Central nervous system manganese induced lesions and clinical consequences in patients with hereditary hemorrhagic telangiectasia

Abstract

BackgroundAround 47–74% of patients with hereditary hemorrhagic telangiectasia (HHT) have hepatic vascular malformations (HVMs); magnetic resonance images (MRI) of the central nervous system (CNS) might show in T1 sequences a hyper-intensity signal in different areas, mainly in the basal ganglia (BG) as consequence of manganese (Mn) deposits as observed in cirrhotic patients. These patients might suffer from different neuropsychiatric disorders (hepatic encephalopathy). In HHT patients, even in the presence of hepatic shunts, hepatocellular function is usually preserved. Additionally, Mn shares iron absorption mechanisms, transferrin and CNS transferrin receptors. In iron deficiency conditions, the Mn may harbor transferrin and access BG. The objectives were to describe frequency of BG Mn deposit-induced lesions (BGMnIL) in HHT patients, its relationship with iron deficiency anemia (IDA) and HVMs. Finally, explore the association between neuropsychological and motor consequences. We performed a cross-sectional study. We determined HHT patients with or without BG-MnIL by the MRI screening of the CNS. We included all patients with lesions and a random sample of those without lesions. All patients underwent standardized and validated neuropsychological assessment to evaluate BG actions. Results were analyzed with multiple logistic regression, adjusting for potential confounders.ResultsAmong 307 participants from a cohort included in the Institutional HHT Registry, 179 patients had MRI performed and Curaçao Criteria ≥3. The prevalence of BG-MnIL was 34.6% (95%CI 27.69-42.09). While neuropsychological symptoms were present in all patients, BG-MnIL patients performed poorly in three of the neuropsychological tests (serial dotting, line tracing time, number connection test A). HVMs frequency in BG-MnIL was 95.1%, versus 71.4% in those without lesions (p < 0.001). IDA frequency was 90.3% versus 54% (p < 0.001). When IDA is present, estimated risk for BG-MnIL is remarkably high (OR 7.73, 95%CI 2.23–26.73). After adjustment for possible confounders (gender, age, presence of HVMs), IDA was still associated with increased risk of BG-MnIL (adjusted OR 6.32, 95% CI 2.32–17.20; p < 0.001).ConclusionsPhysicians should assess BG-MnIL in HHT patients in CNS-MRI. IDA and HVMs present increased risk of lesions. Patients with BG-MnIL have neuropsychological impairment, and they might benefit from sparing IDA, or undergoing future therapeutic options.Trial registration NCT01761981. Registered January 3rd 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0632-2) contains supplementary material, which is available to authorized users.

Reduction of bilateral dislocation of TMJ and Rendu Osler Weber syndrome: case report and physiopathological model

“…The HHT is characterized by spontaneous and recurrent epystaxis, telangiectasia in predetermined areas (oral cavity, nose, fingers and lips), visceral injuries (gastrointestinal, hepatic, pulmonary, cerebral and spinal), and a family history of HHT [ 7 ]. Recent research like that of Serra et al [ 8 ] show that more than a third (4.6%) of patients with HHT have manganese deposits in the dorsal root ganglion. These deposits cause central level injuries that generate neuropsychological deterioration, including extrapyramidal symptoms like dystonia, being able to determine MTF dislocation just as occurred in our patient.…”

Pulmonary arterial hypertension in hereditary hemorrhagic telangiectasia associated with ACVRL1 mutation: a case report

“…A brain magnetic resonance imaging (MRI) ruled out any cranial AVMs but did show increased T1 hyperintensities in the basal ganglia bilaterally. These MRI changes are said to occur in HHT patients, mainly males, and are thought to arise from manganese deposits as a result of hepatic AVMs [ 20 ].…”

Hereditary hemorrhagic telangiectasia (HHT): a practical guide to management

“…In patients with liver AVMs, iron defi ciency results in sub stan tial increased risk of aber rant manga nese depo si tion in the brain, lead ing to Parkinson-like neu rologic symp toms. 27 Paradoxically, an increased risk for throm bo sis has been reported in HHT, which appears to cor re late with iron defi ciency. 28 Such throm botic events are gen er ally treated with anticoagulation, with asso ci ated increased bleed ing risk.…”