Progressive superficial siderosis despite complete remission of intracranial hypotension symptoms following epidural patching: Case report.

Spontaneous intracranial hypotension (SIH) commonly results from ventral spinal cerebrospinal fluid (CSF) leaks and epidural patches are advocated as first-line treatment. Complications such as superficial siderosis can arise but have previously been reported only in the context of long-term persistent, ongoing, CSF leak and SIH. We report a case of a patient with SIH from a ventral spinal CSF leak that was treated with epidural patching and experienced complete resolution of SIH. Four years later SIH symptoms recurred, and brain magnetic resonance imaging unexpectedly showed the interval accumulation of hemosiderin pigmentation on the cerebellum and brainstem during the period when the patient was without symptoms of SIH. This case uniquely demonstrates the progression of superficial siderosis despite the apparent resolution of SIH. Our findings suggest two divergent pathophysiological outcomes from spinal ventral dural tear: (1) CSF loss causing SIH; and (2) persistent low-level bleeding arising from the spinal dural tear leading to superficial siderosis. These divergent pathophysiologies had a discordant response to epidural patching. Epidural patching successfully treated the SIH but did not prevent the progression of superficial siderosis, indicating that some patients may require more than epidural patching despite symptom resolution. This case highlights the need for post-treatment monitoring protocols in patients with ventral spinal CSF leaks and SIH and raises important questions about the adequacy of epidural patching in certain SIH cases arising from ventral spinal CSF leak.

Superficial small cerebellar infarcts in cerebral amyloid angiopathy on 3 T MRI: A preliminary study.

BACKGROUND: Strictly superficial cerebellar microbleeds and cerebellar superficial siderosis have been considered markers of advanced cerebral amyloid angiopathy (CAA), but there are few studies on cerebellar ischemic lesions in CAA. We investigated the presence of superficial small cerebellar infarct (SCI) ≤15 mm and its relation to magnetic resonance imaging (MRI) markers in patients with probable CAA. METHODS: Eighty patients with probable CAA were retrospectively evaluated. The presence of superficial SCIs was examined, along with cerebellar microbleeds and cerebellar superficial siderosis, using 3-T MRI. Lobar cerebral microbleeds, cortical superficial siderosis (cSS), enlargement of the perivascular space in the centrum semiovale, and white matter hyperintensity were assessed and the total CAA-small vessel disease (SVD) score was calculated. RESULTS: Nine of the 80 patients (11.3%) had a total of 16 superficial SCIs. By tentatively defining SCI <4 mm as cerebellar microinfarcts, 8 out of 16 (50%) superficial SCIs corresponded to cerebellar microinfarcts. The total CAA-SVD score was significantly higher in patients with superficial SCIs (p = 0.01). The prevalence of cSS (p = 0.018), cortical cerebral microinfarct (p = 0.034), and superficial cerebellar microbleeds (p = 0.006) was significantly higher in patients with superficial SCIs. The number of superficial cerebellar microbleeds was also significantly higher in patients with superficial SCIs (p = 0.001). CONCLUSIONS: Our results suggest that in patients with CAA, superficial SCIs (including microinfarcts) on MRI may indicate more severe, advanced-stage CAA. These preliminary findings should be verified by larger prospective studies in the future.

Pancreatic iron in pediatric transfusion-dependent beta-thalassemia patients: A longitudinal MRI study.

BACKGROUND: In pediatric transfusion-dependent thalassemia (TDT) patients, we evaluated the prevalence, pattern, and clinical associations of pancreatic siderosis and the changes in pancreatic iron levels and their association with baseline and changes in total body iron balance. PROCEDURE: We considered 86 pediatric TDT patients consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. Iron overload (IO) was quantified by R2* magnetic resonance imaging (MRI). RESULTS: Sixty-three (73%) patients had pancreatic IO (R2* > 38 Hz). Global pancreas R2* values were significantly correlated with mean serum ferritin levels, MRI liver iron concentration (LIC) values, and global heart R2* values. Global pancreas R2* values were significantly higher in patients with altered versus normal glucose metabolism. Thirty-one patients also performed the follow-up MRI at 18 ± 3 months. Higher pancreatic R2* values were detected at the follow-up, but the difference versus the baseline MRI was not significant. The 20% of patients with baseline pancreatic IO showed no pancreatic IO at the follow-up. The 46% of patients without baseline pancreatic IO developed pancreatic siderosis. The changes in global pancreas R2* between the two MRIs were not correlated with baseline serum ferritin levels, baseline, final, and changes in MRI LIC values, or baseline pancreatic iron levels. CONCLUSIONS: In children with TDT, pancreatic siderosis is a frequent finding associated with hepatic siderosis and represents a risk factor for myocardial siderosis and alterations of glucose metabolism. Iron removal from the pancreas is exceptionally challenging and independent from hepatic iron status.

Genome-Wide Association Studies of ARIA From the Aducanumab Phase 3 ENGAGE and EMERGE Studies.

BACKGROUND AND OBJECTIVES: Amyloid-related imaging abnormalities (ARIA) were the most common adverse events reported in the phase 3 ENGAGE and EMERGE trials of aducanumab, an anti-amyloid monoclonal antibody. APOE ε4 carrier status has been shown to increase risk of ARIA in prior trials of aducanumab and other anti-amyloid therapies; however, the remainder of the human genome has not been evaluated for ARIA risk factors. Therefore, we sought to determine in a hypothesis-free manner whether genetic variants beyond APOE influence risk of ARIA in aducanumab-treated patients. METHODS: We performed genome-wide association studies (GWAS) of ARIA in participants in the ENGAGE and EMERGE trials. Participants had mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia and were amyloid-positive on PET scans. All participants underwent regular MRI monitoring to detect and diagnose ARIA. RESULTS: Of the 3,285 participants in the intent-to-treat population, this analysis included 1,691 with genotyping array data who received at least one dose of aducanumab with at least one post-baseline MRI. All participants in the study cohort were of European ancestry; 51% were female. The mean age was 70.3 years. 31% had ARIA-E, 19% had ARIA-H microhemorrhage, and 14% had ARIA-H superficial siderosis. We identified one genome-wide significant (p < 5.0 × 10-8) association at the chromosome 19 locus encompassing APOE. The APOE association with ARIA was stronger in ε4/ε4 homozygotes (OR = 4.28, 4.58, 7.84; p < 2.9 × 10-14 for ARIA-E, ARIA-H microhemorrhage, and ARIA-H superficial siderosis, respectively) than in ε3/ε4 heterozygotes (OR = 1.74, 1.46, 3.14; p ≤ 0.03). We found greater odds of radiographically severe ARIA (OR = 7.04-24.64, p ≤ 2.72 × 10-5) than radiographically mild ARIA (OR = 3.19-5.00, p ≤ 1.37 × 10-5) among ε4/ε4 homozygotes. APOE ε4 was also significantly associated with both symptomatic (ε4/ε4 OR = 3.64-9.52; p < 0.004) and asymptomatic (ε4/ε4 OR = 4.20-7.94, p < 1.7 × 10-11) cases, although among ARIA cases, APOE did not appear to modulate symptomatic status. No other genome-wide significant associations were found. DISCUSSION: We identified a strong, genome-wide significant association between APOE and risk of ARIA. Future, larger studies may be better powered to detect associations beyond APOE. These findings indicate that APOE is the strongest genetic risk factor of ARIA incidence, with implications for patient management and risk-benefit treatment decisions. TRIAL REGISTRATION INFORMATION: Both trials (ENGAGE [221AD301]: NCT02477800 and EMERGE [221AD302]: NCT02484547) were registered in June 2015 at clinicaltrials.gov and enrolled patients from August 2015 to July 2018.

Post-transfusion severe headache in a patient with thalassemia with superficial siderosis of the central nervous system: a case report and literature review.

BACKGROUND: Patients with severe thalassemia may experience adverse effects from transfusion such as fever, rash, and iron overload after long-term transfusion therapy. Severe headaches as a side effect of blood transfusion in patients with thalassemia are not commonly observed, especially when combined with superficial siderosis of the central nervous system, which is easily misdiagnosed and requires excessive examination and treatment. CASE PRESENTATION: A 31-year-old woman was admitted with severe headache and vomiting over 3 days following blood transfusion. She was diagnosed with intermediate α-thalassemia at 2 years of age and had a history of irregular blood transfusions. Physical examination revealed horizontal nystagmus with no other abnormal neurological signs. Magnetic resonance (MR) imaging, MR venography, MR arteriography, and cerebrospinal fluid analysis were normal. However, susceptibility-weighted imaging showed abnormal signals in the bilateral and fourth ventricles. Initial antibiotics, antivirals, decompression of intracranial pressure, iron chelation, and symptomatic treatments were administered; subsequently, small intermittent blood transfusions were cautiously administered for severe anemia. The patient's headache was gradually relieved, and she was discharged on day 9. At the 5-month follow-up, the patient's headache recurred following another transfusion. CONCLUSIONS: Severe post-transfusion headache in patients with thalassemia has not been fully recognized and is easily misdiagnosed, leading to excessive examination and treatment. Understanding the clinical features of transfusion-related headaches can help identify this complication, but the exact pathophysiological mechanism requires further research.

Surgical closure of spinal cerebrospinal fluid leaks improves symptoms in patients with superficial siderosis.

BACKGROUND AND PURPOSE: Spinal cerebrospinal fluid (CSF) leaks may cause a myriad of symptoms, most common being orthostatic headache. In addition, ventral spinal CSF leaks are a possible etiology of superficial siderosis (SS), a rare condition characterized by hemosiderin deposits in the central nervous system (CNS). The classical presentation of SS involves ataxia, bilateral hearing loss, and myelopathy. Unfortunately, treatment options are scarce. This study was undertaken to evaluate whether microsurgical closure of CSF leaks can prevent further clinical deterioration or improve symptoms of SS. METHODS: This cohort study was conducted using data from a prospectively maintained database in two large spontaneous intracranial hypotension (SIH) referral centers in Germany and Switzerland of patients who meet the modified International Classification of Headache Disorders, 3rd edition criteria for SIH. Patients with spinal CSF leaks were screened for the presence of idiopathic infratentorial symmetric SS of the CNS. RESULTS: Twelve patients were included. The median latency between the onset of orthostatic headaches and symptoms attributed to SS was 9.5 years. After surgical closure of the underlying spinal CSF leak, symptoms attributed to SS improved in seven patients and remained stable in three. Patients who presented within 1 year after the onset of SS symptoms improved, but those who presented in 8-12 years did not improve. We could show a significant association between patients with spinal longitudinal extrathecal collections and SS. CONCLUSIONS: Long-standing untreated ventral spinal CSF leaks can lead to SS of the CNS, and microsurgical sealing of spinal CSF leaks might stop progression and improve symptoms in patients with SS in a time-dependent manner.

Validity of an automated screening Dixon technique for quantifying hepatic steatosis in living liver donors.

PURPOSE: This retrospective study aimed to evaluate the validity of an automated screening Dixon (e-DIXON) technique for quantifying hepatic steatosis in living liver-donor patients by comparison with magnetic resonance spectroscopy (MRS) as a reference standard. METHODS: A total of 285 living liver-donor candidates were examined with the e-DIXON technique and single-voxel MRS to assess hepatic steatosis and iron deposition between January 2014 and February 2019. The sensitivity, specificity, and positive and negative predictive values (PPV and NPV) of the e-DIXON technique for hepatic steatosis were calculated. The mean fat signal fractions obtained in MRS were compared between the donors diagnosed with hepatic steatosis and the normal group. The mean R2 values of donors with or without hepatic siderosis also were compared. RESULTS: The e-DIXON technique diagnosed normal in 133 (47%), fat in 124 (44%), iron in one (0.4%), and a combination of both fat and iron in 27 (10%) donors. The sensitivity, specificity, PPV, and NPV ​​for diagnosing hepatic steatosis were 94%, 70%, 64%, and 96%, respectively. There was a significant difference in the mean fat signal fraction obtained in MRS between the steatosis and normal groups (p < 0.001), but R2 values were not significantly different between siderosis and normal groups (p = 0.11). The e-DIXON technique showed a strong correlation with MRS in fat measurement (r2 = 0.92, p < 0.001). CONCLUSION: The e-DIXON technique reliably screens for hepatic steatosis but may not accurate for detecting hepatic iron deposition.

Retained Intraocular Iron Foreign Body Leading to Late-Onset Siderotic Glaucoma: A Challenging Case Report.

BACKGROUND A retained ferrous intraocular foreign body (IOFB), introduced via penetrating ocular trauma, may result in ocular siderosis and visual loss that may occur after days or years. If diagnosis is delayed, therapy may also be delayed, resulting in a poor outcome. The present report presents the case of a 58-year-old man with a retained iron IOFB and late-onset siderotic glaucoma 1 month after the initial trauma. CASE REPORT A 58-year-old man presented with redness and eye pain in the right eye for 1 month after ocular trauma. His visual acuity was very good, with no sign of eye strain. High intraocular pressure had been detected for several weeks, but the B-scan ultrasound and fundus examination were normal and the reason for the high intraocular pressure was unknown. He was later transferred to our senior hospital. The diagnosis of IOFB was confirmed by computed tomography (CT) scan and ultrasound biomicroscopy (UBM). The patient was successfully managed by vitrectomy. CONCLUSIONS This report highlights that a retained IOFB can be challenging to diagnose and that cases associated with siderotic glaucoma require multiple investigations. Early detection of the IOFB using the right tools is vital to reduce the risk of siderotic glaucoma. Although the fundus examination was normal after ocular trauma, the use of CT scan and UBM assisted in finding the IFOB and the patient was successfully treated by vitrectomy.

A case report of superficial siderosis of the central nervous system and literature review.

Superficial siderosis of the central nervous system (SSCNS) is a rare disease characterized by iron deposition on the tissue surface of the middle axis system. We report the case of a man in his late 40 s who was admitted to the hospital with ataxia. A physical examination revealed cerebellar ataxia, sensorineural deafness, and bilateral pyramidal tract injury. Susceptibility-weighted magnetic resonance imaging showed linear hypointense signals on the surface of the cerebral hemispheres, sulcus gyrus, lateral ventricles, and cerebellum. The patient underwent treatment with deferiprone, mecobalamin, and vitamin B1, and the symptoms were not aggravated. The patient's daily living ability was near normal after 1 year of follow-up. A literature review indicated that most SSCNS patients present diverse clinical manifestations. Clinicians may consider SSCNS in patients with hearing impairment and gait ataxia, especially for those receiving anticoagulant therapy and with a history of brain injury or accident.

Impact of previous statin use on first intracerebral hemorrhage in cerebral amyloid angiopathy.

OBJECTIVES: Statins have been associated with an increased risk of spontaneous intracerebral hemorrhage (ICH), but without dedicated study in cerebral amyloid angiopathy (CAA). We aimed to evaluate the association between previous statin treatment and radiological hemorrhagic lesions in a CAA population during a first lobar ICH event. MATERIALS AND METHODS: We retrospectively included all patients meeting the modified Boston criteria for probable CAA and admitted for a first lobar ICH between 2010 and 2021 at Rouen University Hospital. Patients were classified as having previous statin treatment or not. We compared the ICH volume, the number of associated cerebral microbleeds (CMBs), and cortical superficial siderosis (CSS) according to previous statin treatment or not. We also compared functional outcomes and ICH recurrence during the follow-up period between the two groups. RESULTS: We included 99 patients, 27 of whom had statin treatment prior to their ICH. The ICH volume and the number of CMBs did not differ between groups. Disseminated CSS was initially more frequent in the statin group (88% versus 57%; P=0.019), but this was no longer significant after adjustment for antiplatelet treatment (P=0.13). The long-term outcome was similar between the two groups with no increased risk of ICH recurrence in the statin-treated group (29.63% versus 23.61%, P=0.54). CONCLUSIONS: Previous statin treatment was not associated with more severe hemorrhagic lesions in CAA in terms of ICH volume or number of microbleeds, but a trend for increased disseminated CSS was highlighted, which will require further larger studies.

Cortical superficial siderosis is associated with reactive astrogliosis in cerebral amyloid angiopathy.

BACKGROUND: Cortical superficial siderosis (cSS) has recently emerged as one of the most important predictors of symptomatic intracerebral hemorrhage and is a risk factor for post-stroke dementia in cerebral amyloid angiopathy (CAA). However, it remains unknown whether cSS is just a marker of severe CAA pathology or may itself contribute to intracerebral hemorrhage risk and cognitive decline. cSS is a chronic manifestation of convexal subarachnoid hemorrhage and is neuropathologically characterized by iron deposits in the superficial cortical layers. We hypothesized that these iron deposits lead to local neuroinflammation, a potentially contributory pathway towards secondary tissue injury. METHODS: Accordingly, we assessed the distribution of inflammatory markers in relation to cortical iron deposits in post-mortem tissue from CAA cases. Serial sections from the frontal, parietal, temporal, and occipital lobes of nineteen autopsy cases with CAA were stained with Perls' Prussian blue (iron) and underwent immunohistochemistry against glial fibrillary acidic protein (GFAP, reactive astrocytes) and cluster of differentiation 68 (CD68, activated microglia/macrophages). Digitized sections were uploaded to the cloud-based Aiforia® platform, where deep-learning algorithms were utilized to detect tissue, iron deposits, and GFAP-positive and CD68-positive cells. RESULTS: We observed a strong local relationship between cortical iron deposits and reactive astrocytes. Like cSS-related iron, reactive astrocytes were mainly found in the most superficial layers of the cortex. Although we observed iron within both astrocytes and activated microglia/macrophages on co-stains, there was no clear local relationship between the density of microglia/macrophages and the density of iron deposits. CONCLUSION: Iron deposition resulting from cSS is associated with local reactive astrogliosis.

Cerebral Microbleed Patterns and Cortical Amyloid-ß: The ARIC-PET Study.

BACKGROUND: Cerebral microbleeds (CMBs) are associated with cognitive decline, but their importance outside of cerebral amyloid angiopathy and the mechanisms of their impact on cognition are poorly understood. We evaluated the cross-sectional association between CMB patterns and cerebral Aß (amyloid-ß) deposition, by florbetapir positron emission tomography. METHODS: The longitudinal ARIC study (Atherosclerosis Risk in Communities) recruited individuals from 4 US communities from 1987 to 1989. From 2012 to 2014, the ARIC-PET (Atherosclerosis Risk in Communities - Positron Emission Tomography) ancillary recruited 322 nondemented ARIC participants who completed 3T brain magnetic resonance imaging with T2*GRE as part of ARIC visit 5 to undergo florbetapir positron emission tomography imaging. Magnetic resonance imaging images were read for CMBs and superficial siderosis; on positron emission tomography, global cortical standardized uptake value ratio >1.2 was considered a positive Aß scan. Multivariable logistic regression models evaluated CMB characteristics in association with Aß positivity. Effect modification by sex, race, APOE status, and cognition was evaluated. RESULTS: CMBs were present in 24% of ARIC-PET participants. No significant associations were found between CMBs and Aß positivity, but a pattern of isolated lobar CMBs or superficial siderosis was associated with over 4-fold higher odds of elevated Aß when compared with those with no CMBs (odds ratio, 4.72 [95% CI, 1.16-19.16]). A similar elevated risk was not observed in those with isolated subcortical or mixed subcortical and either lobar CMBs or superficial siderosis. Although no significant interactions were found, effect estimates for elevated Aß were nonsignificantly lower (P>0.10, odds ratio, 0.4-0.6) for a mixed CMB pattern, and odds ratios were nonsignificantly higher for lobar-only CMBs for 4 subgroups: women (versus men); Black participants (versus White participants), APOE ε4 noncarriers (versus carriers), and cognitively normal (versus mild cognitive impairment). CONCLUSIONS: In this community-based cohort of nondemented adults, lobar-only pattern of CMBs or superficial siderosis is most strongly associated with brain Aß, with no elevated risk for a mixed CMB pattern. Further studies are needed to understand differences in CMB patterns and their meaning across subgroups.

Age-related macular degeneration is associated with probable cerebral amyloid angiopathy: A case-control study.

BACKGROUND: Age-related macular degeneration (AMD) is a common retinal degenerative disorder among older individuals. Amyloid deposits, a hallmark of cerebral amyloid angiopathy (CAA), may be involved in the pathogenesis of AMD. Since amyloid deposits may contribute to the development of both AMD and CAA, we hypothesized that patients with AMD have a higher prevalence of CAA. OBJECTIVE: To compare the prevalence of CAA in patients with or without AMD matched for age. METHODS: We conducted a cross-sectional, 1:1 age-matched, case-control study of patients ≥40 years of age at the Mayo Clinic who had undergone both retinal optical coherence tomography and brain MRI from 2011 to 2015. Primary dependent variables were probable CAA, superficial siderosis, and lobar and deep cerebral microbleeds (CMBs). The relationship between AMD and CAA was assessed using multivariable logistic regression and was compared across AMD severity (none vs early vs late AMD). RESULTS: Our analysis included 256 age-matched pairs (AMD 126, no AMD 130). Of those with AMD, 79 (30.9%) had early AMD and 47 (19.4%) had late AMD. The mean age was 75±9 years, and there was no significant difference in vascular risk factors between groups. Patients with AMD had a higher prevalence of CAA (16.7% vs 10.0%, p=0.116) and superficial siderosis (15.1% vs 6.2%, p=0.020), but not deep CMB (5.2% vs 6.2%, p=0.426), compared to those without AMD. After adjusting for covariates, having late AMD was associated with increased odds of CAA (OR 2.83, 95% CI 1.10-7.27, p=0.031) and superficial siderosis (OR 3.40, 95%CI 1.20-9.65, p=0.022), but not deep CMB (OR 0.7, 95%CI 0.14-3.51, p=0.669). CONCLUSIONS: AMD was associated with CAA and superficial siderosis but not deep CMB, consistent with the hypothesis that amyloid deposits play a role in the development of AMD. Prospective studies are needed to determine if features of AMD may serve as biomarkers for the early diagnosis of CAA.

[Classical cortical superficial siderosis presenting as extensive higher brain dysfunction with hypoperfusion in the frontoparietal lobe on the 123I-IMP-SPECT: a case report].

A 72-year-old male developed neurological symptoms such as difficulty in charging his electronic money card and making his mobile-phone call ten months before admission. On admission, neurological examination revealed extensive higher brain dysfunction such as impairment in recent memory, executive function disorders, constructional disturbance, agraphia and acalculia. Brain MRI revealed a low intensity lesion on the surface of the cerebral cortex diffusely and symmetrically on T2*-weighted images. MRI images are consistent with superficial siderosis. However, the lack of hemosiderin deposition in the brain stem and cerebellar hemisphere was atypical of the classical type of superficial siderosis. 123I-IMP-SPECT revealed hypoperfusion dominantly in the left hemisphere, particularly in the left frontal and parietal lobes. According to the Boston criteria, the patient with the cerebral microbleeds and cortical superficial siderosis was diagnosed with probable CAA (cerebral amyloid angiopathy).