[Shortened Title up to 50 Characters]

Brain abscess in a patient with Hereditary Hemorrhagic

Telangiectasia
Marshall D. Rutherford BS; Harris Shaikh, DO; Ammar Rizvi, MS4; Rachel Banach, MS4
1
McLaren Oakland, Pontiac, Michigan
2
Department of Radiology, McLaren Oakland

Corresponding Author:
Harris Shaikh
Email:
Phone:
Fax:

Institutional Review Board Statement:

Financial Support: None. The authors did not receive grant or outside funding in support of their research or preparation of this
manuscript. They did not receive payment or any benefits from commercial entities.

Conflicts of Interest: None. The authors were not compensated or funded in any way for the preparation of this manuscript. This study
has not been submitted elsewhere. We understand and agree that if the manuscript is accepted for publication, copyright in the article,
including the right to reproduce the article in all forms and media, shall be assigned to the publisher.
[Shortened Title up to 50 Characters]
Abstract

Hereditary hemorrhagic telangiectasia (HHT), or Osler-Weber-Rendu syndrome, is an autosomal

dominant disorder characterized by mucosal telangiectasias, epistaxis, visceral vascular malformations

and iron deficiency anemia. Neurological complications such as transient ischemic attacks and brain

abscesses is a common presentation seen in pulmonary arteriovenous malformations (PAVM) in HHT

patients Here we report on two patients with HHT who developed neurological complications

secondary to PAVMs.

Keywords:
[Shortened Title up to 50 Characters]
Brain abscess in a patient with Hereditary Hemorrhagic Telangiectasia

Introduction

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is

an autosomal dominant disorder of the vasculature. HHT most commonly manifests as epistaxis,

gastrointestinal bleeding, iron deficiency anemia, and mucocutaneous telangiectasia. This disease can

lead to arteriovenous malformations (AVMs), which can occur at any age, and tend to occur in the

brain, lung, and liver. Pulmonary AVMs can lead to hypoxemia and right-to-left shunts that can lead to

complications such as an embolic stroke or brain abscess. Unfortunately, most patients are unaware of

their diagnosis of HHT, therefore HHT is subject to underreporting[ CITATION 1 \l 1033 ]. Prompt

diagnosis and screenings is pivotal for patients with HHT and their relatives. Here we report on two

patients with HHT who developed neurological complications secondary to PAVMs.

Case 1

A 71-year-old female presented to the Emergency Department after falling down a flight of

stairs. The patient had no recollection of what happened, she only remembers falling down the stairs.

She also stated that she had not felt “right” for the past couple of days. Her past medical history was

significant for hypertension, hyperlipidemia, diabetes mellitus type 2, left pulmonary AVM, tubal

ligation, endovascular coiling for a brain aneurysm and HHT. The physical exam was significant for

tenderness in the neck and the left side of her chest. The emergency physician ordered a computed

tomography (CT) of the chest, abdomen and pelvis, which revealed a lateral left 5th rib fracture with a

left side pneumothorax (Fig. 1) and a left articular mass fracture of C7. The patient remained in a c-

collar and a Heimlich valve was placed in the left upper chest.

Further imaging studies showed incidental findings of a left parietooccipital cystic brain mass

with surrounding edema on head CT (Fig. 2C, D). As well as an enhancing lung mass within the
[Shortened Title up to 50 Characters]
superior segment of the left lower lobe on (Fig 1), consistent with a pulmonary AVM. The cystic brain

mass was evaluated further with an MRI of the brain. Findings showed a ring-enhancing lesion in the

left parietooccipital lobe associated with restricted diffusion, a moderate amount of surrounding

vasogenic edema and mass effect indicating the finding of a brain abscess (Fig. 2A, B). Neurosurgery

was consulted for evaluation, where the patient underwent a successful left parietooccipital craniotomy

with evacuation of the intraparenchymal abscess. A postoperative CT found no evidence of bleeding or

midline shift (Fig. 3). Abscess fluid tested positive for alpha hemolytic Streptococcus, when infectious

disease was subsequently consulted. The patient was started on antibiotics following infectious disease

recommendations. On the seventh day of admission, the patient was able to ambulate with a walker and

was discharged to a rehabilitation facility. She was sent with instructions to follow up outpatient with

neurosurgery, infectious disease, and pulmonology and to continue the antibiotics as directed.
[Shortened Title up to 50 Characters]
Case 2

A 38-year-old right-handed female presented to the emergency department with a few months

history of intermittent dizziness, vertigo and occasional difficulty writing. She has been evaluated by

the family medicine clinic and underwent MRI recently and received her results today, when she was

instructed to report to the emergency department. Results from her MRI revealed subacute right

cerebellar infarcts. Her past medical history is significant for iron deficiency anemia and daily epistaxis

since childhood. She also has a strong family history of Osler-Weber-Rendu Syndrome. On physical

exam the only significant finding was mucosal telangiectasias on her lower lip and tongue. The patient

was subsequently then admitted for further workup.

Initial blood investigations were notable for iron deficiency anemia. Given her presentation and

significant family history, CT angiography of the chest was performed which revealed a left upper lobe

PAVM measuring 1.5 cm, right lower lobe PAVM measuring 0.5 cm, as well as a hepatic hemangioma

within the dome measuring 2 cm. After returning from CT, the patient experienced left sided numbness

for 20 min. The patient subsequently underwent TEE which revealed no ASD/PFO but was notable for

right-to-left shunting. Cardiac MRI showed no evidence of ASD or PFO.

On day 6, the patient again experienced transient left side paresthesia of the face, when an MRI

of the brain was ordered. Patient underwent MRI with FLAIR revealing contrast enhancement within

the right vermis as well as peripherally within the right cerebellar hemisphere indicating subacute

infarct.

The following day she underwent uncomplicated pulmonary coil embolization for PAVMs in

both the left upper lobe as well as the right lower lobe. Postoperatively there was no complications,

subsequently being discharged the following day. It was recommended to follow up in 1 week for TEE

and in 6 month for CTA of the chest.

[Shortened Title up to 50 Characters]

Discussion

Hereditary hemorrhagic telangiectasia has an estimated prevalence rate between 1/5000 and 1/8000, although
there has been higher rates in isolated populations, for example 1/1330 in Curacao and Bonaire {U 1-6].
Unfortunately, most patients are unaware of their diagnosis of HHT, therefore HHT is subject to underreporting
[1].

Being a hereditary disorder, with autosomal dominant transmission, there is multiple identifiable genes
involved in HHT. The three most prominent of these genes are ENG (HHT1), ACVRL1 (HHT2), and SMAD4 (JPHT)
– juvenile polyposis-HHT. ENG and ACVRL1 translate to transmembrane glycoproteins endoglin and activin
receptor-like kinase1 (ALK-1), respectively. Endoglin and ALK-1 are present on vascular endothelial cells, while
SMAD4 is a part of the signal transduction cascade. [8] [9] [10] [11] [12] Together these proteins affect the
signaling pathway via the TGF-beta superfamily ligands. [2] [5] All of the clinical features associated with HHT
can be seen with mutation in all three of these genes but, pulmonary and cerebral AVMs are more closely
associated with mutations in ENG. [13] [5] The main mechanism believed to be the cause of these mutations is
seen within the termination codon, causing a nonsense mutation. These nonsense mutations cause insufficient
production of their respective proteins leading to vascular defects. [7] One example of these vascular defects
are arteriovenous shunts and can present as pulmonary AVMs (sacs), nidal AVMs (small collection of
intervening vessels), or arteriovenous fistulas (direct high-flow connection). There is still uncertainty regarding
why certain vascular beds are more prone to develop AVMs. It is also unclear as to whether VEGF is directly
involved from what has previously been coined, or has it adopted a TGF-beta superfamily disease, or do these
observations reflect the role of angiogenesis as a “second-hit” phenomenon. [5]

HHT most commonly manifests as epistaxis, gastrointestinal bleeding, mucocutaneous telangiectasias, and a
tendency to develop iron deficiency anemia secondary to blood loss. Aiding in making the clinical diagnosis
easier is the Curacao criteria (Table 1), which is based on: multiple site of telangiectasia, epistaxis, visceral
involvement and family history. [2] Visceral AVMs usually are clinically silent, but can cause significant
pathology, as seen in both of our patients. The incidence of visceral AVMs in patients suffering from HHT
reported: 67% have hepatic involvement, 50% of patients developing Pulmonary AVMs (PAVMs), and around
33% have cerebral vascular malformations.[3]

 Hepatic AVMs are usually silent, when symptoms do occur, they seem to cause high-output cardiac
failure, portal hypertension or biliary disease. {U,74-76}}
 The pathogenic cause of brain AVMs is not well understood. The size varies widely and sometimes
over time they can remodel, growth or regress. {c 4,5} Cerebral AVMs are believed to begin to
develop in childhood and have a variable age at presentation. When found they can present
between 10-40 and most often are numerous. In children, AVMs can develop macrocephaly or
hydrocephalus, due to the systemic overload or hydrovenous dysfunction. Cerebral AVMs can also
manifest as seizures, strokes or hemorrhage. {U38,43,60,69}} Other malformations CAPILLARY
TELANGIECTASIA of brain????
[Shortened Title up to 50 Characters]
Pulmonary AVMs precise pathogenic cause is unknown. Pulmonary AVMs are uncharacteristically thin walled
vessels that have an abnormal connection between the pulmonary artery and vein. With lacking the capillary
component, this results in a right-to-left shunt. The shunting between the two systems prevents proper
oxygenation, from the lack of the capillary component, resulting in hypoxemia. PAVMs are usually clinically
silent, with about one third of affected patients present with symptoms, with the most common being dyspnea
and hemoptysis. Other symptoms of patients with PAVMs can present with are: platypnea, chest pain, cough,
clubbing, cyanosis and murmurs. For individuals that initially present or are incidentally found to have a PAVM,
studies have suggested that up to 90% of have underlying HHT. [6]

Pulmonary AVMs are a significant factor in those with HHT and put them at increased risk of complications.
PAVMs are associated with a variety of complications such as: pulmonary hypertension, polycythemia, anemia,
hemothorax, hemoptysis and neurological complications. The most common complication of PAVMs is also the
most serious, strokes and brain abscesses. {{P13,18}} The most likely pathogenesis for both strokes as well as
brain abscesses arise from the paradoxical embolization across the PAVM possible by the right-to-left shunt. It
has also been noted that paradoxical embolization occurs more often when feeding arteries are >2-3 mm in
diameter. Increased risk of neurological complications is also associated with an increased number of PAVMs
and patient age. [5] For patients with HHT and PAVMs, iron deficiency anemia has started to emerge as a
strong risk factor for ischemic strokes. Those with serum iron of 6 micromol/L were two times more likely to
have a stroke than those compare in the normal range (7 – 27 micromol/L). [{iron def.}} Patients with iron
deficiency anemia was also associated with enhanced platelet aggregation in response to 5-hydroxytryptamine.
[U-86}}

It has been well documented that brain abscesses are the most serious neurological complications of PAVMs,
which tends to occur in about 5-10% of patients. [5] Brain abscesses initially begin with an area of
unencapsulated inflammation and edema, with this early stage being referred to as cerebritis. After 2-3 weeks,
a collection of pus accumulates, and liquefactive necrosis occurs. This is then covered by a distinct capsule
consisting of an inner layer of granulation tissue, a middle collagenous layer and an outer astroglial layer, while
the surrounding brain parenchyma is often edematous. [14] The most common bacteria involved in cerebral
brain abscesses are Staphylococcus aureus and Streptococcus viridans. In this case report our patient tested
positive for alpha hemolytic Streptococcus, while anaerobic and Staphylococcus bacteria were ruled out.

The management and treatment for those with HHT is mainly reserved for specific vascular lesions, unless
there is significant bleeding. Epistaxis is usually the cause of iron deficiency anemia, due to the possibility of
daily recurrences, there are local and systemic therapies available. {{Mg3,17-19}} For hepatic lesions, most
remain asymptomatic and the small proportion that does experience symptoms, standard hepatic care is often
sufficient. For those with highly symptomatic cerebral lesions treatment is appropriate and feasible with many
options that include surgical excision, endovascular techniques, and stereotactic radiotherapy
{http://www.arubastudy.org/ (Accessed on 7/10/2019}} However, in contrast to symptomatic cerebral lesions,
current literature is less clear that asymptomatic individuals with HHT should be treated aggressively. This is
due to the results in the ARUBA trial, which revealed a threefold increased risk of bleeding with treatment of
asymptomatic cerebral AVMs. [4] However, the ARUBA trial specifically refers only to cerebral AVMs.
Treatment for pulmonary AVMs is highly recommended to reduce risks of neurologic complications. Patients
should receive antibiotics prior to dental procedures, surgery, and any potential nonsterile procedure with the
overall goal to reduce bacteremia. [5] Although indications are not defined, It has been recommended that
[Shortened Title up to 50 Characters]
patients with a feeding artery > 2 mm and those who are symptomatic, regardless of size, should receive
embolotherapy. [[P 5-7,9-11}} Patients who are not suitable for embolotherapy due to an inaccessible lesion
should be referred for surgery. It is recommended for those with feeding arteries <2 mm to be followed
clinically with non-contrast CT every 3-5 years. [[P 7,9-15}}

Strategies for screening individuals is mainly reserved to diagnose AVMs in high risk individuals, or those with
HHT who are asymptomatic. The screening tools consists of the following: Basic clinical exam, evaluation for
Iron deficiency anemia, PAVM screenings, and discussion with the patient regarding screening vs non-screening
for other AVMs (cerebral, hepatic, spinal). { vascern}} It is recommended that patients with HHT be screened
for PAVM due to the high incidence of silent pulmonary lesions, in addition to the evidence of risk reduction of
stroke and brain abscesses with treatment. It is recommended for individuals over 16 years of age with HHT to
begin screening process. The initial screening test should assess the shunt fraction of the PAVM, with a
transthoracic contrast echocardiography (TTCE; also known as “bubble echocardiography”). {{P 49,50,52-58)
Additional testing with non-enhanced CT depends on the grade results of TTCE

Conclusion

● Individuals with HHT have abnormal blood vessels and have vascular lesions which place them

at an increased risk for hemorrhage, AVM or detrimental effects from right-to-left shunting.

● The worst outcome from a paradoxical embolus is brain abscess, caused by either S. aureus or

S. viridans.

● If you have a patient that has recently been diagnosed or has a previous history of HHT, it is

recommended to treat specific high-risk vascular lesions together long term surveillance to

prevent further complications.

Arthur = 1

Bideau = 2

Dakeishi = 3

Kjeldsen = 4

Guttmacher HHT = 5

Westermann = 6

Shovlin CL Buscarini, European = 7

13 = mcalister = 8
[Shortened Title up to 50 Characters]
5 = mohr , medical management = 9

2 = hall = 10

3 = abdalla = 11

Garcia = 12

DeLeve = 13

Buscarini Liver involvement = 14

Mohr kejda-sc Dx and tx avm = 15

Moftakhar = 16

Haitjema = 17

Fulbright = 18

Bharatha = 19

Maher, piepgras = 20

6 = Shovlin uptodate = 21

Swanson = 22

Wong = 23

IRON DEF ANEMIA = 24

Woods = 24

14 - Bordaeau = 25

Geisthoff = 26

Silva = 27

Elphick = 28

Chamali = 29

Aruba = 30

4 - Shovlin HHT = 31
[Shortened Title up to 50 Characters]
Gossage JR, kanj PAVM= 32

Mager = 33

Cottin, plauchu = 34

Moussouttas = 35

White = 36

Shovlin primary det = 37

Velthuis, buscar, van gent = 38

Hewes = 39

Todo = 40

Lee = 41

Shovlin embolization = 42
[Shortened Title up to 50 Characters]

References

H. Arthur, U. Geisthoff, J. Gossage and et al., "Executive summary of the 11th HHT international

scientific conference.," Angiogenesis, p. 18:511, 2015.

S. Abdalla and M. Letarte, "Hereditary haemorrhagic telangiectasia: current views on genetics

and mechanisms of disease.," Journal of Medical Genetics, pp. 43, 97-110, 2006.
C. Shovlin and M. Letarte, "Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous

malformations: issues in clinical management and review of pathogenic mechanisms.,"

Thorax, p. 54:714, 1999.

J. Mohr, M. Parides, C. Stapf and et al., "Medical management with or without interventional

therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-

blinded, randomised trial.," Lancet, p. 383:614, 2014.

C. Shovlin and e. b. L. a. T. J. UptoDate, "Clinical manifestations and diagnosis of hereditary

hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)," 2019. [Online]. Available:

https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-

hemorrhagic-telangiectasia-osler-weber-rendu-syndrome?

source=history_widget#references.
L. Pawlikowska, J. Nelson, D. Guo and et al., "he ACVRL1 c.314-35A>G polymorphism is

associated with organ vascular malformations in hereditary hemorrhagic telangiectasia

patients with ENG mutations, but not in patients with ACVRL1 mutations.," Am J Med

Genet A, p. 167:1262, 2015.

F. Govani, A. Giess, I. Mollet and et al., "Directional next-generation RNA sequencing and

examination of premature termination codon mutations in endoglin/hereditary

haemorrhagic telangiectasia.," Mol Syndromol, p. 4:184, 2013.

J. N. Berg, C. J. Gallione, T. Stenzel and et al., "The activin receptor-like kinase 1 gene: genomic

structure and mutations in hereditary hemorrhagic telangiectasia type 2," Am J Hum

[Shortened Title up to 50 Characters]
Genet, p. 61:60, 1997.
K. Gkatzis, J. Thalgott, D. Dos-Santos-Luis and et al., "Interaction Between ALK1 Signaling and

Connexin40 in the Development of Arteriovenous Malformations.," Arterioscler Thromb

Vasc Biol, p. 36:707, 2016.

F. S. Govani and C. L. Shovlin, "Hereditary haemorrhagic telangiectasia: a clinical and scientific

review," EUR J Hum Genet, p. 17; 860, 2009.

D. Johnson, J. Berg, M. Baldwin and et al., "Mutations in the activin receptor-like kinase 1 gene

in hereditary haemorrhagic telangiectasia type 2," Nat Genet, p. 13:189, 1996.

K. McAllister, K. Grogg, D. Johnson and et al., "Endoglin, a TGF-beta binding protein of

endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1.," Nat

Genet, p. 8:345., 1994.

A. Bourdeau, U. Cymerman, M. Paquet and et al., "Endoglin expression is reduced in normal

vessels but still detectable in arteriovenous malformations of patients with hereditary

hemorrhagic telangiectasia type 1.," Am J Pathol, p. 156:911, 2000.

M. Bokhari and F. Mesfin, "Brain Abscess. [Updated 2018 Nov 14].," In: StatPearls [Internet].

Treasure Island (FL): StatPearls Publishing, p. Available from:

https://www.ncbi.nlm.nih.gov/books/NBK441841/, 2019 Jan-. .

W. Hall, "Hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease) presenting with

polymicrobial brain abscess.," J Neurosurg., pp. 81:294-6, 1994.

[Shortened Title up to 50 Characters]
[Shortened Title up to 50 Characters]

Tables

Table 1
Curaçao diagnostic criteria – Definite diagnosis: presence of 3 criteria, Suspected or possible diagnosis:
presence of 2 criteria, and unlikely if fewer than that.[ CITATION 6 \l 1033 ]
Epistaxis Spontaneous and recurrent epistaxis
Telangiectasia Multiple at characteristic sites: lips, tongue, fingers, nose
Visceral involvement Gastrointestinal telangiectasia
PAVM
Hepatic AVM
Cerebral AVM
Spinal AVM
Family history First-degree relative
[Shortened Title up to 50 Characters]
Figures