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Brain Arteriovenous Malformations in Patients With Hereditary Hemorrhagic Telangiectasia: Clinical Presentation and Anatomical Distribution
Pediatric Neurology 49 (2013) 445e450
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Original Article
Brain Arteriovenous Malformations in Patients With Hereditary Hemorrhagic Telangiectasia: Clinical Presentation and Anatomical Distribution Maha Saleh MD a, b, Melissa T. Carter MSc, MD, FRCPC a, b, Giuseppe A. Latino BS a, Peter Dirks MD, FRCPC d, Felix Ratjen MD, PhD, FRCPC a, c, * a
Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada Division of Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada c Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada d Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada b
abstract BACKGROUND: Hereditary hemorrhagic telangiectasia is an autosomal dominant genetic disease with a wide array of vascular malformations involving multiple organs. Brain arteriovenous malformations can lead to intracranial hemorrhage and are often diagnosed only after patients become symptomatic. Early diagnosis and interventional treatment may prevent neurologic sequelae or death. Because of the rarity of defined cases, the spectrum of presentations in children with brain arteriovenous malformations and hereditary hemorrhagic telangiectasia has not been explored in detail. Here, we report our experience in children with hereditary hemorrhagic telangiectasia and brain arteriovenous malformations regarding both disease manifestations at presentation and the spectrum of brain arteriovenous malformation manifestations. METHODS: A retrospective review of demographics, clinical manifestations, and brain magnetic resonance imaging/computed tomography scan findings in 115 patients with confirmed hereditary hemorrhagic telangiectasia (HHT) was conducted using the Hospital for Sick Children’s HHT Clinic database for the years 1997-2012. RESULTS: Eleven patients (four girls and seven boys) were diagnosed with hereditary hemorrhagic telangiectasia and brain arteriovenous malformations during this period. Five patients initially presented with epistaxis, four presented with intracranial hemorrhage, and two were asymptomatic with a positive family history of confirmed hereditary hemorrhagic telangiectasia. Although all children had an index case with hereditary hemorrhagic telangiectasia in the family, in three patients, hereditary hemorrhagic telangiectasia was not diagnosed before the child’s presentation with intracranial hemorrhage. Multiple brain arteriovenous malformations were found in five patients, with one patient having bithalamic arteriovenous malformations. CONCLUSIONS: This study highlights the importance of both family history and early clinical signs to prompt further diagnostic testing to avoid intracranial hemorrhage from brain arteriovenous malformations in children with hereditary hemorrhagic telangiectasia. Keywords: hereditary hemorrhagic telangiectasia, vascular malformations, arteriovenous malformations, intracranial hemorrhage
Pediatr Neurol 2013; 49: 445-450 Ó 2013 Elsevier Inc. All rights reserved. Introduction
Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is an autosomal
Article History: Received 12 April 2013; Accepted in final form 30 July 2013 * Communications should be addressed to: Dr. Ratjen; Division of Respiratory Medicine; Department of Pediatrics; Hospital for Sick Children; Toronto, Ontario, Canada. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2013.07.021
dominant disorder with high penetrance and variable expressivity. It is characterized by mucocutaneous telangiectases and arteriovenous malformations (AVMs) most often found in the cerebral, pulmonary, and hepatic circulation.1 Diagnosis of HHT is based on clinical signs and symptoms, family history, and presence of a pathogenic mutation. A clinical diagnosis is established if three of four criteria are present. These include: (1) history of spontaneous and recurrent epistaxis; (2) presence of mucocutaneous telangiectases; (3) a first-degree relative with confirmed HHT; and (4) the presence of visceral AVM.2,3
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TABLE 1. Characteristics of the study population
Patient
Gender
Family History
Familial HHT Confirmed Before Child’s Diagnosis
Affected Parent
Index Case
Clinical Signs at Initial Presentation
Age at Initial Presentation (yr)
Age at Diagnosis (yr)
Affected Gene
Mutation
1 2
F F
þ þ
þ
Mother Mother
Child Mother
ICH None
16 0
16 0.33
N/A* ENG
3 4 5 6 7 8 9 10 11
M M M M F M M F M
þ þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ
Father Father Mother Father Father Mother Mother Father Father
Father Father Child Father Father Mother Mother Father Child
Epistaxis Epistaxis ICH ICH Epistaxis Epistaxis Epistaxis None ICH
6.5 8 12 0.6 5 6 4 0.67 1.7
7.5 8 12 0.6 6 6 4 0.67 1.7
ENG ENG N/A* ACVRL1 ENG ENG ENG ENG ENG
N/A Exon 12: c.1738-1741dup c.360þ1G > A c.588 G > A N/A c.1454 G > A c.657_658delCA c.588 G > A c.360þ1G > A c.657_658delCA Deletion exon 2
Abbreviations: ICH ¼ Intracranial hemorrhage F ¼ Female M ¼ Male N/A ¼ Not available * No pathogenic mutation was identified in either ENG or ACVRL1.
HHT is caused by mutations in at least three genes involved in the transforming growth factor-b/bone morphogenetic protein signaling cascade: ENG, the gene encoding the cell surface co-receptor endoglin,4e11 ACVRL1 (Activin receptor type IIelike 1[ALK1]),12,13 another gene encoding a cell surface receptor, and SMAD4, a gene encoding an intracellular signaling molecule.14,15 These mutations cause HHT1, HHT2, and the juvenile polyposis-HHT overlap syndrome, respectively, but at least two other as-yet unidentified genes can cause the disease as well. Up to 15% of patients have no identifiable disease causing mutation in ENG, ACVRL1, or SMAD4.16 HHT is an underdiagnosed disorder with estimates of diagnosed patients representing only 30% of its prevalence in North America.17 Clinical manifestations of HHT show agedependent variable expression; up to 90% of patients with HHT have recurrent epistaxis by 21 years of age, but usually not before 10 years.18-20 Cutaneous telangiectasia are often absent in children.18 Given the later presentation of these manifestations, the diagnosis of children with HHT is challenging. Genetic testing to identify the familial mutation is useful to determine whether asymptomatic children of an affected adult need to be monitored closely for clinical symptoms. Although uncommon, children may present with intracranial hemorrhage (ICH) resulting from ruptured brain AVMs.19,21-24 Consensus guidelines for HHT recommend screening as soon as the diagnosis is made.1,18,25 The spectrum of presentations in children with brain AVMs and HHT has not been explored in detail. In this study, we report our experience with children with HHT and brain AVMs, exploring disease manifestations at presentation and spectrum of brain AVM manifestations. We hope this information will encourage clinicians to consider HHT in the differential diagnosis of ICH. Materials and Methods We reviewed clinical data from Hospital for Sick Children’s (Toronto, Canada) HHT Clinic database for the years 1997-2012. The Research Ethics Board of the hospital approved the study, and parental consent was obtained. Our review included patients aged 0-18 years with a
definite HHT diagnosis (i.e., children with either a definite clinical diagnosis or a confirmed genetic diagnosis) and a confirmed brain AVM at either baseline screening or after presentation with ICH. Screening, as
FIGURE 1. Patient 2: Axial T2 turbo spin-echo magnetic resonance imaging scan showing a hematoma or hemorrhagic infarct in the inferior left frontal region that extends superiorly to the anterior inferior aspect of the left lateral ventricle. This lesion extends to involve the left frontal opercula and anterior left perisylvian region and the left external capsule and left corona radiata. There is associated ex vacuo dilation of the frontal horn and body of the left lateral ventricle.
M. Saleh et al. / Pediatric Neurology 49 (2013) 445e450
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FIGURE 2. Computed tomography angiogram of patient 11. A left temporal lobe hematoma is identified with intraventricular extension into the left lateral ventricle. A left pial arteriovenous fistula is seen in the temporoparietal region. It is fed by an enlarged branch of the left posterior cerebral artery and by an enlarged branch of the middle cerebral artery.
well as diagnostic testing for brain AVMs, involved head magnetic resonance imaging (MRI). Currently, screening for brain AVM at our pediatric HHT center is performed at the time of diagnosis and at 5-year intervals thereafter.
Results
A total of 115 patients with a confirmed clinical diagnosis of HHT (of which 99 had a confirmed mutation) were available for analysis. Eleven patients (four girls and seven boys) with brain AVMs were identified; the characteristics of this population are summarized in Table 1. All 11 patients met clinical diagnostic criteria for HHT and had a positive family history of HHT. In three cases, the child was the index case in the family, and all three presented with ICH as the first recognized manifestation of HHT. A disease-causing mutation was identified in 9/11 patients. Eight were in ENG and one was in the ACVRL1 gene. Five of 11 patients had recurrent epistaxis as the initial presentation, four presented with ICH (Figs 1-3), and two were asymptomatic and diagnosed based on a positive family history and confirmatory genetic testing for the familial mutation. The mean age at presentation was 5.5 years (range 0.3-16 years); the mean age at diagnosis of brain AVM was 8.91 years (0.6-18 years). The distribution of brain AVMs is summarized in Table 2. Six patients had right-sided brain AVM (three frontal [27%], two occipital [18%], and one parietal [9%]), four patients had left-sided brain AVMs (two frontal [18%], one parietal [9%], and one temporal [9%]), and one (9%) had bithalamic AVMs.
Five patients had two brain AVMs. In 4/11 (36%) patients, both first and second brain AVMs were diagnosed at the same time (i.e., four patients had multiple brain AVMs noted on their first MRI screen). One patient had the second brain AVM diagnosed 4 years after the first on a subsequent brain MRI scan. Two of the five patients also had a cervical spine AVM. In one patient, a spinal AVM was diagnosed on a 5-year follow-up MRI scan, whereas in the other, bilateral lower limb spasticity prompted investigation. Six of 11 patients had ICH secondary to brain AVMs; the mean age of at presentation was 8 years (range 0.6-16 years). In two of those six patients, ICH developed shortly after the diagnosis of HHT. In one patient (patient 8) ICH occurred a few months following the presentation with epistaxis; a brain CT was done and ICH was noted. The other patient (patient 2) was diagnosed by cord blood testing that confirmed the familial mutation. The child demonstrated signs of right-sided hemiparesis, and brain MRI at 9 months of age revealed an old ICH from a ruptured brain AVM in the left frontal lobe near the anterior aspect of the left sylvian fissure that was missed on a previous ultrasound done at 3 months. Of the four patients with ICH at initial presentation, two (patients 1 and 5) had a history of epistaxis a few years before the initial presentation with ICH. Patient 1, a 16-yearold girl, experienced mild epistaxis for several years, but came to medical attention only after a seizure was triggered by ICH. Patient 5, a 12-year-old boy, began having mild epistaxis around the time of presentation with ICH. Patient 11 presented with ICH at 1.7 years of age without a
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M. Saleh et al. / Pediatric Neurology 49 (2013) 445e450
The procedure was successful on first attempt in 7/8 patients, and the unsuccessful attempt was repeated with success on the second attempt. There was no reported mortality related to the procedure or during the follow-up period (mean, 5.64 years). Discussion
FIGURE 3. Patient 11: Magnetic resonance imaging scan of the brain without contrast. A large hematoma within the left superior temporal lobe lies anterosuperior to the large vascular pouch within the left middle cranial fossa. The hematoma has extruded into the lateral ventricle and is surrounded by edema with mass effect from the hematoma and pouch, demonstrated by partial effacement of the occipital horn and body of left lateral ventricle, distortion of the temporal gyri, and effacement of the temporal sulci.
preceding history of epistaxis. The fourth patient (patient 8) had a known index case with HHT in the family, but the child was lost to follow-up. Brain MRI screen was not done, and a missed brain AVM ruptured at the age of 6 years caused dense right-sided hemiparesis. All 11 children with brain AVM underwent diagnostic cerebral angiography, and eight patients required arterial embolization to manage ICH or control large brain AVMs.
In our review of 11 pediatric patients with HHT and brain AVMs, we identified four with ICH as the presenting feature of the disorder. ICH could have potentially been avoided with earlier diagnosis, screening, and arterial embolization of asymptomatic brain AVMs. The majority of children with brain AVMs had HHT symptoms (i.e., epistaxis) before presentation with ICH, and all had a relative with HHT. However, epistaxis was mild and by itself would not have required medical attention. This highlights the need for early diagnosis of HHT to enable screening for brain AVM and to avoid preventable complications. Cascade genetic screening of first-degree relatives at risk for HHT should occur as soon as possible after diagnosis in the index patient, regardless of age. Several studies have reported ICH in pediatric HHT patients. Morgan et al. reported the first case of ICH secondary to a ruptured AVM in a neonate confirmed to have HHT1 by genetic testing and eight additional cases of ICH secondary to cerebral AVMs in the context of a positive family history of HHT.18 The outcome of these nine cases was catastrophic, with five deaths and four patients with significant cognitive and motor impairments as a result of the ICH. Delaney et al. reported a case of a girl born to a woman with HHT who presented at 2 days of age with seizures due to ICH from a ruptured AVM, despite normal prenatal ultrasounds.24 Although outcomes in our population were more favorable, these reports support our contention that early diagnosis of HHT is important to enable screening for disease manifestations may be potentially life-saving.1,26
TABLE 2. Clinical features of brain AVMs in the study population
Patient
Age at First Diagnosis of Brain AVM (yr)
Diagnostic Modality
Brain Region
Multiple Brain AVM (n)
Location of Second Brain AVM
Site of Spine AVM
ICH
Age at ICH (yr)
Brain AVM Embolization (Age, yr)
Age at Last Follow-up (yr)
1 2
16 0.67
MRI MRI
Right frontal Left frontal
No Yes (2)
Yes Yes
16 0.67
Yes (16) Yes (0.75)
17 4.25
3
12
MRI
Right occipital
Yes (2)
No
13.67
4 5
18 12
MRI CT
Right frontal Right frontal
No No
Left posterior perisylvian Right posterior parafalcine
No Yes
12
18 15
6 7 8 9
0.6 8 6 14
CT MRI CT MRI
Bithalamic Right parietal Left posterior frontal Right mesial occipital
No Yes (2) No Yes (2)
Right temporal Occipitofrontal
C2
Yes No Yes No
0.6 6
Yes (12 and 12.25) Yes (1.5) Yes (8.5) Yes (6)
4 15 6 18
10 11
9 1.7
MRI MRI
Left parietal Left superior temporal
No Yes (2)
Left frontal
No Yes
1.7
Yes (9) Yes (1.7)
11 2
Abbreviations: AVM ¼ Arteriovenous malformation CT ¼ Computed tomography ICH ¼ Intracranial hemorrhage MRI ¼ Magnetic resonance imaging
syrinx C5C7
M. Saleh et al. / Pediatric Neurology 49 (2013) 445e450
Although brain AVMs are an important cause of hemorrhagic stroke, especially in children and young adults, little is known about how brain AVMs develop and progress.15,27-32 Previous studies reported that 32% to 50% of patients with HHT and brain AVM(s) have multiple brain AVMs33-38 and that the multiplicity of brain AVMs is highly predictive of the diagnosis of HHT in adults.32-34 A large series recently confirmed that brain AVM multiplicity is present in 39% of patients with HHT and brain AVMs.39,40 In our study, there was no consistent pattern with regard to the distribution of these brain AVMs, but that rate of multiplicity (45%) was similar to that reported in previous studies in adults26,34-36 as well as small case series in children with HHT.35,41 Two patients of 11 with brain AVMs also had a cervical spine AVM, one of which was symptomatic. This raises the question whether screening for spinal AVMs should be performed in children with HHT. Because having multiple brain AVMs has previously been suggested to be associated with spinal AVMs,35,36 spinal MRI should at least be considered in those patients. Genetic testing for pathogenic mutations in the ENG and AVCRL1 genes is an important part of the diagnostic process for HHT. However, HHT remains a clinical diagnosis because genetic testing does not reveal a pathogenic mutation in 100% of families, suggesting the existence of at least one other causative gene not yet identified. A disease-causing mutation was identified in 81% of the families in this study, primarily within the ENG gene.25 Previous genotypephenotype correlation studies demonstrated association of ENG mutation and brain AVMs,30-32,42,43 though brain AVMs were also reported in small numbers of patients with ACVRL6,15,17,41,44-46 or SMAD4 mutations.47 Recently, a large study of adults with HHT confirmed that brain AVM frequency is higher in patients with ENG mutations.16 Our study is too small to explore genotype-phenotype correlations, but a preponderance of ENG mutations in patients with brain AVM was also observed in this study. In conclusion, pediatric patients with HHT may present with ICH resulting from rupture of brain AVMs. The resulting sequelae may be catastrophic, and potentially preventable. A detailed family history of recurrent spontaneous epistaxis and other manifestations of HHT such mucocutaneous telangiectasias and visceral AVMs are crucial for early and accurate diagnosis. Diagnosis of HHT, regardless of genetic type or family history of brain AVMs, is an indication for screening children with brain MRI to identify asymptomatic brain AVMs and prevent ICH. Because there is still a lack of detailed knowledge on the spectrum of brain AVMs and their natural history, further longitudinal studies are needed to explore. Currently, a National Institutes of Healthesponsored study is under way to fill this gap. The authors declare no conflicts of interest. The first draft of this manuscript was written by Maha Saleh. No honorarium, grant, or other form of payment was given to produce the manuscript.
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Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Brain Arteriovenous Malformations in Patients With Hereditary Hemorrhagic Telangiectasia: Clinical Presentation and Anatomical Distribution Maha Saleh MD a, b, Melissa T. Carter MSc, MD, FRCPC a, b, Giuseppe A. Latino BS a, Peter Dirks MD, FRCPC d, Felix Ratjen MD, PhD, FRCPC a, c, * a
Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada Division of Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada c Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada d Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada b
abstract BACKGROUND: Hereditary hemorrhagic telangiectasia is an autosomal dominant genetic disease with a wide array of vascular malformations involving multiple organs. Brain arteriovenous malformations can lead to intracranial hemorrhage and are often diagnosed only after patients become symptomatic. Early diagnosis and interventional treatment may prevent neurologic sequelae or death. Because of the rarity of defined cases, the spectrum of presentations in children with brain arteriovenous malformations and hereditary hemorrhagic telangiectasia has not been explored in detail. Here, we report our experience in children with hereditary hemorrhagic telangiectasia and brain arteriovenous malformations regarding both disease manifestations at presentation and the spectrum of brain arteriovenous malformation manifestations. METHODS: A retrospective review of demographics, clinical manifestations, and brain magnetic resonance imaging/computed tomography scan findings in 115 patients with confirmed hereditary hemorrhagic telangiectasia (HHT) was conducted using the Hospital for Sick Children’s HHT Clinic database for the years 1997-2012. RESULTS: Eleven patients (four girls and seven boys) were diagnosed with hereditary hemorrhagic telangiectasia and brain arteriovenous malformations during this period. Five patients initially presented with epistaxis, four presented with intracranial hemorrhage, and two were asymptomatic with a positive family history of confirmed hereditary hemorrhagic telangiectasia. Although all children had an index case with hereditary hemorrhagic telangiectasia in the family, in three patients, hereditary hemorrhagic telangiectasia was not diagnosed before the child’s presentation with intracranial hemorrhage. Multiple brain arteriovenous malformations were found in five patients, with one patient having bithalamic arteriovenous malformations. CONCLUSIONS: This study highlights the importance of both family history and early clinical signs to prompt further diagnostic testing to avoid intracranial hemorrhage from brain arteriovenous malformations in children with hereditary hemorrhagic telangiectasia. Keywords: hereditary hemorrhagic telangiectasia, vascular malformations, arteriovenous malformations, intracranial hemorrhage
Pediatr Neurol 2013; 49: 445-450 Ó 2013 Elsevier Inc. All rights reserved. Introduction
Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is an autosomal
Article History: Received 12 April 2013; Accepted in final form 30 July 2013 * Communications should be addressed to: Dr. Ratjen; Division of Respiratory Medicine; Department of Pediatrics; Hospital for Sick Children; Toronto, Ontario, Canada. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2013.07.021
dominant disorder with high penetrance and variable expressivity. It is characterized by mucocutaneous telangiectases and arteriovenous malformations (AVMs) most often found in the cerebral, pulmonary, and hepatic circulation.1 Diagnosis of HHT is based on clinical signs and symptoms, family history, and presence of a pathogenic mutation. A clinical diagnosis is established if three of four criteria are present. These include: (1) history of spontaneous and recurrent epistaxis; (2) presence of mucocutaneous telangiectases; (3) a first-degree relative with confirmed HHT; and (4) the presence of visceral AVM.2,3
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TABLE 1. Characteristics of the study population
Patient
Gender
Family History
Familial HHT Confirmed Before Child’s Diagnosis
Affected Parent
Index Case
Clinical Signs at Initial Presentation
Age at Initial Presentation (yr)
Age at Diagnosis (yr)
Affected Gene
Mutation
1 2
F F
þ þ
þ
Mother Mother
Child Mother
ICH None
16 0
16 0.33
N/A* ENG
3 4 5 6 7 8 9 10 11
M M M M F M M F M
þ þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ
Father Father Mother Father Father Mother Mother Father Father
Father Father Child Father Father Mother Mother Father Child
Epistaxis Epistaxis ICH ICH Epistaxis Epistaxis Epistaxis None ICH
6.5 8 12 0.6 5 6 4 0.67 1.7
7.5 8 12 0.6 6 6 4 0.67 1.7
ENG ENG N/A* ACVRL1 ENG ENG ENG ENG ENG
N/A Exon 12: c.1738-1741dup c.360þ1G > A c.588 G > A N/A c.1454 G > A c.657_658delCA c.588 G > A c.360þ1G > A c.657_658delCA Deletion exon 2
Abbreviations: ICH ¼ Intracranial hemorrhage F ¼ Female M ¼ Male N/A ¼ Not available * No pathogenic mutation was identified in either ENG or ACVRL1.
HHT is caused by mutations in at least three genes involved in the transforming growth factor-b/bone morphogenetic protein signaling cascade: ENG, the gene encoding the cell surface co-receptor endoglin,4e11 ACVRL1 (Activin receptor type IIelike 1[ALK1]),12,13 another gene encoding a cell surface receptor, and SMAD4, a gene encoding an intracellular signaling molecule.14,15 These mutations cause HHT1, HHT2, and the juvenile polyposis-HHT overlap syndrome, respectively, but at least two other as-yet unidentified genes can cause the disease as well. Up to 15% of patients have no identifiable disease causing mutation in ENG, ACVRL1, or SMAD4.16 HHT is an underdiagnosed disorder with estimates of diagnosed patients representing only 30% of its prevalence in North America.17 Clinical manifestations of HHT show agedependent variable expression; up to 90% of patients with HHT have recurrent epistaxis by 21 years of age, but usually not before 10 years.18-20 Cutaneous telangiectasia are often absent in children.18 Given the later presentation of these manifestations, the diagnosis of children with HHT is challenging. Genetic testing to identify the familial mutation is useful to determine whether asymptomatic children of an affected adult need to be monitored closely for clinical symptoms. Although uncommon, children may present with intracranial hemorrhage (ICH) resulting from ruptured brain AVMs.19,21-24 Consensus guidelines for HHT recommend screening as soon as the diagnosis is made.1,18,25 The spectrum of presentations in children with brain AVMs and HHT has not been explored in detail. In this study, we report our experience with children with HHT and brain AVMs, exploring disease manifestations at presentation and spectrum of brain AVM manifestations. We hope this information will encourage clinicians to consider HHT in the differential diagnosis of ICH. Materials and Methods We reviewed clinical data from Hospital for Sick Children’s (Toronto, Canada) HHT Clinic database for the years 1997-2012. The Research Ethics Board of the hospital approved the study, and parental consent was obtained. Our review included patients aged 0-18 years with a
definite HHT diagnosis (i.e., children with either a definite clinical diagnosis or a confirmed genetic diagnosis) and a confirmed brain AVM at either baseline screening or after presentation with ICH. Screening, as
FIGURE 1. Patient 2: Axial T2 turbo spin-echo magnetic resonance imaging scan showing a hematoma or hemorrhagic infarct in the inferior left frontal region that extends superiorly to the anterior inferior aspect of the left lateral ventricle. This lesion extends to involve the left frontal opercula and anterior left perisylvian region and the left external capsule and left corona radiata. There is associated ex vacuo dilation of the frontal horn and body of the left lateral ventricle.
M. Saleh et al. / Pediatric Neurology 49 (2013) 445e450
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FIGURE 2. Computed tomography angiogram of patient 11. A left temporal lobe hematoma is identified with intraventricular extension into the left lateral ventricle. A left pial arteriovenous fistula is seen in the temporoparietal region. It is fed by an enlarged branch of the left posterior cerebral artery and by an enlarged branch of the middle cerebral artery.
well as diagnostic testing for brain AVMs, involved head magnetic resonance imaging (MRI). Currently, screening for brain AVM at our pediatric HHT center is performed at the time of diagnosis and at 5-year intervals thereafter.
Results
A total of 115 patients with a confirmed clinical diagnosis of HHT (of which 99 had a confirmed mutation) were available for analysis. Eleven patients (four girls and seven boys) with brain AVMs were identified; the characteristics of this population are summarized in Table 1. All 11 patients met clinical diagnostic criteria for HHT and had a positive family history of HHT. In three cases, the child was the index case in the family, and all three presented with ICH as the first recognized manifestation of HHT. A disease-causing mutation was identified in 9/11 patients. Eight were in ENG and one was in the ACVRL1 gene. Five of 11 patients had recurrent epistaxis as the initial presentation, four presented with ICH (Figs 1-3), and two were asymptomatic and diagnosed based on a positive family history and confirmatory genetic testing for the familial mutation. The mean age at presentation was 5.5 years (range 0.3-16 years); the mean age at diagnosis of brain AVM was 8.91 years (0.6-18 years). The distribution of brain AVMs is summarized in Table 2. Six patients had right-sided brain AVM (three frontal [27%], two occipital [18%], and one parietal [9%]), four patients had left-sided brain AVMs (two frontal [18%], one parietal [9%], and one temporal [9%]), and one (9%) had bithalamic AVMs.
Five patients had two brain AVMs. In 4/11 (36%) patients, both first and second brain AVMs were diagnosed at the same time (i.e., four patients had multiple brain AVMs noted on their first MRI screen). One patient had the second brain AVM diagnosed 4 years after the first on a subsequent brain MRI scan. Two of the five patients also had a cervical spine AVM. In one patient, a spinal AVM was diagnosed on a 5-year follow-up MRI scan, whereas in the other, bilateral lower limb spasticity prompted investigation. Six of 11 patients had ICH secondary to brain AVMs; the mean age of at presentation was 8 years (range 0.6-16 years). In two of those six patients, ICH developed shortly after the diagnosis of HHT. In one patient (patient 8) ICH occurred a few months following the presentation with epistaxis; a brain CT was done and ICH was noted. The other patient (patient 2) was diagnosed by cord blood testing that confirmed the familial mutation. The child demonstrated signs of right-sided hemiparesis, and brain MRI at 9 months of age revealed an old ICH from a ruptured brain AVM in the left frontal lobe near the anterior aspect of the left sylvian fissure that was missed on a previous ultrasound done at 3 months. Of the four patients with ICH at initial presentation, two (patients 1 and 5) had a history of epistaxis a few years before the initial presentation with ICH. Patient 1, a 16-yearold girl, experienced mild epistaxis for several years, but came to medical attention only after a seizure was triggered by ICH. Patient 5, a 12-year-old boy, began having mild epistaxis around the time of presentation with ICH. Patient 11 presented with ICH at 1.7 years of age without a
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The procedure was successful on first attempt in 7/8 patients, and the unsuccessful attempt was repeated with success on the second attempt. There was no reported mortality related to the procedure or during the follow-up period (mean, 5.64 years). Discussion
FIGURE 3. Patient 11: Magnetic resonance imaging scan of the brain without contrast. A large hematoma within the left superior temporal lobe lies anterosuperior to the large vascular pouch within the left middle cranial fossa. The hematoma has extruded into the lateral ventricle and is surrounded by edema with mass effect from the hematoma and pouch, demonstrated by partial effacement of the occipital horn and body of left lateral ventricle, distortion of the temporal gyri, and effacement of the temporal sulci.
preceding history of epistaxis. The fourth patient (patient 8) had a known index case with HHT in the family, but the child was lost to follow-up. Brain MRI screen was not done, and a missed brain AVM ruptured at the age of 6 years caused dense right-sided hemiparesis. All 11 children with brain AVM underwent diagnostic cerebral angiography, and eight patients required arterial embolization to manage ICH or control large brain AVMs.
In our review of 11 pediatric patients with HHT and brain AVMs, we identified four with ICH as the presenting feature of the disorder. ICH could have potentially been avoided with earlier diagnosis, screening, and arterial embolization of asymptomatic brain AVMs. The majority of children with brain AVMs had HHT symptoms (i.e., epistaxis) before presentation with ICH, and all had a relative with HHT. However, epistaxis was mild and by itself would not have required medical attention. This highlights the need for early diagnosis of HHT to enable screening for brain AVM and to avoid preventable complications. Cascade genetic screening of first-degree relatives at risk for HHT should occur as soon as possible after diagnosis in the index patient, regardless of age. Several studies have reported ICH in pediatric HHT patients. Morgan et al. reported the first case of ICH secondary to a ruptured AVM in a neonate confirmed to have HHT1 by genetic testing and eight additional cases of ICH secondary to cerebral AVMs in the context of a positive family history of HHT.18 The outcome of these nine cases was catastrophic, with five deaths and four patients with significant cognitive and motor impairments as a result of the ICH. Delaney et al. reported a case of a girl born to a woman with HHT who presented at 2 days of age with seizures due to ICH from a ruptured AVM, despite normal prenatal ultrasounds.24 Although outcomes in our population were more favorable, these reports support our contention that early diagnosis of HHT is important to enable screening for disease manifestations may be potentially life-saving.1,26
TABLE 2. Clinical features of brain AVMs in the study population
Patient
Age at First Diagnosis of Brain AVM (yr)
Diagnostic Modality
Brain Region
Multiple Brain AVM (n)
Location of Second Brain AVM
Site of Spine AVM
ICH
Age at ICH (yr)
Brain AVM Embolization (Age, yr)
Age at Last Follow-up (yr)
1 2
16 0.67
MRI MRI
Right frontal Left frontal
No Yes (2)
Yes Yes
16 0.67
Yes (16) Yes (0.75)
17 4.25
3
12
MRI
Right occipital
Yes (2)
No
13.67
4 5
18 12
MRI CT
Right frontal Right frontal
No No
Left posterior perisylvian Right posterior parafalcine
No Yes
12
18 15
6 7 8 9
0.6 8 6 14
CT MRI CT MRI
Bithalamic Right parietal Left posterior frontal Right mesial occipital
No Yes (2) No Yes (2)
Right temporal Occipitofrontal
C2
Yes No Yes No
0.6 6
Yes (12 and 12.25) Yes (1.5) Yes (8.5) Yes (6)
4 15 6 18
10 11
9 1.7
MRI MRI
Left parietal Left superior temporal
No Yes (2)
Left frontal
No Yes
1.7
Yes (9) Yes (1.7)
11 2
Abbreviations: AVM ¼ Arteriovenous malformation CT ¼ Computed tomography ICH ¼ Intracranial hemorrhage MRI ¼ Magnetic resonance imaging
syrinx C5C7
M. Saleh et al. / Pediatric Neurology 49 (2013) 445e450
Although brain AVMs are an important cause of hemorrhagic stroke, especially in children and young adults, little is known about how brain AVMs develop and progress.15,27-32 Previous studies reported that 32% to 50% of patients with HHT and brain AVM(s) have multiple brain AVMs33-38 and that the multiplicity of brain AVMs is highly predictive of the diagnosis of HHT in adults.32-34 A large series recently confirmed that brain AVM multiplicity is present in 39% of patients with HHT and brain AVMs.39,40 In our study, there was no consistent pattern with regard to the distribution of these brain AVMs, but that rate of multiplicity (45%) was similar to that reported in previous studies in adults26,34-36 as well as small case series in children with HHT.35,41 Two patients of 11 with brain AVMs also had a cervical spine AVM, one of which was symptomatic. This raises the question whether screening for spinal AVMs should be performed in children with HHT. Because having multiple brain AVMs has previously been suggested to be associated with spinal AVMs,35,36 spinal MRI should at least be considered in those patients. Genetic testing for pathogenic mutations in the ENG and AVCRL1 genes is an important part of the diagnostic process for HHT. However, HHT remains a clinical diagnosis because genetic testing does not reveal a pathogenic mutation in 100% of families, suggesting the existence of at least one other causative gene not yet identified. A disease-causing mutation was identified in 81% of the families in this study, primarily within the ENG gene.25 Previous genotypephenotype correlation studies demonstrated association of ENG mutation and brain AVMs,30-32,42,43 though brain AVMs were also reported in small numbers of patients with ACVRL6,15,17,41,44-46 or SMAD4 mutations.47 Recently, a large study of adults with HHT confirmed that brain AVM frequency is higher in patients with ENG mutations.16 Our study is too small to explore genotype-phenotype correlations, but a preponderance of ENG mutations in patients with brain AVM was also observed in this study. In conclusion, pediatric patients with HHT may present with ICH resulting from rupture of brain AVMs. The resulting sequelae may be catastrophic, and potentially preventable. A detailed family history of recurrent spontaneous epistaxis and other manifestations of HHT such mucocutaneous telangiectasias and visceral AVMs are crucial for early and accurate diagnosis. Diagnosis of HHT, regardless of genetic type or family history of brain AVMs, is an indication for screening children with brain MRI to identify asymptomatic brain AVMs and prevent ICH. Because there is still a lack of detailed knowledge on the spectrum of brain AVMs and their natural history, further longitudinal studies are needed to explore. Currently, a National Institutes of Healthesponsored study is under way to fill this gap. The authors declare no conflicts of interest. The first draft of this manuscript was written by Maha Saleh. No honorarium, grant, or other form of payment was given to produce the manuscript.
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