Stroke

TOPICAL REVIEW

Uncommon Causes of Nontraumatic Intracerebral

Hemorrhage
Hugo Tartarin, MD; Andrea Morotti , MD; Ellis S. Van Etten , MD, PhD; Moran Hausman-Kedem , MD;
Andreas Charidimou , MD, PhD; Eric Jouvent , MD, PhD; Sophie Susen , MD, PhD; Charlotte Cordonnier , MD, PhD;
Marco Pasi , MD, PhD; Grégoire Boulouis, MD, PhD

ABSTRACT: Nontraumatic intracerebral hemorrhage is an important health issue. Although common causes such as
hypertension and cerebral amyloid angiopathy predominantly affect the elderly, there exists a spectrum of uncommon
etiologies that contribute to the overall incidence of intracerebral hemorrhage. The identification of these rare causes is
essential for targeted clinical management, informed prognostication, and strategic secondary prevention where relevant.
This topical review explores the uncommon intracerebral hemorrhage causes and provides practical clues for their clinical
and imaging identification. By expanding the clinician’s differential diagnosis, this review aims to bridge the gap between
standard intracerebral hemorrhage classification systems and the nuanced reality of clinical practice.

Key Words: arteriovenous malformations ◼ diagnosis ◼ hypertension ◼ incidence ◼ secondary prevention

N
ontraumatic intracerebral hemorrhage (ICH) is an often do not assist in clinical decision-making or in clas-
important health issue representing ≈20% of strokes.1 sifying the more infrequent causes.
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It is associated with considerable morbidity and mor-
tality.2 ICH primarily affects elderly individuals, where the
pathogenesis is dominated by arteriolosclerosis, which is
mostly attributable to hypertension, and sporadic cerebral
amyloid angiopathy (CAA). Other common causes include
macrovascular lesions such as arteriovenous malforma-
tions or cavernomas. Among the means for improving out-
comes in patients with ICH, the identification of potentially
treatable causes might play an important role. The etio-
logical workup is indeed of direct clinical relevance to help
guide effective clinical management, influence prognostic
information, and refine secondary prevention strategies.
Several etiologic classification approaches have been
proposed. For example, the SMASH-U3 scheme proposes
a diagnostic algorithm based on successive elimination,
while the H-ATOMIC4 or, more recently, CLAS-ICH5 stud-
ies consider the potential association of several etiolo-
gies with probability rates. These systems mainly serve
the purpose of comparing patient groups across diverse
studies and creating a research standard. As such, they
In certain situations, the frequent causes for nontrau-
matic ICH have been ruled out by an adequate workup,
raising suspicion for a rarer underlying causative disease.5
Similarly a rare pathogenesis of ICH can be suspected in
patients with atypical presentation, past medical history,
or imaging findings.
In this review, we provide an overview of rare causes
of ICH and atypical presentations of frequent causes and
means for their workup and identification.
ETIOLOGICAL WORKUP FOR
NONTRAUMATIC ICH
General Principles and Rationale
The ICH workup is a systematic sequential process that
integrates clinical evaluations, laboratory testing, and
neuroimaging data.6 The preliminary evaluation should
encompass a thorough history (including past neurosur-
gical procedures) and physical examination, emphasizing

Correspondence to: Grégoire Boulouis, MD, PhD, Diagnostic and Interventional Neuroradiology, CIC-IT 1415, CHRU de Tours, INSERM 1253 iBrain, Tours, Centre Val
de Loire, France. Email gregoireboulouis@gmail.com
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.123.043917.
For Sources of Funding and Disclosures, see page XXX.
© 2024 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str

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 Tartarin et al
vascular risk factors, antithrombotic therapies, substance
abuse, and clinical manifestations. Standard laboratory
Topical Review
tests often include complete blood counts, coagulation
profiles, inflammatory markers, and, when necessary,
urine assays. One prominent, albeit evident, clue for a
rare cause of ICH is a young age. Neuroimaging with
computer tomography (CT) and magnetic resonance
imaging (MRI) including vascular imaging allows to local-
ize the hemorrhage, estimate its extent, identify potential
underlying structural abnormalities or additional brain
anomalies, and may often provide etiological clues.6
These constellation of patterns of the hemorrhage may
aid in suspecting uncommon causes of ICH.
The decision to undertake further etiological tests is
tailored to the patient’s specific presentation and context.
Uncommon Presentations of Conditions
Commonly Causing ICH
Atypical presentations of ICH, originating primarily from
sporadic small vessel diseases, can sometimes chal-
lenge the diagnostic prowess of clinicians. These pre-
sentations often demand a nuanced approach, diverging
from the straightforward identification process generally
adopted in the right clinical contexts. A prevalent pattern-
recognition approach, based largely on brain MRI results,
can sometimes lead to oversimplification and, on rare
occasions, misdiagnosis, particularly when small vessel
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pathology exhibits unusual manifestations.
For instance, the sporadic CAA-related ICH in the
elderly, typically identified by lobar patterns and the pres-
ence of cerebral microbleeds in expected brain regions,
allows for a quick spot diagnosis following the Bos-
ton criteria. However, CAA can, on occasions, manifest
unusually—being highly asymmetrical, affecting a single
hemisphere or lobe,7 or presenting with multiple synchro-
nous lobar ICH. An in-depth understanding of the Boston
criteria and the entire spectrum of small vessel disease
markers proves beneficial in such situations.8
Furthermore, employing amyloid positron emission
tomography and cerebro spinal fluid neurodegeneration
markers, particularly in suspected CAA cases, is advised,
preferably in consultation with specialized high-volume
CAA centers. In cases of significant diagnostic uncer-
tainty, a brain biopsy, remains the gold standard, offering
direct histopathologic evidence. It should be performed if
there is a potential for clinical management modification.
PRACTICAL WORKUP OF UNCOMMON
CAUSES OF ICH
Lesions Identified on Parenchymal Imaging
Malignancy
Fast-growing and highly vascularized neoplasms with
fragile vascular architecture are prone to ICH9 and
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Rare Causes of Intracerebral Hemorrhage
constitute ≈3% of ICH cases.10 Only a small propor-
tion of intratumoral hemorrhages are inaugural to the
diagnosis of malignancy. On initial imaging, vasogenic
edema,11 which is out of proportion is a suspect feature
of underlying malignancy, especially if it is present in
the first hours following onset (suggesting that it was
present before ICH occurrence; Figure S1). Practically,
vasogenic edema-to-mean-hematoma diameter ratios
>100% present a positive predictive value of 71% for
a malignancy (and a ratio >150% a positive predictive
value of 100%).11 Contrast-enhanced imaging on CT or
MRI can identify tumoral focal enhancement.
Metastases account for the majority of intraparenchy-
mal solid tumors, with intratumoral hemorrhage within
these metastases frequently reported,12 notably in cases
of melanoma, renal cell, and breast and lung cancers
(Figure S1). While prostate cancer rarely metastasizes
to the brain, it makes up for a significant portion of
cancer-related ICH.13 Less common malignancies, such
as thyroid cancer, hepatocellular carcinoma, and chorio-
carcinoma, are infrequent sources of brain metastases
but exhibit an elevated propensity for bleeding when
present in the brain.
Among primary tumors, glioblastoma multiforme is the
most associated with ICH regarding its incidence but also
its neo angiogenesis and highly invasive and destructive
behavior. Low-grade anaplastic oligodendroglioma, less
frequently? contains highly hemorrhagic fragile retiform
capillaries causing hemorrhage.
A few cases of primary central nervous system
(CNS) lymphoma presenting with intratumoral ICH were
reported but also hemorrhagic disseminated intravascu-
lar lymphoma14,15 (Figure 1). Hematologic malignancies
can also lead to ICH through coagulopathy or leucosta-
sis.13 In these scenarios, ICH are typically multiple, and
overt anomalies are present on initial blood samples.
Infectious Causes
The occurrence of ICH accompanied by evidence of sep-
sis should alert to a possible infectious pathogenesis and
prompt further investigation for indicative biological and
imaging signs.
On imaging, there can be hints of an underlying infec-
tious cause that are specific to the pathogenesis and
should be searched based on clinical-biological suspicion.
In bacterial endocarditis, neurological involvement
represents the most frequent extra-cardiac compli-
cation, with ICH being the second most common
neurological complication after ischemia.16 If a brain
hematoma is discovered, the presence of a new heart
murmur, or unexplained fever should raise suspicion
of endocarditis and prompt a comprehensive clini-
cal, imaging, and biological examination. Parenchymal
imaging may reveal suggestive signs: mainly acute
or subacute ischemia in fluid-attenuated inversion
recovery and diffusion, microbleeds on blood sensi-
tive sequences, hemorrhagic stroke areas defined by
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 Tartarin et al
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expansive lesions with central restriction, as well as
brain abscesses. Vascular irregularities and vessel wall
uptake can be found, suggestive of vasculitis. Time-
of-flight and contrast-enhanced T1 MRI or CT angiog-
raphy show equivalent sensitivity in detecting mycotic
aneurysms (Figure 2).
Bacterial meningitis is typically linked to ischemic
complications, but has been linked to ICH in 1.9% of
cases in a cohort of 2306 patients.17 Lobar location
of the hematoma is the most prevalent and 2 or more
hematomas are found in half of the patients.17 Imaging
can reveal meningeal thickening and enhancement, and
oftentimes ventriculitis visible on T1 and fluid-attenuated
inversion recovery sequences after gadolinium injection.
Vascular irregularities suggesting an underlying vasculitis
can be found in a few patients.17
Finally, parenchymal insult through viral encepha-
litis can also cause ICH. Herpes Simplex Virus (HSV1
primarily and HSV2) accounts for 50% to 70% of the
identified pathogens among cases of acute viral enceph-
alitis.18 Exceptionally (2.7% according to Modi et al19), it
may progress to a hemorrhagic form (Figure S2), which
Stroke. 2024;55:00–00. DOI: 10.1161/STROKEAHA.123.043917
Rare Causes of Intracerebral Hemorrhage
Topical Review
Figure 1. Disseminated intravascular
lymphoma.
A 62-year-old female presenting with mild,
progressively worsening headache, altered
consciousness, and behavior changes.
Magnetic resonance imaging shows
multiple areas of hemorrhagic necrosis
with susceptibility artifacts (A), as well as
multifocal cytotoxic edema (indicated by
dotted white circles) on diffusion-weighted
imaging (B), corresponding to scattered
tumefactive fluid-attenuated inversion
recovery hyperintensities (C and D). While
acute hemorrhagic leukoencephalitis was
initially suspected, a biopsy revealed diffuse
B-cell lymphoma.
usually occurs after hospital admission and is often
manifested only by a lack of clinical improvement. The
imaging typically reveals cytotoxic edema asymmetrically
involving 1 or both temporal lobes in fluid-attenuated
inversion recovery and diffusion sequences, with pos-
sible parenchymal enhancement.
Acute Inflammatory Processes
CNS Vasculitides
In the evaluation of rare causes of ICH, CNS vasculitides
stand as an important category of inflammatory disor-
ders. These conditions are characterized by the inflam-
mation of vessel walls leading to various destructive
changes that can cause blood to extravasate.
Diagnosing CNS vasculitis often relies on parenchymal
imaging data, as well as vessel wall imaging. In smaller
vessel insults, patients bear clinical and radiological pro-
files resembling nonspecific meningoencephalitis, which
can showcase elements that include ICH and white mat-
ter abnormalities, often without identifiable signs of vas-
cular wall inflammation on imaging. Varicella-zoster virus
vasculitis is the most common viral vasculitis and a major
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 Tartarin et al Rare Causes of Intracerebral Hemorrhage
Topical Review

Figure 2. Endocarditis.
A 53-year-old patient with fever and fatigue, leading to the discovery of infectious endocarditis. Frontoparietal intracerebral hemorrhage with
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substantial subarachnoid hemorrhage and coexisting acute occipital hematoma (A). Stenosis (white arrowhead) of the M2 segment of the middle
cerebral artery (B), exhibiting wall enhancement (C), passing through the hematoma. Computed tomography angiography (D) and magnetic
resonance angiography (E) showing arterial irregularities with mycotic aneurysms (arrows). Mycotic aneurysm also presents parietal enhancement
(F), within the smaller occipital hematoma.

cause of ischemic stroke in children. It has been reported
to be associated with ICH in rare instances.20 Invasive
fungal infections (eg, aspergillus, mucor) can cause CNS
vasculitis due to their angio-invasive nature,21 which can
lead to massive subarachnoid hemorrhage and occasion-
ally ICH.
Medium and large vessel vasculitides have been asso-
ciated with ICH in rare instances, typically through micro-
aneurysm development. Antineutrophil cytoplasmic
antibodies–associated vasculitides display limited CNS
involvement, with ischemic strokes being more common
than ICH.
Variable vessel vasculitis with CNS involvement is
dominated by Behcet disease.22 Cerebral venous sinus
thrombosis (CVST) is present in 12% to 20% of cases,
causing lobar hemorrhage, and is by far the most fre-
quent risk factor for ICH in these patients.
Primary Angiitis of the CNS
Primary angiitis of the CNS is a transmural vasculi-
tis mostly of medium-sized and small arteries of the
neuraxis. Imaging can reveal parenchymal nonspecific
abnormalities, which combine ischemic events (in half
of patients), subcortical white matter hyperintensi-
ties, cerebral microbleeds, and possibly parenchymal
enhancement. Hemorrhagic manifestations can some-
times be the initial symptoms (Figure 3) and are found
in 63.6% of cases, with 84% of them being ICH.23 If
the clinical and radiological features of primary angi-
itis of the CNS often allow differentiation from revers-
ible cerebral vasoconstriction syndrome (RCVS) upon
patient admission and MRI, the presence of ICH makes
the distinction more challenging, raising questions
about the presence of an atypical or severe form of
RCVS associated with parenchymal abnormalities and
a possible overlap with posterior reversible encepha-
lopathy syndrome (PRES).
CAA-Related Inflammation and Amyloid-β–Related
Angiitis
CAA-Related Inflammation (CAA-ri) typically manifests
clinically with confusion, seizures, rapid cognitive decline,
and headache. It is characterized by perivascular inflam-
mation without inflammation of the vessel wall MRI

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 Tartarin et al Rare Causes of Intracerebral Hemorrhage

Topical Review
Figure 3. Primary angiitis of the central nervous system.
A 57-year-old female presenting diffuse mild headache and blurry vision. Axial slice computed tomography shows a lobar parietal hematoma (A).
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Axial slice of magnetic resonance imaging (MRI) demonstrates diffuse bilateral white matter hyperintensities (B), multifocal punctate parenchymal
(white arrowheads) and leptomeningeal enhancements (C, white arrow). MRI shows parietal arterial enhancement (D) and multiple distal
narrowings on MR angiography (E, black arrowheads). Susceptibility imaging presents supra and infra tentorial cerebral microbleeds (F). The
whole radiological pattern was indicative of vasculitis. The final diagnosis was that of primary angiitis. Symptoms partially recovered after initiation
of corticosteroids.

findings include cerebral microbleeds, cortical superfi-
cial siderosis, and occasionally ICH. CAA-ri differs from
CAA by the prominence of (commonly asymmetrical)
vasogenic edema within the white matter that is absent
in CAA. Meningeal enhancement is common, but there
is typically no parenchymal enhancement.24 In CAA-ri
cerebral angiograms show no abnormalities. Amyloid-β–
related angiitis is characterized by an inflammatory infil-
trate toward amyloid-β deposits in the vessel walls and
can have a more acute onset than CAA-ri (in its nonhem-
orrhagic forms). In a patient treated for Alzheimer disease
with amyloid-modifying therapies (eg, Aducanumab),
radiological abnormalities similar to CAA-ri may seem and
are referred to as amyloid-related imaging abnormalities.
a pediatric population, AHLE mostly occurs in young
adults with a male predominance.26 In AHLE, patients
initially present with mild neurological deficits followed
by a fulminant neurological deterioration that often leads
to coma/death in about 1 week from the time of onset.26
ANE, a postinfectious inflammatory condition that occurs
a few days after a viral infection (primarily influenza and
parainfluenza26) is characterized by symmetrical micro-
hemorrhagic necrosis centered on the thalami, without
macroscopic hematoma.
During COVID-19, pandemic several cases have
been reported presenting with more hemorrhagic forms
of AHLE in comparison with the typical forms of the pre-
COVID era.27

Demyelinating Diseases Genetic Causes

Acute hemorrhagic leukoencephalitis (AHLE) and acute
necrotizing encephalitis (ANE) are rare acutely demy-
elinating conditions. AHLE is an acute postinfectious
inflammatory brain disease considered a severe form of
acute disseminated encephalomyelitis.25 Unlike acute
disseminated encephalomyelitis, which touches mostly
Nontraumatic ICH has been reported in almost all mono-
genic neurovascular disorders.
In cerebral small vessel disease, stroke is exception-
ally the first manifestation, so a monogenic cerebral small
vessel disease is unlikely in adult patients with ICH in the
absence of at least moderate white matter abnormalities,

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 Tartarin et al
lacunes, or microbleeds.28 Cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoencepha-
Topical Review
lopathy due to mutations in the NOTCH3 gene is the
most common monogenic form of cerebral small vessel
disease and may be responsible for ICH mainly in Asian
patients.29 WMHs of the temporal lobes and superior
frontal gyri are often seen,30 but are not specific (Figure
S3). The second most frequent form is related to autoso-
mal dominant HTRA1 mutations, which closely resemble
sporadic forms in the elderly, with a presumably high fre-
quency of numerous dilated perivascular spaces in the
basal ganglia état criblé. The presence of a porencephalic
cavity close to the lateral ventricles is a clue to COL4A1/
A2 mutations, as well as the coexistence of intracranial
aneurysms or dolichoectasia.31 In these patients, white
matter hyperintensity pattern is highly variable. Excep-
tionally, biallelic mutations in the HTRA1 gene may be
responsible for cerebral autosomal recessive arteriopa-
thy with subcortical infarcts and leukoencephalopathy.
The MRI pattern of white matter hyperintensity appears
similar to cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy, and
clinical features such as early alopecia or spondylo-
sis can help in orienting the diagnosis. The presence
of calcifications and cysts should prompt a search for
SNORD118 mutations.32 New phenotypes, such as
cathepsin-A-related arteriopathy with strokes and leu-
koencephalopathy or LAMB1 (laminin subunit beta-1)
disorders, have been identified too recently to highlight
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specific patterns.33 The association of cerebral small ves-
sel disease and large vessel alterations should prompt a
search for GLA (galactosidase alpha) mutations (Fabry
disease), especially in patients with suggestive clini-
cal (acroparesthesia, hypoacousia) or imaging (pulvinar
sign on T1w sequences) signs. Finally, in the presence of
Moyamoya-type manifestations, exceptional Mendelian
forms may be suspected in the presence of severe syn-
dromic manifestations.34
Over time, the specificity of MRI patterns for a given
cause appears to be increasingly low. Therefore, rather
than targeting specific genes when a monogenic cause
of ICH is suspected, gene panels should be performed.
Familial Forms of CAA
There are several rare genetic mutations that cause
familial CAA, mostly but not exclusively located in the
APP gene. These often-autosomal dominant forms of
CAA have a similar clinical and radiological manifesta-
tion compared with sporadic CAA, except they gener-
ally present at an earlier age and follow an accelerated
disease course. The phenotype is heterogenous even in
individuals with the same mutation; therefore, the age
of onset can differ considerably.35 Radiological features
cannot sufficiently differentiate between sporadic and
familial forms of CAA. Genetic testing should be con-
sidered in all ICH patients who have a family history of
6   May 2024
Rare Causes of Intracerebral Hemorrhage
ICH or dementia, or who have CAA below the age of
50. History of neurosurgical procedures or other treat-
ments involving cadaveric human material can point in
the direction of the newly recognized iatrogenic CAA. An
approach to diagnostic investigation has been recently
provided.36
Vascular Malformations, Focus on Vascular
Imaging
Vascular imaging is at the cornerstone of ICH workup.6
About 20% of young patients with nontraumatic ICH
have a macrovascular origin,37 due to common condi-
tions that include arteriovenous shunts (arteriovenous
malformation) and cavernoma. Apart from the frequently
hemorrhagic cavernoma, other slow-flow vascular anom-
alies represented by brain capillary telangiectasia and
developmental venous anomalies can exceptionally be
responsible for bleeding. MRI enhances the diagnostic
sensitivity in slow-flow malformations, and for the detec-
tion of arteriovenous shunts using dynamic sequences
with exogenous (gadolinium-based) or endogenous
(arterial spin labeling) contrast agents38 may be benefi-
cial. The role of digital subtraction angiography in identi-
fying macrovascular lesions is beyond the scope of this
review, and we refer the reader to current guidelines.6
Side Wall and Fusiform Aneurysms
While aneurysms often result in subarachnoid hem-
orrhage, they can also cause ICH. Distal aneurysm
locations and larger sizes are correlated with ICH occur-
rences.39,40 Beyond genetic susceptibilities in typically
proximal bifurcation aneurysms that cause subarachnoid
hemorrhage, rarer causes for aneurysms that can cause
ICH include high-flow related aneurysms from arteriove-
nous malformation, mycotic aneurysms due to bacterial
wall invasion, drug-induced and (possibly delayed) post-
traumatic causes.
Hemorrhagic Dural Arteriovenous Fistula
Dural arteriovenous fistula can present with ICH, with
a predominance in males in the sixth decade.41 In the
context of ICH, certain imaging signs might suggest the
presence of a dural arteriovenous fistula. These are char-
acterized by asymmetrical or dilated dural arteries, mul-
tiple enlarged cortical veins, and distinct sinus-related
indicators. Notably, a shaggy appearance of a dural
venous sinus or the tentorium cerebelli, uneven attenua-
tion of the venous sinuses, the possibility of dural sinus
thrombosis, and the presence of transcalvarial channels
can be indicative (Figure SIV).
Cerebral Cavernous Malformation
The diagnosis is mainly based on T2*-weighted mag-
netic susceptibility imaging. The characteristic signal
anomalies of cavernous malformations are related to
the recentness or absence of central bleeding, possible
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 Tartarin et al
thromboses of different ages surrounded by glial tis-
sue, and peripheral hemosiderin deposition. The classic
appearance is berry-like (type 2) with often an associ-
ated developmental venous anomalies (Figure S5). The
presence of multiple cavernous malformations hints at a
familial form and prompts for a complete neuraxis imag-
ing as well as genetic investigation.
Reversible Cerebral Vasoconstriction Syndrome and
Posterior Reversible Encephalopathy Syndrome
RCVS and PRES exhibit overlapping pathophysiological,
clinical, and neuroradiological characteristics, stemming
from shared mechanisms like blood-brain barrier break-
down and endothelial dysfunction42,43 that can lead to
ICH. In both instances, clinical context, as well as associ-
ated imaging markers can facilitate the diagnosis.
RCVS typically afflicts women aged 20 to 50 years
and is often triggered by factors like recreational drug use
or postpartum periods. Hemorrhagic RCVS constitutes a
third of all cases, manifesting usually as localized sub-
arachnoid hemorrhage (SAH) and, in one-tenth of cases,
ICH.43 Clinically, the syndrome is marked by repeated
thunderclap severe headaches. Imaging often reveals
characteristic arterial vasoconstriction patterns (Figure 4).
Importantly, hemorrhagic forms can sometimes show ini-
tial normal imaging but later develop SAH or ICH. Notably,
RCVS might present with PRES-like forms, and hemor-
rhagic RCVS often showcases this phenomenon. When
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present, ICH is usually superficial and associated with
SAH.44 Infarctions are less frequent than hemorrhages.
On MR or catheter angiography, the classic presentation
associates arterial vasoconstriction, more often diffuse,
asymmetrical, and bilateral, but sometimes focal as well.
Early angiograms can also seem normal; the initial dis-
tal involvement and the string of beads aspect are better
seen on digital subtraction angiography.43,45
Figure 4. Reversible cerebral vasoconstriction syndrome.
Intracerebral hemorrhage (ICH) and intraventricular hemorrhage in a 2-d postpartum 39-year-old patient presenting repeated thunderclap
headache and altered level of consciousness 3 d after giving birth. Axial computed tomography (CT) scan demonstrates deep frontal hemorrhage
with intraventricular extension (A). Serial CT angiography show diffuse arterial narrowing (B, white arrowheads) that worsens in a centripetal
manner after 9 d (C) and had completely resolved on magnetic resonance angiography after 3 mo (D).
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Rare Causes of Intracerebral Hemorrhage
PRES is a multifaceted condition, not strictly restricted
to but predominant in the posterior brain regions. It is
Topical Review
associated with situations that induce endothelial dys-
function, such as preeclampsia, organ transplanta-
tion, and substance use. The hallmark of PRES is the
hypodense vasogenic edema on CT whereas on MRI,
hyperintensity on T2 (better seen on fluid-attenuated
inversion recovery), and restricted diffusion are noted.46
Hemorrhagic forms are more prevalent in transplan-
tation scenarios. Symptoms might manifest acutely or
subacutely, with encephalopathy and seizures being the
most common. Hemorrhagic PRES usually presents with
headaches and, at times, the combination of PRES and
RCVS can cause sudden severe headaches. Imaging
typically reveals vasogenic edema patterns, On MRI, ICH
is the most frequent hemorrhagic manifestation and is
isolated in most cases without concomitant sulcal SAH
(unlike RCVS). The hematoma is often small and formed
by petechiae. Microbleeds are present in the majority of
cases of susceptibility-weighted imaging (65%).47
Cerebral Venous Thrombosis
Cerebral venous thrombosis (CVT) represents ≈0.5% of
all cerebrovascular disorders. It is complicated by bleed-
ing in 40% of cases.48 In young patients with ICH, CVT
is approximated to be the cause of bleeding in 5% of
cases.49
Predisposing factors for CVT are both local, repre-
sented by infections and tumors, traumas (fractures
radiating to a dural sinus or jugular bulb), and systemic,
dominated by prothrombotic conditions such as cancer,
the use of oral contraceptives, and peripartum. Prodro-
mal headaches, which are unusual in other causes of
ICH, should raise suspicion of CVT. The diagnosis can be
challenging, but the presence of a lobar hematoma cen-
tered on the cortex and extending subcortically should
always prompt consideration of thrombosis given its
May 2024   7
 Tartarin et al
severe course in the absence of adequate treatment. In
the acute context, many centers prioritize CT with con-
Topical Review
trast due to its accessibility, good sensitivity (95%), and
specificity (90%). The examination should focus on find-
ing the classic intraluminal hyperdensity, a less sensitive
sign that is only found in 25% to 56% of cases within the
first 2 weeks. Venous CT angiography allows visualiza-
tion of the filling defect (empty delta sign when involving
the superior sagittal sinus), but it may be less effective in
the acute setting due to the spontaneously hyperattenu-
ating clot and in the chronic phase due to recanalization
channels (Figure S6).
Deep venous thrombosis, less frequent, often pres-
ents with bithalamic edematous congestion with hemor-
rhagic transformation in 19% of cases. It should prompt
consideration of differential diagnoses such as toxic or
metabolic infectious involvement, a tumor, or ischemia
due to distal basilar trunk. Unlike arterial transformation,
venous hemorrhagic transformation occurs in a centrip-
etal manner. Profound edema should raise suspicion of
an atypical form of PRES syndrome.48
Advances in CT and MRI have reduced a lot the role
of digital subtraction angiography in the diagnosis of
CVT but can still be performed in case of strong suspi-
cion without proof.
Moyamoya
Moyamoya disease is a rare, progressive cerebrovas-
cular disorder characterized by the narrowing of basal
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brain arteries. Moyamoya syndrome, meanwhile, refers to
conditions with similar vascular patterns caused by cer-
tain underlying diseases or factors, such as sickle cell
disease or neurofibromatosis, rather than the idiopathic
(unknown cause) nature of Moyamoya disease itself.
Figure 5. Moyamoya syndrome.
A 12-year-old male with deep hemorrhage and intraventricular bleeding (A). Perfusion imaging shows asymmetrical perfusion with increased flow
in right frontal lobe (B) due to arterial collateralization, downstream from a tight middle cerebral artery stenosis (C, black arrowhead). Incidental
distal aneurysm (D) developed on a collateral artery.
8   May 2024
Rare Causes of Intracerebral Hemorrhage
Moyamoya disease and Moyamoya syndrome are also
risk factors for ICH, especially in adults, which are most
often due to the development of intracranial aneurysms
on basal or pial collaterals (Figure 5).
ICH due to Moya Moya is extremely rare in children
with the noneast Asian phenotype, and the incidence
increases with age.50 Patients with sickle cell may
develop various types of arteriopathies including moya-
moya arteriopathy and aneurysms and me be more prone
to ICH with increasing age.51 In patients with a MoyaM-
oya vascular pattern and an ICH, an aneurysm should be
excluded.
ICH With an Infrequent but Probable Cause
Hematologic Disease
Bleeding diathesis is identified with routine laboratory
work, drawn at the acute phase of ICH during initial eval-
uation (complete blood count, prothrombin time/interna-
tional normalized ratio/partial thromboplastin time).6
Intracranial hemorrhage (ICH) is the most serious
bleeding event in patients with hemophilia and inherited
rare coagulation such as severe deficiencies of fibrino-
gen, factor (F) II, FV, FVII, and FXIII, leading to disabil-
ity and death. ICH occurs among all ages but is more
frequent in newborns and adults, describing a U-shaped
curve over a lifetime.52
ICH may occur in all patients with all severities of
hemophilia treated on-demand or receiving prophy-
laxis and in adults with comorbidities but the severity
of hemophilia is the most relevant risk factor. A recent
systematic review and meta-analysis52 concluded that
ICH is an important problem in hemophilia requiring
adequate preventive strategies. The authors observed
Stroke. 2024;55:00–00. DOI: 10.1161/STROKEAHA.123.043917
 Tartarin et al
that spontaneous hemorrhages were relatively com-
mon but also probably associated with trivial head
trauma without a clear impact. Although new prophy-
lactic treatment options for bleeding disorders and
in particular hemophilia reduce other bleeds such as
muscular and joint bleeds, we do not know yet their
efficacy on reducing the frequency of ICH and their
influence on outcome.
Sneddon syndrome, a rare noninflammatory throm-
botic arteriopathy, primarily affects small to medium-
sized arteries53,54 affecting 4 per million annually.
Hemorrhagic strokes, although less frequent, are sig-
nificant, accounting for around 7% of all strokes in this
condition. Cortical watershed microbleeds associated
with the syndrome, originally noted in familial cases, are
found in sporadic cases as well, sparing the basal gan-
glia and brainstem.55
Remote Postsurgical ICH
A less common pathogenesis of intraparenchymal bleed-
ing is remote cerebellar hemorrhage, where bleeding
occurs at a location distant from the surgical site. This
complication is seen following supratentorial cranioto-
mies (0.08% to 0.6% of interventions of all types, espe-
cially in cases involving the opening of cisterns or the
ventricular system), and less frequently after spinal sur-
geries (Figure S7).56 The hemorrhage primarily affects
the superior aspect of the cerebellum. The occurrence
of bilateral subarachnoid hemorrhage (74%) creates the
Downloaded from http://ahajournals.org by georgenunesmendes@gmail.com on April 8, 2024
highly suggestive zebra sign, which appears as streaky
curvilinear hyperattenuating areas in the sulci and folia.57
It is crucial not to mistake remote cerebellar hemorrhage
for more serious conditions such as hemorrhagic infarc-
tion or Duret hemorrhage. The latter occurs in the floor
of the fourth ventricle and results from transtentorial her-
niation, leading to damage to perforating arteries arising
from the basilar artery. The involvement of the activat-
ing reticular formation explains the dreadful prognosis of
Duret hemorrhage toxic-related ICH.
Methanol Intoxication
ICH is a classic complication of methanol intoxication, a
substance found in many commercial products (eg, gas-
oline anti-freeze, organic solvents, perfumes) but also in
adulterated alcohol. This widespread intoxication often
occurs in the context of misuse of illicit alcoholic bever-
ages, suicide attempts, accidents, or misuse.58
Within 12 to 24 hours following intoxication, symp-
toms include generalized weakness, nausea, vomit-
ing, headache, abdominal pain, breathlessness, and,
in severe cases, convulsions and coma.59 Within a
few days, cytotoxic edema appears with bilateral and
symmetrical infarction of the superficial white matter
and putamen. It is in a later stage of the disease, after
several days, that macro hemorrhages occur in the
infarcted areas, with a clear predominant involvement
of the putamen.58–60
Stroke. 2024;55:00–00. DOI: 10.1161/STROKEAHA.123.043917
Rare Causes of Intracerebral Hemorrhage
Toxic and Radiation-Induced ICH
Cocaine is well documented as being associated with
Topical Review
neurovascular complications such as hemorrhagic
(ICH, SAH, intraventricular hemorrhage) and ischemic
strokes.61,62 The risk of hemorrhagic events (ICH, SAH)
after cocaine use is correlated with metabolite concen-
trations in the serum. This risk was found to be more
prominently increased with recent cocaine use than the
risk of ischemia, and in general, hemorrhagic complica-
tions are twice as frequent.
IPHs occurring after cocaine use are classically sub-
cortical in location, predominantly affecting the basal
ganglia. A lobar location should prompt consideration
of performing a catheter angiography. Cocaine use is a
known risk factor for RCVS, with an increased risk of
hemorrhagic forms.63
It should be noted that heroin or amphetamines after
prolonged exposure can also result in neurovascular com-
plications. Ecstasy or 3,4-methylenedioxymethamphetamine
(a drug derived from amphetamines) can induce immune-
mediated vasculitis and prolonged vasospasm of small
vessels, primarily at risk of ischemia but also, albeit less fre-
quently, of hemorrhage.62
Radiation-induced cerebral vasculopathy is a late
complication of brain irradiation. It results from a com-
plex dose-dependent process affecting blood ves-
sels of all calibers (arteries and capillaries are more
affected than veins) through progressive endothelial
loss. Large-caliber vessels develop atherosclerosis
with intraplaque hemorrhage, differentiating it from
classic atherosclerosis.64 Imaging may reveal atypi-
cal bilateral atherosclerosis with circumferential wall
enhancement with ectasias, stenoses, and complete
occlusions of large and medium-caliber vessels.64
Cerebrovascular events can be ischemic, with pre-
dominantly lacunar infarcts, but also include cerebral
microbleeds and ICH. The latter does not appear to
occur directly through toxic vasculitis but through the
radiation-induced development of cavernomas, aneu-
rysms, AVMs, or Moyamoya syndrome due to collateral
development.64
Specificities in Childhood
ICH can appear throughout childhood,65 starting from
the fetal period. Etiology depends on age. Perinatal ICH
appearing in term-born babies without a relevant perinatal
risk factor should raise the suspicion of a bleeding diathe-
sis or, if ruled out, of an underlying, monogenic pathogen-
esis, such as COL4A1/A2-related disorders. Other clues
for this group of collagenopathies include white matter
abnormalities, malformations of cortical development or
ophthalmic malformations.66,67 Due to the variable expres-
sion and decreased penetrance, a wide phenotypic range
between family members is seen, even with the same
mutation. Outside the perinatal period, the most common
May 2024   9
 Tartarin et al Rare Causes of Intracerebral Hemorrhage

cause of nontraumatic ICH in children is vascular mal- Table. Synoptic Table of Clinical Imaging Red Flags for an
formations, including cerebral cavernous malformations, Uncommon Cause
Topical Review

brain arteriovenous malformations (bAVMs), arteriove- Clinical—imaging clues ICH cause

nous fistulas (AVFs), or ruptured aneurysms.68 In patients Thunderclap headache RCVS
with multiple cerebral cavernous malformations, a genetic CVT
Aneurysmal SAH
testing to seek for mutations in CCM1-CCM3 genes
should be performed. bAVMs and congenital pial AVFs Fever CNS infection
Endocarditis
can be associated with a genetic syndrome in a minority of Systemic angiitis with CNS involvement
children.69 Hereditary hemorrhagic telangiectasia is asso- History of active cancer Hemorrhagic metastasis
ciated with telangiectatic lesions of the face and inter- Hemorrhagic primary brain tumor
nal organs, leading to recurrent epistaxis, gastrointestinal Severe hemostatic abnormalities
bleeding, and other hemorrhagic complications. As these Coexistence of ischemic and CVT (ischemic lesions do not follow
manifestations mostly appear later in life, it is important to hemorrhagic acute lesions vascular territories)
RCVS
obtain an appropriate family history to discover potentially PRES
affected individuals. Capillary malformation-arteriovenous Endocarditis
malformation (CM-arteriovenous malformation) or Parkes CNS angiitis
DADA2
Weber syndrome are autosomal dominant inherited dis-
Disproportionate edema Metastatic hemorrhages
orders caused by variants in the RASA1 (RAS P21 pro- CVT
tein activator 1) or EPHB4 (EPHrin type B receptor 4) PRES
genes. Atypical capillary malformations on the skin are Multiple ICH Metastatic hemorrhages
often identified. Fast-flow vascular malformations in the CVT
RCVS
skin, muscle, bone, spine, and brain often occur early in
CNS angiitis
life. Excessive growth of an affected limb can occur in Endocarditis
Parkes Weber.68 Connective tissue disorders, such as vas- Leptomeningeal enhancement Meningitidis
cular Ehlers Danlos or Loeys-Dietz syndrome can rarely CNS angiitis
be associated with ICH due to rupture of an aneurysm Associated SAH Aneurysm
or a dissection.70 Typical facies as well as the history of CVT
RCVS
easy bruising, recurrent joint dislocations, and abnormal DAVF
wound healing should raise suspicion for these disorders.
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AVM
Other, rare genetic vascular disorders that can cause ICH Drug use PRES
in children and young adults include metabolic disorders RCVS
such as Menkes disease or glutaric aciduria. Adenosine Cocaine related angiitis

deaminase 2 deficiency, an autosomal recessive disorder Psychiatric symptoms Monogenic SVD

characterized by a wide clinical spectrum, including small-
and medium-sized vessel vasculopathies may be associ-
ated with microbleeds or larger ICH.71 Inherited bleeding
diathesis including thrombocytopenia or coagulopathy of
any cause as well as brain tumors are uncommon causes
of pediatric ICH (mainly subdural hematomas) and should
be sought if there is a history of bleeding from other,
extracranial sites.72
CNS angiitis
Severe/disproportionate white Monogenic SVD
matter hyperintensities and
lacunes
AVM indicates arteriovenous malformation; CNS, central nervous system;
CVT, cerebral venous thrombosis; DADA2, deficiency of adenosine deaminase 2;
DAVF, dural arteriovenous fistula; PRES, posterior reversible encephalopathy syn-
drome; RCVS, reversible cerebral vasoconstriction syndrome; SAH, subarachnoid
hemorrhage; and SVD, small vessel disease.

CONCLUSIONS
The evaluation of ICH requires a comprehensive under-
standing of etiologies. We have outlined the diverse and
rare presentations and presented a practical approach
for investigating the rare causes of ICH, emphasizing the
need to pay special attention to clinical and radiologi-
cal red flags for an uncommon cause (Table). Integrated
with clinical and biological features, advanced parenchy-
mal and vascular imaging play a crucial role in identifying
markers of tumoral, inflammatory, or infectious pro-
cesses, small vessel diseases, or macrovascular causes.
Clinical context will help identify certain infrequent but
probable causes.
ARTICLE INFORMATION
Affiliations
Diagnostic and Interventional Neuroradiology, University Hospital, Tours, France
(H.T., G.B.). Neurology Unit, Department of Clinical and Experimental Sciences,
University of Brescia, Italy (A.M.). Department of Neurology, Leiden University
Medical Center, the Netherlands (E.S.V.E.). Pediatric Neurology Institute, Dana-
Dewk Children’s Hospital, Tel Aviv Sourasky Medical Center, Faculty of Medicine,
Tel Aviv Unisversity, Israel (M.H.-K.). Department of Neurology, Boston University,
MA (A.C.). Neurology Department, Lariboisière Hosp, APHP and Université Paris
Cité, France (E.J.). Hematology and Transfusion Department, Centre Hospitalier
Universitaire de Lille, France (S.S.). Univ. Lille, Inserm, CHU Lille, U1172 - LilN-
Cog - Lille Neuroscience and Cognition, France (C.C.). Stroke unit, CHU Tours,
Centre Val de Loire, France (M.P.). INSERM 1253 iBrain, Tours, Centre Val de
Loire, France (G.B.). CIC-IT 14.15, Tours, Centre Val de Loire, France (G.B.).
Acknowledgments
The authors thank the FCrin Strokelink network for their support. Drs Tartarin,
Morotti, Van Etten, Charidimou, Hausman-Kedem, Jouvent, Susen, and performed

10   May 2024 Stroke. 2024;55:00–00. DOI: 10.1161/STROKEAHA.123.043917

 Tartarin et al
literature review, draft writing—review for critical intellectual content. Dr Boulouis
performed supervision; methods validation; draft writing—review for critical intel-
lectual content.
Sources of Funding
None.
Disclosures
Dr Morotti declares expert meeting and advisory board honoraria from EMG-REG
and AstraZeneca. Dr Cordonnier participated to boards (Novartis), is a member of
steering committees (Biogen, BMS, Bayer). Dr Van Etten declares unpaid consul-
tancy for Alnylam Pharmaceuticals. The other authors report no conflicts.
Supplemental Material
Figures S1–S7
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