• Cerebral Cavernous Malformations (CCM)
  • Sturge-Weber Syndrome (SWS)
    Leptomeningeal Angiomatosis
  • Hereditary Hemorrhagic Telangiectasia (HHT)
    Brain Arteriovenous Malformation (BAVM)

Cerebral Cavernous Malformations (CCM)

Cerebral cavernous malformations (CCM) or angiomas are capillary malformations found in the central nervous system that cause neurological symptoms such as seizures and epilepsy, acute neurological events, and headaches. Patients may become symptomatic at any age with the majority of patients presenting between the second and fifth decades. Estimates of disease prevalence are between 1:200 to 1:800, based on autopsy and brain MRI studies. The two major forms are a) sporadic accounting for up to 80% of cases, and b) familial (FCCM), accounting for at least 20% of cases. Up to 50% of FCCM cases remain asymptomatic or minimally symptomatic throughout life, but there is a large variability of severity in symptomatic cases even within the same family. There are three known genes that cause this disease, but there are a number of familial cases that remain unexplained by currently available genetic tests. Autosomal dominant inheritance is found in all forms. Cutaneous lesions are found in 9% (1) or more, and retinal lesions in 5% (2) though these are rarely symptomatic.

The first gene to be identified is KRIT1, or CCM1 (3,4). Mutations in this gene account for approximately 40-50% of FCCM. A genetic founder mutation in KRIT1 (Q455X) accounts for the largest population of FCCM worldwide (4). It is found in descendants of Hispanic-Americans who settled in northern New Mexico and the southwestern United States, as well as in the northern Mexico states of Chihuahua and Sonora (5). Thousands of patients with this mutation, also known as the common Hispanic mutation or CCM1-CHM, are affected with this disease today. Approximately 20% of FCCM cases are caused by CCM2 (CCM2), and another 20-40% by mutations in PDCD10 (CCM3) (6).

Diagnosis of FCCM is made on the basis of patient and family history, neurological and cutaneous examination, and by brain MRI. FCCM is characterized by multiple lesions on brain MRI with increasing numbers of lesions with increasing age (7). Advances in MRI have improved detection rates of smaller lesions, but individual lesions can also be very large, several centimeters in greatest diameter. Lesions are best identified on MRI using Susceptibility Weighted imaging (SWI) (8,9), or Gradient Echo (GRE) sequences. These techniques may identify hundreds of lesions in a given patient (10). Confirmation of a genetic mutation allows specific genotype identification, and has prognostic implications (11). Histopathologic confirmation is available for surgical or autopsy specimens. Symptomatic relatives can be diagnosed by DNA for genotype, and brain MRI for lesion identification.

Treatment includes symptomatic treatment of seizures and epilepsy, prophylactic and symptomatic management of headaches, and rehabilitation for acute neurological events. Selective surgical resection of accessible symptomatic lesions is available to prevent recurrent hemorrhage. Pharmacologic agents that increase risk of hemorrhage or increase blood pressure should be avoided when possible. Surveillance for changes in lesions can be accomplished with MRI but may not change management unless lesion-related symptoms are changing.

Histopathology shows closely clustered enlarged capillary channels with a single layer of endothelium with no intervening brain parenchyma, often associated with thrombus and intra- and extralesional hemorrhage (12,13). Ultrastructurally, tight junctions between endothelial cells are disrupted. Pathogenesis has been partially elucidated through the study of zebrafish and murine animal models with demonstration of the role of KRIT1 in antiangiogenesis through inhibition of endothelial proliferation, apoptosis, migration, lumen formation, and sprouting angiogenesis in endothelial cells in humans (18). Gene mutations in all types of FCCM are loss of function mutations. A two-hit hypothesis appears to explain the development of localized lesions through loss of a second allele (14). Three pharmacologic agents have been shown to reduce lesion permeability in murine models including simvastatin (15), fasudil (16) and sorefenib (17,18). The three known genes appear to interact and may involve common signaling pathways (18).

 

References:

  1. Sirvente J, Enjolras O, Wassef M, Tournier-Lasserve E, Labauge P. Frequency and phenotypes of cutaneous vascular malformations in a consecutive series of 417 patients with familial cerebral cavernous malformations. J Eur Acad Dermatol Venereol. Sep 2009;23(9):1066-1072.
  2. Labauge P, Krivosic V, Denier C, Tournier-Lasserve E, Gaudric A. Frequency of retinal cavernomas in 60 patients with familial cerebral cavernomas: a clinical and genetic study. Arch Ophthalmol. Jun 2006;124(6):885-886.
  3. Laberge-le Couteulx S, Jung HH, Labauge P, et al. Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet. Oct 1999;23(2):189-193.
  4. Sahoo T, Johnson EW, Thomas JW, et al. Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Hum Mol Genet. Nov 1999;8(12):2325-2333.
  5. Polymeropoulos MH, Hurko O, Hsu F, et al. Linkage of the locus for cerebral cavernous hemangiomas to human chromosome 7q in four families of Mexican-American descent. Neurology. Mar 1997;48(3):752-757.
  6. Liquori CL, Berg MJ, Squitieri F, et al. Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus. Hum Mutat. Jan 2006;27(1):118.
  7. Kattapong VJ, Hart BL, Davis LE. Familial cerebral cavernous angiomas: clinical and radiologic studies. Neurology. Mar 1995;45(3 Pt 1):492-497.
  8. Cooper AD, Campeau NG, Meissner I. Susceptibility-weighted imaging in familial cerebral cavernous malformations. Neurology. Jul 29 2008;71(5):382.
  9. de Souza JM, Domingues RC, Cruz LC, Jr., Domingues FS, Iasbeck T, Gasparetto EL. Susceptibility-weighted imaging for the evaluation of patients with familial cerebral cavernous malformations: a comparison with t2-weighted fast spin-echo and gradient-echo sequences. AJNR Am J Neuroradiol. Jan 2008;29(1):154-158.
  10. Petersen TA, Morrison LA, Schrader RM, Hart BL. Familial versus sporadic cavernous malformations: differences in developmental venous anomaly association and lesion phenotype. AJNR Am J Neuroradiol. Feb;31(2):377-382.
  11. Denier C, Goutagny S, Labauge P, et al. Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet. Feb 2004;74(2):326-337.
  12. Steiger HJ, Markwalder TM, Reulen HJ. Clinicopathological relations of cerebral cavernous angiomas: observations in eleven cases. Neurosurgery. Dec 1987;21(6):879-884.
  13. Tu J, Stoodley MA, Morgan MK, Storer KP. Ultrastructural characteristics of hemorrhagic, nonhemorrhagic, and recurrent cavernous malformations. J Neurosurg. Nov 2005;103(5):903-909.
  14. Gault J, Shenkar R, Recksiek P, Awad IA. Biallelic somatic and germ line CCM1 truncating mutations in a cerebral cavernous malformation lesion. Stroke. Apr 2005;36(4):872-874.
  15. Whitehead KJ, Chan AC, Navankasattusas S, et al. The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat Med. Feb 2009;15(2):177-184.
  16. Stockton RA, Shenkar R, Awad IA, Ginsberg MH. Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity. J Exp Med. Apr 12;207(4):881-896.
  17. Wustehube J, Bartol A, Liebler SS, et al. Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling. Proc Natl Acad Sci U S A. Jul 13;107(28):12640-12645.
  18. Li DY, Whitehead KJ. Evaluating strategies for the treatment of cerebral cavernous malformations. Stroke. Oct;41(10 Suppl):S92-94.
  19. Golden MJ, Saeidi S, Liem B, Marchand E, Morrison LA, Hart BL. Sensitivity of patients with familial cerebral cavernous malformations to therapeutic radiation. Medical Imaging and Radiation Oncology, accepted November 11, 2014.

Sturge-Weber Syndrome (SWS) - Leptomeningeal Angiomatosis

Definition, epidemiology and pathology:

Sturge-Weber Syndrome (SWS) is presence of a facial port-wine birthmark with abnormal vessels on the surface of the brain, increased pressure in the eye, or both. The presence of a port-wine birthmark involving the forehead or upper eyelid raises the suspicion of SWS. Infants and children with the suspicion of SWS must be followed closely for other medical issues, including vision problems, epilepsy, and developmental delays. It can affect one side (in about 85%) or both sides (in about 15%) of the body or brain.

Who gets Sturge-Weber Syndrome?

SWS does NOT run in families. SWS occurs almost equally in boys and girls around the world who have a port wine birthmark around the eye and forehead region of the face.

What causes Sturge-Weber Syndrome?

The underlying cause of SWS is a DNA mutation that occurs after conception. The extent of involvement varies greatly from patient to patient, probably depending on the location and timing of this mutation during fetal development. More research is needed to understand this mutation, how to use that knowledge to treat SWS, and how to prevent the medical and developmental problems resulting from it.

How is Sturge-Weber Syndrome diagnosed?

SWS is a spectrum disorder, and therefore individuals can have brain involvement only, eye involvement only, or skin involvement only; likewise patients can have any combination of involvement. The typical diagnosis of SWS depends on a facial port-wine birthmark combined with glaucoma (increased pressure in the eye) and abnormal blood vessels in the brain. Neurologic, ophthalmologic, dermatologic, and other evaluations are therefore recommended to make the diagnosis of SWS and screen for associated complications.

Infants born with a port-wine birthmark should see a dermatologist to confirm that the birthmark is a port-wine birthmark. Symptoms that suggest brain involvement include seizures, early handedness (hand dominance), or evidence of a visual gaze preference (deviation of eyes, inability to direct gaze), and usually begin in the first two years of life. EEG and MRI imaging of the brain (with contrast) can confirm diagnosis of brain involvement, but these tests may not detect it until after 2 years of life. Neurological symptoms occasionally start in infancy but can start in later childhood or even in adulthood. Eye involvement, specifically glaucoma, has two peak periods: the first in infancy and the second in young adulthood. However, glaucoma can begin at any time and at-risk individuals should be examined by an ophthalmologist every few months for the first years of life and then at least annually for life.

What is/is there treatment for Sturge-Weber Syndrome?

Treatment has been largely based on treating symptoms only and held back by delayed diagnosis and the rarity of the syndrome. Typically, for the brain involvement causing seizures, the use of anti-seizure medications is necessary. Strokes and migraine headaches are also treated. If diagnosed promptly, treatment can save cognitive functioning and lessen the impact of physical limb weakness. However, SWS can be a progressive syndrome, and different outcomes can be seen depending on the age when a person started having seizures. Low dose aspirin is another treatment option utilized by some patients. Eye involvement is typically treated with drops or surgery to decrease the pressure. The birthmark is treated with laser treatment.

FAQ's

My first child has SWS; will any other children be at higher risk for it?

SWS is not caused by a gene defect that is carried in the sperm or egg of a parent. It is caused by a spontaneous mistake (mutation) of the GNAQ gene in one cell at some time after conception has occurred. This cell with the SWS mutation occurring early in fetal development continues to divide and passes the mutation on to the "daughter" cells created in that area of the body. These cells have the mutation and the rest of the body does not. Since the parents are not "carrying" the disease, then the chances of another child having SWS are no higher than they would be for any other parents.

Does having SWS mean there will be brain damage?

A classical diagnosis of SWS includes brain involvement with the abnormal blood vessels-although the term can also refer to those who have skin and eye involvement but no brain involvement at all. Often it is easiest to refer specifically to the type of involvement the individual has, i.e. "Sturge-Weber syndrome brain and skin involvement" or "Sturge-Weber syndrome brain involvement only" etc. Even in those with brain involvement, the degree to which the brain is "damaged", if at all, varies from one individual to another. Some people have blood vessel abnormalities in the brain without seizures, intellectual impairment, or any obvious impact.

If a stroke occurs, will the damage result in permanent disability?

Some children with stroke-like episodes eventually develop permanent weakness, but many regain use of the limb within 72 hours of the onset of weakness. Most of the episodes occur at the time of seizures and treatment is directed toward the associated seizures. Permanent weakness is more likely to occur in infants and young children. If you detect what appears to be the sudden onset of weakness in an arm and hand, leg, or face, seek immediate medical attention.

If SWS has been diagnosed, does that mean I have glaucoma?

No. However, everyone with SWS should be checked regularly by an ophthalmologist. We recommend check-ups every 3 months in the first year of life. Glaucoma may occur with no symptoms at all until it is too late to salvage vision. Routine screening is very important, even if there are no symptoms at all. Telltale signs include a bulging, pain, or excessive watering of the eye (usually the one involved with PWS (Port-Wine Stain). Glaucoma can start at any time so monitoring should continue at least yearly for life.

Should the Port-Wine birthmark of the skin be treated? When?

If left untreated, capillary vascular malformations may develop problems later in life, typically around the 3rd to 4th decade. Over time they may thicken, darken or develop nodules (bumps). Current practice is to treat the malformation with a laser at a very young age. One of the benefits of treating an infant is that the surface area is smaller and can be treated with fewer repeated procedures. However, reducing the size and appearance of the skin lesions DOES NOTHING for the eye and brain complications of SWS.

Does the Port-Wine birthmark rejuvenate itself? If you have laser surgeries when you are younger, will you need to go over the same area in a few years?

Port-Wine birthmarks treated by laser can reoccur with time and may need maintenance treatments periodically to prevent re-darkening of the birthmark.

Will the Port Wine Birthmark get larger?

The Port-Wine birthmark grows commensurate (along with) the child. The PWS may become thicker or produce bumps and nodules in time, but the involved area will not extend or become greater.

 
 

References

  1. Adamsbaum, C., Pinton, F., Rolland, Y., Chiron, C., Dulac, O., and Kalifa, G. (1996). Accelerated myelination in early Sturge-Weber syndrome: MRI-SPECT correlations. Pediatr Radiol 26, 759-762.
  2. Arora, K.S., Quigley, H.A., Comi, A.M., Miller, R.B., Jampel, H.D. (2013). Increased choroidal thickness in patients with Sturge-Weber syndrome. JAMA Ophthalmol 131, 1216-1219.
  3. Assie, G., LaFramboise, T., Platzer, P., Bertherat, J., Stratakis, C. A., and Eng, C. (2008). SNP arrays in heterogeneous tissue: highly accurate collection of both germline and somatic genetic information from unpaired single tumor samples. Am J Hum Genet 82, 903-915.
  4. Bodensteiner JB, R. E. (1999). Sturge Weber Syndrome (Mt. Freedom, NJ, Sturge Weber Foundation).
  5. Comati, A., Beck, H., Halliday, W., Snipes, G. J., Plate, K. H., and Acker, T. (2007). Upregulation of hypoxia inducible factor (HIF)-1alpha and HIF-2alpha in leptomeningeal vascular malformations of Sturge-Weber syndrome. J Neuropathol Exp Neurol 66, 86-97.
  6. Comi, A. M. (2003). Pathophysiology of Sturge-Weber syndrome. J Child Neurol 18, 509-516.
  7. Comi, A.M., Bellamkonda, S., Ferenc, L.M., Cohen, B.A., Germain-Lee, E.L. (2008). Central hypothyroidism and Sturge-Weber syndrome. Pediatr Neurol 39, 58-62.
  8. Comi AM, Weisz CJ, Highet BH, Skolasky RL, Pardo CA, Hess EJ. (2005) Sturge-Weber syndrome:
    Altered blood vessel fibronectin expression and morphology. J Child Neurol 20, 572-7.
  9. Cunha e Sa, M., Barroso, C. P., Caldas, M. C., Edvinsson, L., and Gulbenkian, S. (1997). Innervation pattern of malformative cortical vessels in Sturge-Weber disease: an histochemical, immunohistochemical, and ultrastructural study. Neurosurgery 41, 872-876; discussion 876-877.
  10. Dora, B., and Balkan, S. (2001). Sporadic hemiplegic migraine and Sturge-Weber syndrome. Headache 41,209-210.
  11. Enjolras, O., Riche, M. C., and Merland, J. J. (1985). Facial port-wine stains and Sturge-Weber syndrome.Pediatrics 76, 48-51.
  12. Happle, R. (1987). Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin. J Am Acad Dermatol 16, 899-906.
  13. Juhasz, C., Lai, C., Behen, M. E., Muzik, O., Helder, E. J., Chugani, D. C., and Chugani, H. T. (2007). White matter volume as a major predictor of cognitive function in Sturge-Weber syndrome. Arch Neurol 64, 1169-1174.
  14. Kimple, A.J., Bosch, D.E., Giguere, P.M., Siderovski, D.P. (2011). Regulators of G-protein signaling and their Galpha substrates: promises and challengers in their use as drug discovery targets. Pharmacological Reviews 63(3), 728-749.
  15. Klapper, J. (1994). Headache in Sturge-Weber syndrome. Headache 34, 521-522.
  16. Kossoff, E.H., Bachur, C.D., Quain, A.M., Ewen, J.B., Comi, A.M. (2014). EEG evolution in Sturge-Weber syndrome. Epilepsy Res 108, 816-819.
  17. Kossoff, E.H., Ferenc, L., Comi, A.M. (2009). An infantile-onset, severe, yet sporadic seizure pattern is common in Sturge-Weber syndrome. Epilepsia 50, 2154-2157.
  18. Kramer, U., Kahana, E., Shorer, Z., and Ben-Zeev, B. (2000). Outcome of infants with unilateral Sturge-Weber syndrome and early onset seizures. Dev Med Child Neurol 42, 756-759.
  19. Lance, E.I., Lanier K.E., Zabel, T.A., Comi, A.M. (2014). Stimulant use in patients with Sturge-Weber syndrome: safety and efficacy. Pediatric Neurology 51(5), 675-80.
  20. Lance, E.I., Sreenivasan, A.K., Zabel, T.A., Kossoff, E.H., Comi, A.M. (2013). Aspirin use in Sturge-Weber syndrome: side effects and clinical outcomes. J Child Neurol 28, 213-8.
  21. Lee, J. S., Asano, E., Muzik, O., Chugani, D. C., Juhasz, C., Pfund, Z., Philip, S., Behen, M., and Chugani, H.T. (2001). Sturge-Weber syndrome: correlation between clinical course and FDG PET findings. Neurology 57,189-195.
  22. Lin, D. D., Barker, P. B., Hatfield, L. A., and Comi, A. M. (2006). Dynamic MR perfusion and proton MR spectroscopic imaging in Sturge-Weber syndrome: correlation with neurological symptoms. J Magn Reson Imaging 24, 274-281.
  23. Lin, D.D., Barker, P.B., Kraut, M.A., Comi, A.M. (2003). Early characteristics of Sturge-Weber syndrome shown by perfusion MR imaging and proton MR spectroscopic imaging. American Journal of Neuroradiology 24(9), 1912-15.
  24. Marler, J. J., Fishman, S. J., Kilroy, S. M., Fang, J., Upton, J., Mulliken, J. B., Burrows, P. E., Zurakowski, D.,Folkman, J., and Moses, M. A. (2005). Increased expression of urinary matrix metalloproteinases parallels the extent and activity of vascular anomalies. Pediatrics 116, 38-45.
  25. Mitsuhashi, Y., Odermatt, B. F., Schneider, B. V., and Schnyder, U. W. (1988). Immunohistological evaluation of endothelial markers and basement membrane components in port-wine stains. Dermatologica 176, 243-250.
  26. Pories, S. E., Zurakowski, D., Roy, R., Lamb, C. C., Raza, S., Exarhopoulos, A., Scheib, R. G., Schumer, S.,Lenahan, C., Borges, V., et al. (2008). Urinary metalloproteinases: noninvasive biomarkers for breast cancer risk assessment. Cancer Epidemiol Biomarkers Prev 17, 1034-1042.
  27. Rhoten, R. L., Comair, Y. G., Shedid, D., Chyatte, D., and Simonson, M. S. (1997). Specific repression of the preproendothelin-1 gene in intracranial arteriovenous malformations. J Neurosurg 86, 101-108.
  28. Rydh, M., Malm, M., Jernbeck, J., and Dalsgaard, C. J. (1991). Ectatic blood vessels in port-wine stains lack innervation: possible role in pathogenesis. Plast Reconstr Surg 87, 419-422.
  29. Shirley, M.D., Tang, H., Gallione, C.J., Baugher, J.D., Frelin, L.P., Cohen, B., North, P.E., Marchuk, D.A., Comi, A.M., Pevsner, J. (2013). Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med 368, 1971-1979.
  30. Smith, E. R., Zurakowski, D., Saad, A., Scott, R. M., and Moses, M. A. (2008). Urinary biomarkers predict brain tumor presence and response to therapy. Clin Cancer Res 14, 2378-2386.
  31. Sreenivasan, A.K., Bachur, C.D., Lanier, K.E., Curatolo, A.S., Connors, S.M., Moses, M.A., Comi, A.M. (2013). Urine vascular biomarkers in Sturge-Weber syndrome. Vasc Med 18, 122–128.
  32. Tallman, B., Tan, O. T., Morelli, J. G., Piepenbrink, J., Stafford, T. J., Trainor, S., and Weston, W. L. (1991). Location of port-wine stains and the likelihood of ophthalmic and/or central nervous system complications. Pediatrics 87, 323-327.
  33. Ting, J. C., Roberson, E. D., Miller, N. D., Lysholm-Bernacchi, A., Stephan, D. A., Capone, G. T., Ruczinski, I., Thomas, G. H., and Pevsner, J. (2007). Visualization of uniparental inheritance, Mendelian inconsistencies, deletions, and parent of origin effects in single nucleotide polymorphism trio data with SNPtrio. Hum Mutat 28, 1225-1235.
  34. Turin, E., Grados, M.A., Tierney, E., Ferenc, L.M., Zabel, A., Comi, A.M. (2010). Behavioral and psychiatric features of Sturge-Weber syndrome. J Nerv Ment Dis 198, 905-913.

Hereditary Hemorrhagic Telangiectasia (HHT) - Brain Arteriovenous Malformation (BAVM)

HHT is an autosomal dominant disease with an estimated prevalence of 1/5000 (1) and is thought to be present in all races and parts of the world. Though epistaxis is the most common symptom of HHT and mucocutaneous telangiectasia the most common sign (2), HHT is also frequently complicated by the presence of arteriovenous malformations (AVMs) in the brain, lung, gastrointestinal (GI) tract and liver.

Making the diagnosis of HHT in a patient allows for the appropriate screening and preventative treatment for the patient and their affected family members. HHT has traditionally been diagnosed on the basis of its clinical features but can now also be diagnosed using genetic testing. The clinical diagnostic criteria (3) for HHT are detailed in the Table. The clinical diagnosis is considered “definite” if three or more criteria are present, "possible" if 2 criteria are present and “uncertain” when only one criterion is present (3). Disease expression is age-related, with an average age of onset for epistaxis of 12 years, with nearly 100% affected by age 40 years (2, 4-6). Most patients report the appearance of telangiectasia of the mouth, face or hands 5-30 years after the onset of nosebleeds; most commonly during the third decade. The goal of genetic testing for HHT is to clarify the specific HHT mutation in an HHT family, allowing diagnosis among those relatives (often children and young adults) who do not yet meet clinical diagnostic criteria, but may have unrecognized organ AVMs. Genetic testing is performed first on the index case, for mutations in the endoglin gene (ENG) and the activin A receptor type II-like 1 gene (ACVRL1). Mutations in these genes account for the majority of cases of HHT. At least two other HHT loci have been described, though specific genes at these loci are not yet identified (7, 8). Mutations in the SMAD4 gene can cause a rare syndrome of combined juvenile polyposis and HHT (9).

HHT is associated with cerebral vascular malformations, primarily brain AVMs (BAVMs), in 5-23%. The bleeding risk of BAVMs in HHT has been estimated retrospectively at approximately 0.5% per year (10), though there are no prospective natural history studies. In larger series of sporadic BAVMs (11), the annual rate of rupture is 2-4%/year (11). Asymptomatic screening for BAVMs has been recommended for HHT patients and is routinely performed across North America, though there is less consensus internationally (12). The goal of treatment is to obliterate the BAVM in order to eliminate the future risk of hemorrhage. Although current treatments may provide a large relative risk reduction for cerebral bleeding, procedural risks are significant. There are no published studies of the efficacy or safety of any form of treatment of BAVMs in HHT patients. However, there are several large case series of embolization, microsurgery and stereotactic radiation in non-HHT BAVMs, showing effectiveness for these modalities, though widely ranging (13-26). Based on this non-HHT literature, these treatment modalities are all considered likely effective treatment strategies, alone or in combination, for HHT BAVMs. However, given the rarity of BAVMs and the associated risks of treatment, the International HHT Guidelines (12) recommended that each case should be managed in an individualized manner and that decisions about invasive testing and therapy should occur at centers with significant experience and expertise in all treatment modalities.

PAVMs are present in approximately 15-50% of people with HHT (27, 28). PAVMs have been shown to be associated with disabling and life-threatening complications, such as stroke, TIA, cerebral abscess, massive hemoptysis and spontaneous hemothorax (27, 29-32) in retrospective series. The neurologic complications are presumed to occur via paradoxical embolization through PAVMs whereas the hemorrhagic complications occur due to spontaneous PAVM rupture. These complications have been demonstrated in largely adult series of HHT patients, though they have also been demonstrated in pediatric HHT series (33-35), albeit smaller in size. There have also been small series reporting these same complications during pregnancy (36, 37) and the complication risk appears to be greater during pregnancy. The International HHT Guidelines recommended routine screening all HHT patients for PAVMs, with contrast echocardiography, and preventative treatment with transcatheter embolotherapy (12).

Recurrent spontaneous epistaxis is the most common symptom of HHT and often leads to iron-deficiency anemia (38). Epistaxis appears before the age of 20 years in about 50% of patients, with 78 – 96 % of all HHT patients developing it eventually (2). Non-invasive management of chronic recurrent epistaxis in HHT has focused to date on prevention of epistaxis events through measures to maintain integrity of the nasal mucosa, such as humidification. Procedural therapies for chronic HHT-related epistaxis include endonasal laser, electrical or chemical coagulation techniques, replacement of the fragile endonasal mucosa by skin or buccal mucosa (dermoplasty), nasal artery embolization and closure of the nasal cavity (known as Young’s procedure). There have been no controlled or well-designed comparative studies of any of these procedures in HHT-related epistaxis, for either acute or chronic management. The International HHT Guidelines (12) recommended endonasal coagulation as a first approach, if surgical management is deemed necessary, but also recommended that patients considering surgical management consult an otorhinolarnygologist with HHT expertise, given the likely need for recurrent procedures for this chronic symptom and the risks of surgical management in these cases. There are no well-designed studies of the first-line management of acute epistaxis in HHT. The International HHT Guidelines (12) did, however, recommend that the treatment for acute epistaxis requiring intervention include packing with material or products that have a low likelihood of causing re-bleeding with removal (e.g., lubricated low-pressure pneumatic packing).

Although 80% of patients with HHT have gastric or small intestinal telangiectasia (39) on endoscopy or capsule examination, only 25-30% of patients will develop symptomatic GI bleeding (1, 2, 40, 41) which usually does not present until the fifth or sixth decades of life. Patients rarely develop significant GI bleeding before 40 years of age (1, 2, 40, 41). Women are affected with GI bleeding in a ratio of 2-3:1 (42, 43). Patients with HHT and GI bleeding may or may not be symptomatic, as the bleeding is usually in a slow, chronic and intermittent fashion, often without notable melena. Patients often have few symptoms until they become anemic. In severe cases, HHT GI bleeding causes morbidity, dependency on blood transfusions and increased mortality (42).

Esophagogastroduodenoscopy is the recommended initial test for evaluation of GI bleeding in HHT patients with anemia or iron deficiency, particularly when out of keeping with the severity of epistaxis. Though the majority of patients with HHT will have GI telangiectasia, the utility of endoscopic evaluation is in the anemic or iron-deficient patient. The International HHT Guidelines (12) recommended aggressive management of anemia and iron deficiency, with consideration of limited endoscopic therapy and potential medical therapies (hormonal therapy, anitfibrinolytics) in refractory cases, though evidence is limited.

Liver VMs are present in 32-78% of HHT patients (44-48) (See Table). Though there is no published natural history data regarding liver VMs in HHT, it appears that symptoms occur in only about 8% of the patients with HHT and liver VMs (46, 49). The clinical presentations of liver VMs include high-output heart failure, portal hypertension and biliary necrosis, as detailed in a recent review (50). In patients who have symptoms suggestive of liver VMs(50), Doppler ultrasound or triphasic hepatic CT can be used to confirm the diagnosis. There are uncontrolled case series of treatments of liver VMs, specifically hepatic artery embolization and liver transplantation. Hepatic artery embolization has the objective of reducing arteriovenous or arterioportal shunting by embolizing branches of the hepatic artery. Embolization appears to be effective in improving symptoms related to high output heart failure and mesenteric steal syndrome, (51), however, the effect is transient and symptoms generally recur. More importantly, ischemic complications (ischemic cholangitis, ischemic cholecystitis and/or hepatic necrosis) leading to transplant or death occur in approximately 30% of the treated cases, including 50% of treated portal hypertension cases (51). The 2-year survival with embolization was approximately 73%. With liver transplantation, symptoms resolved in the majority of patients (52, 53). Liver transplantation is associated with high blood transfusion requirements, prolonged hospital stay and a relatively high rate of postoperative complications. However, the reported 5-year survival rate of 83% in the larger series (53) compared favorably to overall survival rates for liver transplantation. The International HHT Guidelines recommended that referral for liver transplantation be considered in patients with liver VMs that develop ischemic biliary necrosis, intractable heart failure or intractable portal hypertension. Though there are no controlled studies to date, there is growing interest in antiangiogenic therapy in HHT, with recent case reports of clinical response to antiangiogeneic therapy (54-56), and even with improvement in symptoms from liver VMs (55).

 

Diagnostic Criteria (Curaçao Criteria) for clinical diagnosis of HHT

Criteria
Description

Epistaxis

Spontaneous and recurrent

Telangiectases

Multiple, at characteristic sites: lips, oral cavity, fingers, nose

Visceral lesions

GI Telangiectasia, pulmonary, hepatic, cerebral or spinal AVMs

Family history

A first degree relative with HHT according to these criteria


References

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