Recurrent Intraventricular Haemorrhage in Cerebral Proliferative Angiopathy – A Case Report and Review of the Literature

Abstract

Cerebral proliferative angiopathy (CPA) is an entity distinct from that of classical arteriovenous malformations. As such, few reports have considered the long-term follow-up of patients with hemorrhage in CPA. Accordingly, herein the authors present a case of recurrent hemorrhage in CPA with 32 years of follow-up and in so doing summarize the literature of hemorrhagic cases in CPA. A 19-year-old presented with focal awareness seizures and diagnostic work-up revealed a left hemispheric vascular lesion. The patient presented again with intracranial hemorrhage at ages 28, 43 and 51. Angioarchitectural workup revealed intermingled brain parenchyma between vascular spaces, absence of dominant feeders and a clear nidus consistent with CPA. The size and diffuse nature of the lesion deemed it inoperable. Given our case and review of the literature it is apparent that CPA has a high risk of re-hemorrhage in the rare event that hemorrhage does occur.

Introduction

Arteriovenous malformations (AVMs) are direct fistulous connections between arteries and veins without intervening capillary networks or normal brain parenchyma. Cerebral proliferative angiopathy (CPA), first defined by Lasjaunias et al. in 1989, is a cerebral vascular malformation with distinct angioarchitectural features. ¹ These features include a large, often hemispheric, size; an absence of dominant feeders or flow-related aneurysms; transdural supply of healthy and pathological tissues; brain parenchyma intermingled between vascular spaces; capillary angioectasisa; and only moderately enlarged veins. ¹ CPA most commonly presents with ischemia, however, when hemorrhage does occur, it often reoccurs. ¹

Very few reports have considered long-term follow-up of patients with hemorrhage in CPA.^2,3 We present a case of recurrent hemorrhage in CPA with 32 years of follow-up. A summary of the published cases of hemorrhage in CPA is also provided.

Case Description

Initial Presentation and First Rupture

A 19-year-old male with no past medical history presented with focal awareness seizures, characterized by right hand twitching, to an outside institution. Diagnostic work-up revealed a large left hemispheric vascular lesion which was diagnosed as a Spetzler-Martin grade 5 AVM and the patient was managed conservatively with antiepileptics.

At age 28, the patient presented again after waking up at night with a severe headache, nausea, and vomiting; non-contrast head CT revealed an intraventricular hemorrhage. The patient was admitted to the neurosurgical unit for observation where he remained stable without need for an external ventricular drain (EVD). MRI without contrast confirmed a 9 cm vascular lesion in the left hemisphere. The lesion was deemed inoperable and conservative care was continued. The patient was discharged home 9 days after admission.

Second Rupture

The patient developed weakness and contracture in the right hand following the first hemorrhage and continued to have intermittent focal awareness seizures characterized by right hand shaking.

At age 43, the patient presented again following an episode of nausea and vomiting and re-hemorrhage into the ventricles was confirmed on CT of the head (Figure 1A). The patient was admitted for monitoring given the development of ventriculomegaly, but again did not require an EVD. MRI with contrast re-demonstrated a 9 cm diffuse left hemispheric vascular lesion with brain parenchyma intermingled between vascular spaces (Figure 1B-C). MR and conventional angiography revealed abnormal, ectatic feeders from the left anterior cerebral artery, left internal carotid artery, and the left middle and left posterior cerebral arteries (Figure 1D-E). Multiple superficial draining veins to the superior sagittal sinus were seen along with deep venous drainage to a large ectactic vein that drained to the internal cerebral vein. Additional findings included the absence of a dominant feeder, a large hemispheric nidus and relatively small draining veins. These radiographic findings were consistent with CPA. ¹

Figure 1.

Investigations at age 43 at the time of the second CPA associated intracranial hemorrhage. (A) Non-contrast head CT demonstrating an axial view of the vascular lesion associated intraventricular hemorrhage. (B) T1 MRI with contrast and (C) T2 MRI both demonstrating an axial view of cerebral proliferative angiopathy with intermingled brain parenchyma. (D) Coronal view of a 3D reconstruction of an MR angiogram. (E) Digital subtraction angiography (DSA). The angiographic findings were consistent with CPA. AP = anteroposterior, CPA = cerebral proliferative angiopathy, ICA = internal cerebral artery, VA = vertebral artery.

Aside from right sided weakness and right focal awareness seizures of his usual semiology, the patient was stabilized and discharged on admission day 4. Following the second rupture the patient developed progressive hemiparesis and aphasia. During the same period, the patient developed increasing perilesional hyperintensities on fluid attenuated inversion recovery (FLAIR) MRI (Figure 2A-C).

Figure 2.

FLAIR images from (A) the first hemorrhage at age 28, (B) second hemorrhage at age 43 and (C) before and (D) after the third hemorrhage at age 51 revealing increasing hyperintensity.

Third Rupture

At age 51, following a seizure and vomiting, head CT demonstrated a left frontotemporal intraparenchymal hemorrhage extending throughout the ventricles, more extensive than the second bleed. CT angiogram and conventional angiography confirmed previous angioarchitectural findings without any major changes over the period of follow-up. The FLAIR signal abnormality further increased on the MRI (Figure 2D). The patient was admitted, and an EVD was placed. The EVD was removed on admission-day 23 and the patient was discharged on admission day 38 with hemiparesis and aphasia trending towards baseline. He was considered to have a fair prognosis of recovering baseline functional mobility and communication.

Systematic Literature Search

Methods

PubMed was searched in May 2023 for cases of hemorrhage in CPA using the search term “Cerebral Proliferative Angiopathy.” Full texts were reviewed for any abstracts reporting cases of CPA. Studies reporting hemorrhage in CPA were included. Studies were assessed for number of cases of hemorrhage in CPA, age, sex, presenting complaint, CPA location, management, follow-up, outcomes at last follow-up and report of recurrent hemorrhage.

Result

A total 554 abstracts were screened, 48 full texts were reviewed of which a final 19 studies were included.^1–19 These included 31 cases of hemorrhage in CPA which are summarized in Table 1. Of note, rebleeding occurred in 12 (39%) cases.

Table 1.

CPA cases with hemorrhage.

Author	n	Age (presentation)	Sex	Presentation	Location	Management	Follow-up (years)	Outcome	Recurrence
Lasjaunias et al., 2008 1	6	NR	NR	NR	NR	NR	NR	1 death by recurrent hemorrhage	Y = 4; N = 2
Fierstra et al., 2011 16	2	21	F	Seizures	L fronto-temporo-parietal	NR	NR	NR	N
		23	M	Seizures	L fronto-temporal	NR	NR	NR	N
Maekawa et al., 2012 5	1	62	F	Gait instability; dysarthria	Tectum and cerebellar vermis	Conservative	9	Death due to initial hemorrhage	N
Kumar et al., 2015 4	1	66	M	Headache; vomiting	L cerebellar	Conservative	1	No deficits	N
Bilaj et al., 2016 6	1	24	M	Headache; seizures	L temporal	CPA resection	NR	NR	Y
Sakata et al., 2016 7	1	0.6	M	Incidental finding	L hemisphere	Endovascular embolization	10	No focal neurology	Y
Maekawa et al., 2018 2	1	12	F	Headache	L cerebellar	Conservative	31	Death of unknown cause	Y
Giragani et al., 2018 8	1	12	M	Headache	R cerebellar	Third ventriculostomy; endovascular embolization	0.5	No deficits	N
Vilela and Tazinaffo, 2018 15	1	46	F	Headache	R cerebellar	Posterior fossa decompressive craniectomy;	3	Ataxia; dysarthria	N
Kimiwada et al., 2019 9	1	13	M	Headache	L fronto-parietal	Indirect revascularization (pre-hemorrhage); hemorrhage managed conservatively	NR	Stable	N
Beniwal et al., 2020 10	1	12	M	Trauma (cricket ball)	R cerebellar	Conservative	1.5	No deficits	N
Ochoa et al., 2020 13	2	5	NR	Headache; vomiting	R temporal	Decompressive craniectomy; ATL	8	No deficits	Y
		16	F	Headache; drowsiness	R cerebellar	Decompressive craniectomy; CPA resection	3	No deficits	N
Xia et al., 2021 11	1	76	M	Dizziness; headache; hemiparesis	R cerebellar	Conservative	1	Death likely related to CPA	N
Rebello et al., 2021 12	1	12	M	Seizures; hemiplegia	R frontal	Conservative	0.1	No deficit	N
Hess et al., 2022 14	1	18	F	Syncope; fall	L hemispheric	Craniotomy for evacuation of subdural hematoma	0.1	No further deficit	N
Srivastava et al., 2022 17	5	19.5	M	Seizure; hemiparesis	R temporo-parietal	Conservative	0.1	Persistent hemiparesis	N
		17	F	Seizure; hemiparesis	R fronto-parietal	NR	0.1	Death	N
		42	M	Seizure; hemiparesis	L temporo-parieto-occipital	NR	0.2	Persistent hemiparesis	N
		17	M	Hemiparesis	L temporo-parietal	NR	14	Recurrent seizures	Y
		20	F	Hemiparesis	L temporo-parietal	NR	3	Stable	Y
Panthi et al., 2022. 18	1	60	M	Seizures; hemiparesis; aphasia	Bilateral temporo-parieto-occipital	Conservative	NR	Stable	N
Shomura et al., 2022. 19	1	20	M	Seizures; hemiplegia	R temporo-occipital	Endovascular embolization	4	Stable	N
Saito et al., 2023. 3	1	5	F	Headache	L frontal	Endovascular embolization of aneurysm	17	No deficit	Y
Present case	1	18	M	Headache; vomiting; seizures	L hemispheric	Conservative	32	Aphasia; hemiplegia; seizures	Y

NR = not reported; n = number of patients; F = female; M = male; R = right; L = left; ATL = anterior temporal lobectomy; cerebral proliferative angiopathy (CPA); Y = yes; N = no.

Discussion

Hemorrhage in the setting of CPA is rare. In Lasjaunias’ original description of 49 cases of CPA, six (12%) had hemorrhagic events; by contrast, 583/1385 (42%) of the classical AVM population presented by Lasjaunias et al. had a history of hemorrhage. ¹ Re-hemorrhage as reported by Lasjaunias was more common in CPA (4/6, 67%) than in classical AVMs (24/583, 4%). ¹ Despite limited/no follow-up of several of the published cases of hemorrhage in CPA,^{8,12,14,16–18} 12/31 (39%) of published cases have had documented recurrent hemorrhages.^{1–3,6,7,13,17} It should be noted that although CPA is generally considered a separate entity from AVM most cases rely on angiographic features rather than more definitive/distinguishing features evident on histopathology; however given the management, which is often non-surgical, this is not surprising. Given such uncertainties in CPA and AVM diagnosis the possibility of misclassification/bias is high as many CPA may be considered AVMs in routine clinical practice.

The third hemorrhage required EVD placement but was otherwise conservatively managed as no clear bleeding point could be identified. Two previous confirmed cases of hemorrhage in CPA resulted in immediate mortality,^1,5 three required immediate decompressive craniectomy,^13,15 and four cases had immediate endovascular embolization of associated aneurysm(s).^3,7,8,19 Most cases have, however, been managed conservatively in both the immediate setting of the hemorrhage and at follow-up.^{2,4,5,9–12,17,18} Following angioarchitectural work up, Kimiwada et al. in 2019 reported a case of indirect revascularization with the aim to prevent further development of fragile collateral vessels before hemorrhage, despite that, the patient developed a hemorrhage. ⁹ CPA resection has been attempted in three cases of smaller CPA without further subsequent hemorrhage at last follow-up.^6,13 Although, hemorrhage is less common in CPA, those that do rupture are at higher risk of re-hemorrhage. Due to their rare occurrence, large size, diffuse nature, and the intermingled brain parenchyma that characterizes these lesions, ruptured CPA lesions remain a challenge for clinicians.

The authors present a case of CPA with 32 years of follow-up with three events of hemorrhage in the periventricular region. Although less likely to present with hemorrhage than their AVM counterparts, CPA lesions are at high risk of re-hemorrhage and are often challenging to treat. Conservative management is the most common strategy, but tailored interventions can be considered on a case-by-case basis. Further investigation is required to better understand the natural history and treatment options for cases of ruptured CPA.

Appendix.

Abbreviations and Acronyms

CPA

Cerebral proliferative angiopathy

AVM

Arteriovenous malformation

CT

Computed tomography

EVD

External ventricular drain

MRI

Magnetic resonance imaging

DSA

Digital subtraction angiography

FLAIR

Fluid attenuated inversion recovery

ORCID iDs

Jakob V. E. Gerstl https://orcid.org/0000-0002-8100-0517

Erickson F. Torio https://orcid.org/0000-0003-0958-704X

Rose Du https://orcid.org/0000-0003-2641-6496