Clinical Note

Basal Ganglia Hyperintensity on T1-Weighted MRIin RenduOslerWeber Disease

Anastasia Oikonomou, MD, PhD,1* Alexandros Chatzistefanou, MD,1

Petros Zezos, MD, PhD,2 Paraskevi Mintzopoulou, MD,1

Konstantinos Vadikolias, MD, PhD,3 and Panos Prassopoulos, MD, PhD1

The purpose of this study was to evaluate possible cen-tral nervous system (CNS) involvement in RenduOslerWeber (ROW) disease in magnetic resonance imaging(MRI). Three patients with symptomatic ROW diseaseunderwent brain MRI. Brain MRI depicted in all three ofthem increased signal intensity on T1-weighted imagesinvolving the globus pallidus and cerebral crura bilater-ally. Laboratory studies of the two men showed iron de-ciency anemia, while all three of them had normal liverfunction tests and increased manganese blood concentra-tion. Gastroscopy and colonoscopy revealed a gastric anda cecal arteriovenous malformation (AVM) in the rst one,while pulmonary and hepatic computed tomography (CT)angiography did not detect any intrahepatic shunts. Liverultrasound in the second one revealed dilatation of intra-hepatic artery branches consistent with intrahepaticshunts, while it was normal in the third patient. Chest ra-diographs were normal in all three patients. Pallidal T1hyperintensity on T1-weighted imaging may be a bio-marker of manganese overload in ROW disease.

Key Words: Rendu Osler Weber diseasel basal ganglial T1MRIJ. Magn. Reson. Imaging 2012;35:426430.VC 2011 Wiley Periodicals, Inc.

RENDUOSLERWEBER DISEASE (ROW) is a domi-nantly inherited disorder characterized by the pres-ence of angiodysplastic lesions, which can affect prac-tically all organs with an extremely variableexpressivity presenting with epistaxis and mucocuta-neous telangiectases and visceral arteriovenous mal-

formations, particularly in the brain, lungs, liver, andgastrointestinal tract (1).It has been reported in only two other case reports

in the literature that in patients with ROW and docu-mented intrahepatic portosystemic shunts manga-nese, a paramagnetic metal, escapes to the systemiccirculation and accumulates at high doses in thebrain, becoming neurotoxic (2,3). The purpose of thisstudy was to describe the magnetic resonance imag-ing (MRI) ndings of brain changes in ROW diseasewith or without obvious hepatic involvement.

CASE SERIES PRESENTATION

A 53-year-old man (rst patient) with history of ROWdisease was admitted to the hospital with melenae. Healso reported recurrent episodes of epistaxis. Physicalexamination revealed multiple telangiectases of thelips, tongue, and ngertips. Laboratory studiesshowed iron deciency anemia with normal liver func-tion and increased serum manganese concentration(5.2 mg/dL, normal values 0.82.5 mg/dL). Gastros-copy showed a small arteriovenous malformation(AVM) in the body of the stomach. Colonoscopyrevealed a cecal AVM, with active bleeding. Pulmonaryand hepatic computed tomography (CT) angiographydid not detect any obvious AVMs.A 67-year-old man (second patient) with a family

history of ROW disease presented with uncontrollednasal bleeding. Physical examination revealed multi-ple telangiectases of the lips, tongue, and ngertipsand nasal AVMs. Laboratory studies showed irondeciency anemia with normal liver function andincreased serum manganese concentration (4.9 mg/dL, normal values 0.82.5 mg/dL). Ultrasound of theliver detected dilatation of the branches of thehepatic artery parallel to branches of the portal vein,a nding consistent with arterioportal shunt (4)(Fig. 1). Chest radiograph did not reveal any obviousAVMs.The 38-year-old daughter (third patient) of the sec-

ond patient reported only mild spontaneous epistaxissince childhood. Physical examination revealed fewtelangiectases of the lips and tongue. Laboratory

1Department of Radiology, University Hospital of Alexandroupolis,Democritus University of Thrace, Alexandroupolis, Greece.2Department of Gastroenterology, University Hospital ofAlexandroupolis, Democritus University of Thrace, Alexandroupolis,Greece.3Department of Neurology, University Hospital of Alexandroupolis,Democritus University of Thrace, Alexandroupolis, Greece.

*Address reprint requests to: A.O., Department of Radiology, Univer-sity Hospital of Alexandroupolis, Democritus University of Thrace,Dragana, 68100 Alexandroupolis, Greece.E-mail: aoikonom@med.duth.gr

Received March 31, 2011; Accepted October 13, 2011.

DOI 10.1002/jmri.22892View this article online at wileyonlinelibrary.com.

JOURNAL OF MAGNETIC RESONANCE IMAGING 35:426430 (2012)

CME

VC 2011 Wiley Periodicals, Inc. 426

studies showed increased serum manganese concen-tration (3.4 mg/dL, normal values 0.82.5 mg/dL).Chest radiograph and ultrasound of the liver wereunremarkable.The patients underwent brain MRI in order to inves-

tigate possible central nervous system (CNS) involve-ment. MRI depicted in all cases signicantly increasedsignal intensity on T1-weighted images (T1W), as com-pared to the white matter, involving the basal ganglia,and specically globus pallidus and cerebral crusbilaterally (Figs. 24). There was no enhancement af-ter gadolinium intravenous administration. T2W anduid attenuated inversion recovery (FLAIR) images didnot show abnormal signal intensity at the basal gan-glia. A tortuous ow-void lesion was noted in bothcerebellar hemispheres of patient 1, consistent withsmall cerebrovascular malformations in the form ofcapillary malformations (telangiectases) or venous

developmental abnormalities (venous angiomas) (5)(Fig. 5).

DISCUSSION

ROW disease, also known as hereditary hemorrhagictelangiectasia (HHT), is an autosomal dominant disor-der with an estimated incidence of 1/8000 (1). It ischaracterized by angiodysplastic lesions, which canaffect all organs with an extremely variable expressiv-ity, including telangiectases, aneurysms, and AVMs,particularly in the brain, lungs, liver, and gastrointes-tinal tract, as occurred in two of our patients (6,7).Defects in endothelial cell junctions, endothelial celldegeneration, and weakness of perivascular connec-tive tissue are thought to cause dilation of capillariesand postcapillary venules. Spontaneous and recurrent

Figure 1. Ultrasound of theliver (B-mode on the left andcolor Doppler on the right)shows dilation of a branch ofthe hepatic artery (dottedarrow), parallel to a branch ofthe portal vein, dilatation ofthe branches of the hepaticartery parallel to branches ofthe portal vein, a nding con-sistent with arterioportalshunt secondary to intrahe-patic arteriovenous malforma-tions (second patient). [Colorgure can be viewed in theonline issue, which is avail-able at wileyonlinelibrary.com.]

Figure 2. a,b: A 53-year-old manwith a history of ROW. T1W imagesat the level of basal ganglia showsignicantly increased signal inten-sity compared to white matter,which specically involves theglobus pallidus (arrows) and the cer-ebral crus bilaterally (arrowheads)(rst patient).

Brain MRI Findings In ROW Disease 427

epistaxis is usually the initial symptom, as was thecase in two of our patients. Occasionally, the onset ofROW disease may be manifested mainly by hemor-rhagic life-threatening complications such as hemor-rhagic stroke, hemoptysis, hemothorax, hematemesis,or melena (8). Similarly, our rst patient presentedwith melena and the second one with massive rhinor-rhagia that could be added to the list of life-threaten-ing hemorrhagic complications. Additionally, evensmall hepatic portal-systemic shunts may result inincomplete removal of various toxins from the portalcirculation, like manganese, leading to manganesedeposition in CNS (9). Manganese (Mn) is a paramag-netic heavy metal that is indispensable for promotingubiquitous enzymatic reactions that are involved inneurotransmitter metabolism, the formation of bone,cartilage, and connective tissue (10). It is estimatedthat 1%3.5% of the ingested Mn is absorbed andenters the portal venous system from the gastrointes-tinal tract. Subsequently, it passes through liverparenchyma, where 98% of it is cleared and excreted

through the bile. A number of acquired or congenitalabdominal diseases lead to increased blood Mn con-centration and deposition to the brain parenchyma:hepatic cirrhosis with portosystemic shunt, congenitalbiliary atresia, primary biliary cirrhosis, congenital in-trahepatic portosystemic shunt without liver dysfunc-tion, ROW disease with diffuse intrahepatic portosys-temic shunt, and patent ductus venosus. Othercauses of Mn accumulation in the brain are Mn over-load from total parenteral nutrition and welding-related Mn intoxication (2,9). Although small amountsof Mn are essential for cellular homeostasis and brainfunctioning, excessive accumulation in the nervoussystem may become neurotoxic (10). The mechanismsof Mn neurotoxicity are not well understood. Mn hasbeen reported to induce cellular toxicity with a num-ber of mechanisms, including formation of reactiveoxygen species (ROS), oxidation of biological mole-cules, and the destruction of Ca2 and iron homeosta-sis. All the above may lead to an oxidative stress withsubsequent apoptosis and necrosis in several tissues,

Figure 3. a,b: A 68-year-old manwith a family history of ROW. T1Wimages at the level of basal gangliashow signicantly increased signalintensity compared to white matter,which specically involves theglobus pallidus (arrows) and the cer-ebral crus bilaterally (arrowheads)(second patient).

Figure 4. a,b: A 38-year-oldwoman with a family history ofROW (daughter of the patientpresented in Fig. 2). T1W imagesat the level of basal ganglia showsignicantly increased signal in-tensity compared to white matter,which specically involves theglobus pallidus (arrows) and thecerebral crus bilaterally (arrow-heads) (third patient).

428 Oikonomou et al.

including neuronal damage (10). Mn toxicity is seenin the CNS as degeneration of basal ganglia, particu-larly the medial segment of the globus pallidus, anding that is consistent with the T1 hyperintensityof the globus pallidus found in the three cases of thepresent study (9). Histopathologically, gliosis andmineralization of the globus pallidus without deple-tion of neurons have been reported. The major neuro-logic symptom of Mn accumulation in the brain withhigh signal basal ganglia is parkinsonism associatedwith variable combinations of behavioral and cognitivedysfunction (3,9).It is worth noting that radiologic manifestations

may precede any clinical symptoms (3,9). Mn-inducedparkinsonism differs from idiopathic Parkinsons dis-ease (PD) in that there is a rapid progression of themotor symptoms and early gait and postural impair-ment with focal dystonia, there is an absence of rest-ing tremor, and nally it is restrictive to L-dopa ther-apy, which is the mainstay of treatment for idiopathicPD (11). The cardinal radiologic ndings of Mn deposi-tion in the brain include high signal intensity on T1WMRI particularly in the globus pallidus, the midbrain,and anterior pituitary gland in a bilateral andsymmetric fashion (2,9). It is crucial to note that noabnormal signal intensity is detected on T2W MRI andon FLAIR images and this helps differentiate Mn toxic-ity from other causes of bilateral hyperintensity of theglobus pallidi on T1W MRI, such as calcication dueto hypoparathyroidism or Fahrs disease, hypoxic-is-chemic encephalopathy, non-ketotic hyperglycemicepisodes, hamartomas of neurobromatosis type 1, orhemorrhage due to Japanese encephalitis (2,9). More-over, idiopathic PD does not present with T1 hyperin-

tensity at the basal ganglia (11). Brain MRI may be auseful tool for monitoring Mn deposition in the brain,to support initiation of treatment (10,11), and assess-ment of treatment response.There have been only two other cases, to the best of

our knowledge, of ROW so far reported in the litera-ture with hyperintense basal ganglia on T1W MRIassociated with hypermanganesemia and accompa-nied by multiple hepatic intrahepatic shunts (2,3).Since Mn is primarily metabolized in the liver,impaired clearance due to liver dysfunction or intra-hepatic shunting could lead to Mn overload despitenormal Mn intake (3).Our patients did not have any neurologic decit.

Findings from their clinical investigation, related to theknown history of ROW, were a small gastric AVM, ahemorrhagic cecal AVM, and cerebellar vascular mal-formations in the rst, nasal AVMs in the second, andhypermanganesemia in all three of them. High serumMn concentration was also reected by bilateral andsymmetric areas of increased signal intensity on T1WMRI involving the globus pallidus and cerebral crura.It is speculated that T1 shortening on brain MR imagesmay be caused by lower concentration of Mn than thatrequired to produce neurologic symptoms (2). One ofour patients had intrahepatic shunts, in the form ofarterioportal shunts, detected on liver ultrasound (4,5).Arterioportal shunts are the most common type ofshunting in ROW, with the other two types being arte-riosystemic (hepatic artery to portal veins) and porto-systemic (portal vein to hepatic veins or vena cava)(4,5). In the other two patients there were no detecta-ble intrahepatic shunts on CT angiography and liverultrasound. We could speculate that probably verysmall intrahepatic shunts in these two patients mighthave been present, being responsible for the escape ofMn to the systemic circulation, but due to very smallsize during the early stages, they might have goneundetected on imaging. Thus, absence of obvious in-trahepatic shunts on abdominal imaging does notexclude the detection of Mn accumulation in the brain.Brain MRI may be valuable in detecting Mn deposi-

tion in ROW disease, even in the subclinical stagewith no neurologic symptoms and no evident hepaticvascular malformations, rendering the pallidal andcrural T1 hyperintensity a signicant biomarker ofMn overload.

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