Efficacy and safety of calcium channel blockers in preventing cardiac siderosis in thalassemia patients: An updated meta-analysis with trial sequential analysis.

OBJECTIVES: Iron overload in patients with thalassemia represents a serious complication by affecting numerous organ systems. This meta-analysis aims to establish an evidence regarding the effect of amlodipine on cardiac iron overload in thalassemia patients. METHODS: We searched PubMed, Scopus, Web of Science, Cochrane Central, and EMBASE for all relevant randomized controlled trials (RCTs). The primary outcomes were cardiac T2* and myocardial iron concentration (MIC). Secondary outcomes were liver iron concentration (LIC), risk of Gastrointestinal (G.I.) upset and risk of lower limb edema. We used Hedges' g to pool continuous outcomes, while odds ratio was used for dichotomous outcomes. RESULTS: Seven RCTs were eligible for this systematic review and meta-analysis, comprising of 233 patients included in the analysis. Amlodipine had a statistically significant lower MIC (Hedges' g = -0.82, 95% confidence interval [CI] [-1.40, -0.24], p < .001) and higher cardiac T2* (Hedges' g = 0.36, 95% CI [0.10, 0.62], p = .03). Amlodipine was comparable to standard chelation therapy in terms of the risk of lower limb edema and GI upset. CONCLUSION: Our meta-analysis found that amlodipine significantly increases cardiac T2* and decreases MIC, hence decreasing the incidence of cardiomyopathy-related iron overload in thalassemia patients.

Quantitative clinical and radiological recovery in post-operative patients with superficial siderosis by an iron chelator.

BACKGROUND: Superficial siderosis is a rare neurodegenerative disease caused by hemosiderin deposition on the brain surface. Although the efficacy of the iron chelator-deferiprone-in superficial siderosis has recently been documented, a comparative study of patients who underwent surgical ablation of their bleeding source and subsequently received treatment with or without deferiprone has not yet been conducted. METHODS: Fifteen postoperative patients with superficial siderosis were recruited, and seven patients were administered deferiprone (combination therapy group). Quantitative changes in the hypointense signals on T2*-weighted magnetic resonance images were acquired; additionally, cerebellar ataxia was assessed (International Cooperative Ataxia Rating Scale score and Scale for the Assessment and Rating of Ataxia). Audiometry was performed and the results were compared with those of patients who did not receive deferiprone (surgical treatment group; controls). RESULTS: Significant improvements in signal contrast ratios were noted in the lateral orbitofrontal gyrus, superior temporal lobe, insular lobe, brainstem, lingual gyrus, and cerebellar lobe in the combination therapy group. The scores of patients in the combination therapy group on the cerebellar ataxia scales significantly improved. The degree of signal improvement in the cerebellar lobe correlated with the improvement of cerebellar ataxia scores. Early deferiprone administration after disease onset and long-term administration were correlated with greater signal improvements on magnetic resonance imaging. No adverse effects were observed in the clinical or laboratory parameters. CONCLUSIONS: Deferiprone administration significantly improved radiological and clinical outcomes in patients with postoperative superficial siderosis. Earlier and longer courses of deferiprone could result in better patient prognosis.

Different etiologies of superficial siderosis / Diferentes etiologias de siderose superficial

Superficial Siderosis (SS) is an uncommon condition caused by hemosiderin deposition into the subarachnoid space. SS is characterized by cerebellar ataxia, progressive sensorineural hearing loss and pyramidal signs, but is often an unrecognized disorder. Magnetic Resonance Imaging (MRI) is the diagnostic procedure of choice due its high sensitivity to hemosiderin deposits in addition to being a non-invasive exam. This paper aims to describe a case of SS and to perform a literature review about SS etiologies, neuroimaging features and clinical characteristics. A 65-year-old man came to a neurology outpatient clinic with seizures and cerebellar ataxia with a history of car accident and severe traumatic brain injury 45 years ago. MRI SWAN showed a hyposignal in the cisterns of the base and on the cerebellar surface and T1-weighted images left hippocampal sclerosis.

A Siderose Superficial (SS) é uma condição rara causada por depósitos de hemossiderina no espaço subaracnóideo. SS é caracterizada por ataxia cerebelar, perda neurosensorial auditiva progressiva e sinais piramidais, mas é frequentemente uma desordem de difícil diagnóstico. A Ressonância Magnética (RM) é o exame de escolha para o diagnóstico devido a sua alta sensibilidade aos depósitos de hemossiderina, além de ser um exame não invasivo. Este artigo tem como objetivo descrever um caso de SS e realizar uma revisão da literatura sobre as etiologias da SS, suas características na neuroimagem e suas características clínicas. Um homem de 65 anos de idade procurou o ambulatório de neurologia com convulsões e ataxia cerebelar. Ele informou histórico de acidente automobilístico e lesão cerebral traumática grave há 45 anos. A RNM SWAN mostrou hipossinal nas cisternas da base e na superfície cerebelar e as imagens em T1 evidenciaram a presença de esclerose hipocampal esquerda.

Treatment Response of Deferiprone in Infratentorial Superficial Siderosis: a Systematic Review.

Superficial siderosis describes haemosiderin deposition on the surface of the brain. When present on infratentorial structures, it can cause ataxia, sensorineural hearing loss and pyramidal signs. There is no proven treatment and patients experience slow progression of symptoms. Iron-chelating agents have been suggested as a therapeutic option and deferiprone is suited as it crosses the blood-brain barrier. However, deferiprone is reported to have a 1-2% risk of agranulocytosis. We performed a systematic review on treatment of infratentorial superficial siderosis with deferiprone based on PRISMA guidelines. Studies were included if in English or an English language translation was available, were about human subjects and referred to patients with ataxia. Studies were excluded if they did not possess an English translation, included animal studies or did not have ataxia. Studies were excluded if they discussed cerebral amyloid angiopathy or siderosis of other regions. Eleven papers were included. We identified 69 patients. Seventeen patients (25%) discontinued the drug. The most encountered adverse effect was anaemia (21.7%). Neutropaenia was observed in 8.7% and agranulocytosis in 5.8% of patients. Clinically, response varied, and stability or improvement was seen across neurological domains in 6 studies while 5 showed a mixed response. On imaging, 13 (28.9%) patients improved, 24 (53.3%) stabilised and 8 (17.8%) deteriorated. A prospective international centralised register of patients should be developed to inform the design and conduct of a multicentre, placebo-controlled, randomised clinical trial to evaluate the efficacy of deferiprone. The evidence from this systematic review is that deferiprone is a promising intervention.

A case of post-splenectomy transfusion-dependent homozygous beta-thalassemia major complicated with myocardial siderosis and osteoporosis and usage of iron-chelating therapy with deferiprone in pregnancy.

Beta-thalassemia major is a subtype component of hemoglobinopathies; autosomal recessive disorders complicated with anemia that affect at least 50,000 babies each year. It contributes to problems in reproductive entities such as infertility due to iron deposition in the endocrine organs, which leads to malfunction of the hypothalamus-pituitary axis. Due to this, there have been very few pregnancies discovered and reported with this type of condition as they usually required an ovulation-induction agent with assisted reproductive technique to achieved pregnancy. We report a successful spontaneous pregnancy in a woman with beta-thalassemia major who underwent splenectomy with lifelong transfusion-dependence complicated with myocardial siderosis and osteoporosis. The close monitoring and regular blood transfusion are a core of successful support to this type of pregnancy. The unintentional consumption of Fosamax, hydroxyurea and deferiprone (Ferriprox) up till 20 weeks of gestation did not show any adverse effects on fetal well-being. As expected, this pregnancy ended with the preterm delivery via cesarean section due to intrauterine growth restriction with oligohydramnios, and currently, this child is thriving. We concluded that pregnancy is not a contraindication in beta-thalassemia major; complex individual care is needed to achieve a safe outcome for the mother.

Failure of Tafamidis to Halt Progression of Ala36Pro TTR Oculomeningovascular Amyloidosis.

Oculomeningovascular amyloidosis is a variant of transthyretin (TTR) amyloidotic polyneuropathy, which is associated with blindness and brain ischemia, microhemorrages, and siderosis due to prominent production of the abnormal TTR in the eye and in the choroid plexuses. Tafamidis is a TTR stabilizer that is orally administered and, by interfering with amyloid fibril formation and deposition, is capable of slowing progression of TTR polyneuropathy and of early-stage cardiomyopathy. However, the ocular manifestations of amyloid deposition progressed despite tafamidis therapy in Val30Met TTR amyloidosis, and the effects of tafamidis on meningovascular amyloidosis are unknown. We observed failure of tafamidis to halt progression of oculomeningovascular amyloid deposition in a patient with familial Ala36Pro TTR amyloidosis. She received molecular diagnosis at age 24 and presented at age 26 with paresthesias of the lower limbs and bowel dysfunction. Echography showed minimal amyloid opacities in the corpus vitreum. Treatment with tafamidis meglumine was started. Sixteen months later, she complained of severe headache followed by left hemiparesthesias and numbness lasting 20 minutes. Magnetic resonance imaging showed multiple focal and diffuse hemosiderin deposits compatible with microbleeds and early siderosis. Echography showed a marked increase of "vitreal opacities." Our observation confirms that tafamidis fails in halting increase of vitreal amyloid deposits and indicates that it is presumably ineffective in preventing clinical onset due to progression of meningovascular amyloidosis. These failures may be due to the incapability of tafamidis to cross the blood-retina and blood-brain barriers. Therapeutic options targeting oculomeningovascular TTR amyloidoses in humans are required.

Clinical features of high-degree centrum semiovale-perivascular spaces in cerebral amyloid angiopathy.

BACKGROUND: There is no doubt that cerebral amyloid angiopathy (CAA) is a key risk factor for recurrent lobar ICH, however, the exact mechanism and interaction with MRI markers of disease severity are less well known. Centrum semiovale-perivascular spaces (CSO-PVS) have been suggested as adjunctive diagnostic criteria in order to enhance diagnostic power. The purposes of this study were to investigate the prevalence of CSO-PVS and its association with other imaging signatures {lobar microbleeds (CMB), cortical superficial siderosis (CSS), white matter hyperintensity (WMH)} in lobar ICH patients as well as recurrent lobar ICH risk, especially in patients taking antithrombotic agents. METHODS: This retrospective study included 85 patients who visited our institute between 2005 and 2013 with lobar ICH on magnetic resonance imaging(MRI). CSO-PVS were rated on axial T2-weighted sequences using a validated 2-point visual rating scale (high degree >20, low degree ≤20). The CSS, CMB and WMH were also evaluated. The relationship between CSO-PVS, CSS, CMB, antithrombotic usage and recurrent bleeding were explored. RESULTS: A high degree of CSO-PVS was present in 71.8% of patients. The prevalence of CSS and CMB was higher in patients with a high degree of CSO-PVS (CSS, 49.2% vs. 16.7%, P=0.006; CMB count, 7.3% vs. 2.1%, P=0.002). A high degree of CSO-PVS and antithrombotic usage following lobar ICH was not associated with recurrent hemorrhage. In multivariate logistic regression analysis of predictors of recurrent lobar ICH in lobar ICH patients, post-ICH antithrombotics use and disseminated CSS are independently associated with increased risk of recurrent lobar ICH. CONCLUSIONS: High-degree CSO-PVS is highly prevalent in probable cerebral amyloid angiopathy and is related to CSS and CMB. Disseminated CSS was associated with recurrent ICH in CAA. Our study might help physicians decide whether or not to use antithrombotic agents in hemorrhagic stroke patients with a high risk of ischemic stroke. A large prospective study is warranted to validate these findings.

Cerebral microbleeds and macrobleeds: should they influence our recommendations for antithrombotic therapies?

Intracerebral hemorrhage (ICH, or macrobleeds) and cerebral microbleeds-smaller foci of hemosiderin deposits commonly detected by magnetic resonance imaging of older adults with or without ICH-are both associated with an increased risk of future ICH. These hemorrhagic pathologies also share risk factors with ischemic thromboembolic conditions that may require antithrombotic therapy, requiring specialists in cardiology, internal medicine, and neurology to weigh the benefits vs hemorrhagic risks of antithrombotics in individual patients. This paper will review recent advances in our understanding of hemorrhage prone cerebrovascular pathologies with a particular emphasis on use of these markers in decision making for antithrombotic use.

Agranulocytosis with deferiprone treatment of superficial siderosis.

Superficial siderosis of the central nervous system is a rare neurological disorder caused by deposits of haemosiderin on subplial brain matter. Characterised by a thin dark layer surrounding the brain stem, cerebellum and cortical fissures on the T2-weighted MRI, symptoms include sensorineural hearing loss and progressive gait ataxia. A specific aetiology for the blood in the subarachnoid space is identified in less than 50% of cases. While identification of a specific vascular defect allows for vascular repair, treatment options are limited for idiopathic superficial siderosis. Recently, a pilot safety study demonstrated promising results using an iron chelator, deferiprone. While this approach is promising, we present a potential serious complication of this therapy-the first report of agranulocytosis in the treatment of superficial siderosis following deferiprone therapy.

Treatment of superficial siderosis with iron chelation therapy.

Superficial siderosis is caused by recurrent haemorrhage in the subarachnoid space leading to haemosiderin deposition. It typically causes the triad of ataxia, deafness and myelopathy. We report a patient who developed superficial siderosis following neurosurgery for syringomyelia and who had an improvement in his hearing and mobility following treatment with a new iron chelation therapy that can penetrate the blood-brain barrier. It provides an intriguing insight into a therapy that could potentially modify the course of this rare neurodegenerative disorder. Further studies are required to assess the clinical efficacy of deferiprone in superficial siderosis.

[A case of superficial siderosis treated with intravenous and oral hemostatic drugs].

A 39-year-old man suffering from progressive dysarthria, gait disturbance, and sensorineural deafness for 2 years was admitted to our hospital. He scored 28 points on the mini-mental state examination. He had previously undergone surgery at 24 years and 39 years of age for a cerebellar tumor (pilocytic astrocytoma). Superficial siderosis (SS) was diagnosed based on bloody cerebrospinal fluid (CSF) and the findings of T2-weighted head MRI that revealed marginal hypointensity of the surface of the cerebellum, brainstem, and cerebral cortex. After intravenous infusion and the oral use of hemostatic drugs (carbazochrome, tranexamic acid), the CSF became watery clear and his condition improved. Hemostatic drug therapy should be considered for SS.

[Superficial siderosis of the central nervous system treated with prednisolone]. / Superficiel siderose i centralnervesystemet behandlet med prednisolon.

Superficial siderosis (SS) of the central nervous system is a rare disorder in which the most common clinical manifestations are gait ataxia, sensorineural deafness and affection of the corticospinal tracts. Knowledge of this disorder is important since early diagnosis and treatment is crucial for the prognosis. Furthermore, new treatment strategies are emerging. The effect of corticosteroids on SS without an identifiable bleeding source has been debated. We present a case with a good clinical effect of steroids.

Pilot safety trial of deferiprone in 10 subjects with superficial siderosis.

BACKGROUND AND PURPOSE: Superficial siderosis is a neurodegenerative disease caused by toxic accumulation of hemosiderin on the surface of the brain and spinal cord for which there is no known effective treatment. METHODS: Oral deferiprone, a lipid-soluble iron chelator with ability to cross the blood-brain barrier, at a dose of 30 mg/kg per day was tested for safety in an open pilot study in 10 subjects with superficial siderosis. RESULTS: Over a 90-day period, deferiprone had no significant adverse effects on hematologic, liver, or neurological function. Ad hoc MRI assessments of the brain indicated a reduction in hemosiderin deposition in some subjects. CONCLUSIONS: Deferiprone proved safe in this small population of superficial siderosis subjects. There was MRI evidence of reduced hemosiderin deposition with deferiprone. Prospectively designed efficacy studies are necessary to determine the clinical efficacy of deferiprone in superficial siderosis.

Deferiprone reduces hemosiderin deposits in the brain of a patient with superficial siderosis.

A man with superficial siderosis showed improvement in symptoms and reduction in hemosiderin by MR imaging following treatment with deferiprone, a lipid-soluble iron chelator.