted MRI, (B) and the patient had an mRS score of 1. She subsequently suffered 3 hemorrhages, as shown on T1-weighted contrast-enhanced MRI (first ictus, C; second ictus, D and E; third ictus, F). The associated DVA was remarkable. The patient did not receive any treatment and had an mRS score of 2 at her most recent follow-up visit.

  • View in gallery

    Case 3. Axial MR images obtained in a patient who was treated with surgical excision of her CM. This 28-year-old woman suffered a hemorrhagic ictus of a right thalamic CM with a mRS score of 3 at initial diagnosis. The lesion presented with surrounding edema and subacute hemorrhage on T2-weighted (A) and T1-weighted (B) MRI. Additional hemorrhages occurred at 51.7 and 76.0 months after diagnosis and were identified based on T1-weighted images (C and D, respectively). Although the preoperative mRS score was 2, the patient underwent resection of the CM via a parietooccipital transventricular approach. The postoperative T1-weighted images obtained before (E) and after (F) administration of a contrast agent indicated complete resection.

  • View in gallery

    Kaplan-Meier analysis of hemorrhage-free survival. A: The estimated median hemorrhage-free survival time for the overall cohort was 78.6 months. B: Kaplan-Meier analysis showed a significant difference in hemorrhage-free survival between patients with or without an initial presentation of hemorrhage, and a presentation of hemorrhage predicted the trend of subsequent hemorrhage. C: Hemorrhage-free survival was worse for patients with an initial presentation of hemorrhage and FND than for patients without hemorrhagic presentation and for those with hemorrhage but without FND (p = 0.002). D: Patients with associated DVA were more likely to experience prospective hemorrhage than those without DVA (p = 0.001). Figure is available in color online only.

References

  • 1

    Abla AASpetzler RF: Cavernous malformations of the thalamus: a relatively rare but controversial entity. World Neurosurg 79:6416442013

  • 2

    Aiba TTanaka RKoike TKameyama STakeda NKomata T: Natural history of intracranial cavernous malformations. J Neurosurg 83:56591995

  • 3

    Al-Holou WNO'Lynnger TMPandey ASGemmete JJThompson BGMuraszko KM: Natural history and imaging prevalence of cavernous malformations in children and young adults. J Neurosurg Pediatr 9:1982052012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Al-Shahi Salman RBerg MJMorrison LAwad IA: Hemorrhage from cavernous malformations of the brain: definition and reporting standards. Stroke 39:322232302008

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Al-Shahi Salman RHall JMHorne MAMoultrie FJosephson CBBhattacharya JJ: Untreated clinical course of cerebral cavernous malformations: a prospective, population-based cohort study. Lancet Neurol 11:2172242012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Al-Shahi Salman RKitchen NThomson JGanesan VMallucci CRadatz M: Top ten research priorities for brain and spine cavernous malformations. Lancet Neurol 15:3543552016

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Banks JLMarotta CA: Outcomes validity and reliability of the modified Rankin scale: implications for stroke clinical trials: a literature review and synthesis. Stroke 38:109110962007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Barker FG IIAmin-Hanjani SButler WELyons SOjemann RGChapman PH: Temporal clustering of hemorrhages from untreated cavernous malformations of the central nervous system. Neurosurgery 49:15252001

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Bertalanffy HBenes LMiyazawa TAlberti OSiegel AMSure U: Cerebral cavernomas in the adult. Review of the literature and analysis of 72 surgically treated patients. Neurosurg Rev 25:1552002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Cakirer S: De novo formation of a cavernous malformation of the brain in the presence of a developmental venous anomaly. Clin Radiol 58:2512562003

  • 11

    Cantu CMurillo-Bonilla LArauz AHiguera JPadilla JBarinagarrementeria F: Predictive factors for intracerebral hemorrhage in patients with cavernous angiomas. Neurol Res 27:3143182005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Chang EFGabriel RAPotts MBBerger MSLawton MT: Supratentorial cavernous malformations in eloquent and deep locations: surgical approaches and outcomes. Clinical article. J Neurosurg 114:8148272011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Del Curling O JrKelly DL JrElster ADCraven TE: An analysis of the natural history of cavernous angiomas. J Neurosurg 75:7027081991

  • 14

    Ferroli PSinisi MFranzini AGiombini SSolero CLBroggi G: Brainstem cavernomas: long-term results of microsurgical resection in 52 patients. Neurosurgery 56:120312142005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Flemming KDLink MJChristianson TJBrown RD Jr: Prospective hemorrhage risk of intracerebral cavernous malformations. Neurology 78:6326362012

  • 16

    Gross BABatjer HHAwad IABendok BR: Cavernous malformations of the basal ganglia and thalamus. Neurosurgery 65:7192009

  • 17

    Gross BABatjer HHAwad IABendok BRDu R: Brainstem cavernous malformations: 1390 surgical cases from the literature. World Neurosurg 80:89932013

  • 18

    Gross BADu ROrbach DBScott RMSmith ER: The natural history of cerebral cavernous malformations in children. J Neurosurg Pediatr 17:1231282016

  • 19

    Gross BALin NDu RDay AL: The natural history of intracranial cavernous malformations. Neurosurg Focus 30:6E242011

  • 20

    Henrich WStupin JHBühling KJBührer CBassir CDudenhausen JW: Prenatal sonographic findings of thalamic cavernous angioma. Ultrasound Obstet Gynecol 19:5185222002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Horne MAFlemming KDSu ICStapf CJeon JPLi D: Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data. Lancet Neurol [epub ahead of print]2015

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Jeon JSKim JEChung YSOh SAhn JHCho WS: A risk factor analysis of prospective symptomatic haemorrhage in adult patients with cerebral cavernous malformation. J Neurol Neurosurg Psychiatry 85:136613702014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Kim DSPark YGChoi JUChung SSLee KC: An analysis of the natural history of cavernous malformations. Surg Neurol 48:9181997

  • 24

    Kobata HKondo AIwasaki KHattori I: Massive subependymal hemorrhage caused by an occult vascular malformation—two case reports. Neurol Med Chir (Tokyo) 39:3023071999

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Kondziolka DLunsford LDFlickinger JCKestle JR: Reduction of hemorrhage risk after stereotactic radiosurgery for cavernous malformations. J Neurosurg 83:8258311995

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Kondziolka DLunsford LDKestle JR: The natural history of cerebral cavernous malformations. J Neurosurg 83:8208241995

  • 27

    Kupersmith MJKalish HEpstein FYu GBerenstein AWoo H: Natural history of brainstem cavernous malformations. Neurosurgery 48:47542001

  • 28

    Labauge PBrunereau LLaberge SHoutteville JP: Prospective follow-up of 33 asymptomatic patients with familial cerebral cavernous malformations. Neurology 57:182518282001

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Labauge PBrunereau LLévy CLaberge SHoutteville JP: The natural history of familial cerebral cavernomas: a retrospective MRI study of 40 patients. Neuroradiology 42:3273322000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Li DHao SYJia GJWu ZZhang LWZhang JT: Hemorrhage risks and functional outcomes of untreated brainstem cavernous malformations. J Neurosurg 121:32412014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Li DHao SYTang JXiao XRJia GJWu Z: Clinical course of untreated pediatric brainstem cavernous malformations: hemorrhage risk and functional recovery. J Neurosurg Pediatr 13:4714832014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Li DYang YHao SYWang LTang JXiao XR: Hemorrhage risk, surgical management, and functional outcome of brainstem cavernous malformations. J Neurosurg 119:99610082013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Li DZhang JHao STang JXiao XWu Z: Surgical treatment and long-term outcomes of thalamic cavernous malformations. World Neurosurg 79:7047132013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Lin FWu JWang LZhao BTong XJin Z: Surgical treatment of cavernous malformations involving the posterior limb of the internal capsule: utility and predictive value of preoperative diffusion tensor imaging. World Neurosurg 88:5385472016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Mathiesen TEdner GKihlström L: Deep and brainstem cavernomas: a consecutive 8-year series. J Neurosurg 99:31372003

  • 36

    Mehdorn HMBarth HBuhl RNabavi AWeinert D: Intracranial cavernomas: indications for and results of surgery. Neurol Med Chir (Tokyo) 38:Suppl2452491998

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Mhoyan AFulbright RBannykh SI: Cavernous hemangioma of the thalamus. J Neurooncol 71:2572005

  • 38

    Moriarity JLWetzel MClatterbuck REJavedan SSheppard JMHoenig-Rigamonti K: The natural history of cavernous malformations: a prospective study of 68 patients. Neurosurgery 44:116611731999

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Nikoubashman ODi Rocco FDavagnanam IMankad KZerah MWiesmann M: Prospective hemorrhage rates of cerebral cavernous malformations in children and adolescents based on MRI appearance. AJNR Am J Neuroradiol 36:217721832015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Notelet LChapon FKhoury SVahedi KChodkiewicz JPCourtheoux P: Familial cavernous malformations in a large French kindred: mapping of the gene to the CCM1 locus on chromosome 7q. J Neurol Neurosurg Psychiatry 63:40451997

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41

    Nyáry IMajor OHanzély ZSzeifert GT: Histopathological findings in a surgically resected thalamic cavernous hemangioma 1 year after 40-Gy irradiation. J Neurosurg 102:Suppl56582005

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42

    Otani NFujioka MOracioglu BMuroi CKhan NRoth P: Thalamic cavernous angioma: paraculminar supracerebellar infratentorial transtentorial approach for the safe and complete surgical removal. Acta Neurochir Suppl 103:29362008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Pandey PWestbroek EMGooderham PASteinberg GK: Cavernous malformation of brainstem, thalamus, and basal ganglia: a series of 176 patients. Neurosurgery 72:5735892013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Pannek HWOppel F: Minimally invasive lesionectomies through a stereotactically guided working sleeve. Neurol Res 21:51591999

  • 45

    Porter PJWillinsky RAHarper WWallace MC: Cerebral cavernous malformations: natural history and prognosis after clinical deterioration with or without hemorrhage. J Neurosurg 87:1901971997

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Pozzati E: Thalamic cavernous malformations. Surg Neurol 53:30402000

  • 47

    Pozzati EAcciarri NTognetti FMarliani FGiangaspero F: Growth, subsequent bleeding, and de novo appearance of cerebral cavernous angiomas. Neurosurgery 38:6626701996

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Rangel-Castilla LSpetzler RF: The 6 thalamic regions: surgical approaches to thalamic cavernous malformations, operative results, and clinical outcomes. J Neurosurg 123:6766852015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Rigamonti DDrayer BPJohnson PCHadley MNZabramski JSpetzler RF: The MRI appearance of cavernous malformations (angiomas). J Neurosurg 67:5185241987

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50

    Robinson JRAwad IALittle JR: Natural history of the cavernous angioma. J Neurosurg 75:7097141991

  • 51

    Tew JM JrLewis AIReichert KW: Management strategies and surgical techniques for deep-seated supratentorial arteriovenous malformations. Neurosurgery 36:106510721995

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    Washington CWMcCoy KEZipfel GJ: Update on the natural history of cavernous malformations and factors predicting aggressive clinical presentation. Neurosurg Focus 29:3E72010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53

    Zabramski JMWascher TMSpetzler RFJohnson BGolfinos JDrayer BP: The natural history of familial cavernous malformations: results of an ongoing study. J Neurosurg 80:4224321994

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

TrendMD

Cited By

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 229 229 46
Full Text Views 438 375 9
PDF Downloads 218 196 7
EPUB Downloads 0 0 0

PubMed

Google Scholar