Kumar, Neeraj

Superficial siderosis of the central nervous system results from subpial hemosiderin deposition due to chronic low‐grade bleeding into the subarachnoid space. The confluent and marginal subpial hemosiderin is best appreciated on iron‐sensitive magnetic resonance imaging sequences. With widespread use of magnetic resonance imaging, the disorder is increasingly being recognized, including in asymptomatic individuals. Gait ataxia, often with hearing impairment is a common clinical presentation. A clinical history of subarachnoid hemorrhage is generally not present. A macrovascular pathology is generally not causative. The most common etiology is dural disease, often dural tears. Prior or less commonly ongoing symptoms of craniospinal hypovolemia may be present. Common etiologies for dural tears include disc disease and trauma, including surgical trauma. Patients with dural tears due to herniated and calcified discs often have a ventral intraspinal fluid collection due to cerebrospinal fluid leak. A precise identification of the dural tear relies on multimodality imaging. It has been speculated that chronic bleeding from fragile blood vessels around the dural tear may be the likely underlying mechanism. Surgical correction of the bleeding source is a logical therapeutic strategy. Clinical outcomes are variable, although neuroimaging evidence of successful dural tear repair is noted. The currently available data regarding use of deferiprone in patients with superficial siderosis is insufficient to recommend its routine use in patients. ANN NEUROL 2021;89:1068–1079

Abstract Background: Copper deficiency is an established cause of hematological abnormalities, traditionally described in malnourished infants and persons with malabsorption or short bowel syndromes, particularly those requiring long-term parenteral nutrition. With the recent increase in bariatric (weight reduction) surgery, acquired copper deficiency may be increasing in incidence but the diagnosis is frequently delayed. Methods: To outline the natural history of copper deficiency we searched the Mayo Clinic database and our heavy metals laboratory for patients diagnosed with low serum copper during the years 1974–2005. Copper deficiency was defined as a serum level < 0.75 μg/ml. Results: We identified 123 patients with a low serum copper. 77 patients were excluded as the the hypocupremia was either transient or due to other factors such as Wilson’s disease. The remaining 46 patients were all symptomatic. 25 patients had hematological abnormalities, 20 of these patients also had neurological involvement. 5 had isolated hematological manifestations and 21 patients had isolated neurological findings, most commonly myeloneuropathy. 13 presented with anemia and leukopenia, 5 with pancytopenia, 6 with anemia and 1 with isolated neutropenia. In 10 of the 25 cases, a secondary contributing cause for the hematological findings was identified. These included possible anemia of chronic disease (4), renal insufficiency (2), iron deficiency (1), B12 deficiency (1), GI hemorrhage (1), and splenomegaly (1) while copper deficiency was the only identifiable cause in the remaining 15 patients. Hematological parameters at diagnosis are outlined in the table. 15 of the 25 patients with hematological manifestations had a history of GI surgery, including 6 patients who had bariatric surgery. The median time from surgery to diagnosis was 11.5 years (range 8 months - 45 years) and was shorter for bariatric surgery (10 years, range: 8 months - 25 years) than for non-bariatric surgery (18 years, range: 2–45 years). 1 patient had a history of excessive zinc ingestion, 1 had malabsorption secondary to chronic pancreatitis and 1 patient had celiac disease. In 7 cases, no explanation was found. 24 of 25 patients received treatment with oral or intravenous copper, 5 were lost to follow up. In 16 patients the hematologic parameters either improved significantly or normalized, while in the remaining 3 patients there was no improvement. Factors that may explain the lack of response in these patients included splenomegaly (1), renal insufficiency (1) and multiorgan illness (1). Conclusion: Copper deficiency is an increasingly frequent cause of hematological abnormalities, and can manifest with refractory cytopenias with or without associated neurological symptoms. Thrombocytopenia is relatively rare. Previous GI surgery, especially bariatric surgery, appears to be a major causative factor. Most patients will have an improvement in hematological parameters after copper supplementation. Recognition of copper deficiency is therefore assuming greater importance in view of the increasing frequency of bariatric surgery, ease of treatment and potential for irreversible neurological damage if diagnosis is delayed. Hematologic parameters at diagnosis HgB (g/dL) MCV (fL) WBC (x109/L) ANC(x109/L) Plts(x109/L) Median 10.6 99 3.0 1.25 215 Range 7.9-13.6 83.9-114.1 1-5.6 0.18-4.0 54-554

Abstract Background: Copper deficiency is increasingly being diagnosed in adults with malabsorption syndromes, especially following GI surgery such as gastric and bowel resections and bariatric surgery. The most common hematologic manifestations are refractory anemia and neutropenia and patients have been misdiagnosed as having myelodysplasia. Certain findings on bone marrow examination are felt to be characteristic for copper deficiency such as maturation arrest in the myeloid lineage, vacuolization of the erythroid and myeloid precursors and ringed sideroblasts. Methods: We reviewed all cases of copper deficiency diagnosed at the Mayo Clinic from 1974 – 2005. We also reviewed all cases of low serum copper (< 0.75 μg/ml) identified in our heavy metals laboratory. Results: 123 patients with hypocupremia were identified. 77 patients were excluded as the hypocupremia was either transient or due to other factors such as Wilson’s disease. Twenty-five patients had hematologic manifestations, including anemia and leukopenia (13), isolated anemia (6), pancytopenia (5), and isolated neutropenia (1). Eighteen patients had a bone marrow biopsy. We were able to retrieve and review bone marrow slides in 11 cases. The bone marrow examination findings are shown in the table. The marrow cellularity was decreased in four cases. All cases had granulocytic hypoplasia but preserved megakaryopoiesis. Nine cases had relative erythroid hyperplasia. All but one bone marrow had cytoplasmic vacuoles in pronormoblasts and myelocytes. Increased iron within macrophages was seen in 9 cases and increased iron in plasma cells was noted in 8 cases. This was especially prominent in the cases with low peripheral white blood count. Ringed sideroblasts were seen in 4 cases and were more commonly seen in anemic patients. The initial bone marrow examination commonly suggested toxic effect (drugs or alcohol), myelodysplasia or were non-diagnostic. Conclusion: We have described the bone marrow findings in 11 copper deficient patients with abnormal blood counts. None of these patients was suspected of copper deficiency based on the initial marrow examination. The initial impression was commonly toxic effect due to the presence of cytoplasmic vacuolization. Patients with ringed sideroblasts were suspected of having MDS. Copper deficiency should be considered in patients with cytopenias and the described bone marrow findings, especially if there is evidence of malabsorption or a history of GI surgery such as gastric resection or bariatric surgery. Bone marrow findings Patient Cellularity Ery/gran/meg Vacuoles Iron (mø/PC) RS Hgb/Plt WBC/ANC nl: normal, 0: absent, Ery/gran/meg: erythro-/granulo-/megakaryopoiesis, Iron (mø/PC): Iron in macrophages and plasma cells, RS: Ringed sideroblasts 1 ↓ ↑/↓/nl Yes ↑/↑ No 11.3/203 3.2/1.1 2 Nl ↑/↓/nl Yes 0/0 No 11.4/192 5.6/4.0 3 Nl ↑/↓/nl No ↑/0 No 10.6/95 3.0/2.2 4 ↓ ↑/↓/nl Yes ↑/↑ No 13.6/128 4.2/0.92 5 Nl ↑/↓/nl Yes ↑/↑ 10% 9.8/215 1.4/0.6 6 ↓ ↑/↓/nl Yes ↑/↑ No 7.9/292 1.8/0.18 7 Nl ↑/↓/nl Yes ↑/↑ No 10.6/280 2.7/1.4 8 Nl nl/↓/nl Yes ↑/↑ 20% 8.1/330 1.5/0.24 9 Nl ↑/↓/nl Yes ↑/↑ <1% 9.4/252 1.3/0.25 10 ↓ Nl/↓/nl Yes 0/0 No 10.5/167 2.4/1.67 11 Nl ↑/↓/nl Yes ↑/↑ yes 12.5/224 4.2/3.9

Abstract Introduction Varied presentations of vitamin B12 (B12) deficiency include hematologic (megaloblastic anemia) and neurologic (myelopathy, peripheral neuropathy). Delayed recognition and treatment may have serious consequences. Assessing B12 status can be challenging due to diverse laboratory assays and thresholds, resulting in a wide range of reported prevalence of B12 deficiency from 3-26%. Comorbidities may also spuriously elevate or suppress B12 levels. Methylmalonic acid (MMA) level, often used as a companion test to assess for B12 deficiency, may also be affected by differing laboratory thresholds and other medical comorbidities, such as renal dysfunction. Our institutional approach to B12 assessment, termed the pernicious anemia (PA) cascade, consists of reflexive testing to 1) document low B12 stores (B12 levels with or without MMA), and 2) diagnose pernicious anemia (intrinsic factor binding antibody [IFBA] with or without gastrin assay). In this study, our objectives were: (1) assess the usefulness of our B12 testing algorithm and associated laboratory thresholds for identifying B12 deficiency, and (2) evaluate clinical follow-up of test results as part of a quality project. Methods In this retrospective study, adult (age ≥18 years) inpatients who had B12 testing from 2007 to 2013 were identified. Medical records for those patients with B12 levels 150-400 ng/L were reviewed. Data abstracted included patient demographics, indication for B12 testing, B12 levels, results for MMA, IFBA, gastrin, serum creatinine, complete blood count, and clinical outpatient follow-up. The PA cascade algorithm is as follows: 1) for B12 <150 ng/L, IFBA is performed; 2) if IFBA is negative or indeterminate, then gastrin is performed; 3) for B12 150-400 ng/L, MMA is performed; 4) if MMA is >0.40 nmol/mL, then IFBA is performed. Reference range for B12 is 180-914 ng/L. Patients were determined to be B12 deficient if B12 level was <180 ng/L, or if B12 was 150-400 ng/L with elevated MMA and macrocytosis in the absence of significant renal dysfunction, defined as serum creatinine ≥2.0 mg/dL. Results Records of 326 patients (150 female) were reviewed. Indications for B12 testing were: hematologic, 175 patients (53.7%); neurologic, 127 patients (39.0 %), psychiatric, 18 patients (5.5%); other, 4 patients (1.2%). Fifty-nine of 326 (18.1%) patients were B12 deficient, of whom 17 of 59 (28.8%) had PA. There were 54 cases of elevated MMA, >0.40 nmol/mL, of which 30 cases had mildly elevated MMA, >0.40 nmol/mL and ≤0.60 nmol/mL, considered to be the MMA "gray zone". Thirty-two of the total 326 patients had serum creatinine ≥2.0 mg/dL, of which 23 patients also had elevated MMA. Elevated MMA in 13 of these 23 patients was more likely due to renal dysfunction than to B12 deficiency. B12 testing results were not mentioned in hospital discharge summaries for 173 patients, including 8 patients with B12 deficiency. For 22 B12-deficient patients, there was no documentation of B12 replacement. Conclusions The PA cascade detected B12 deficiency in a significant number of inpatients with low-normal B12 levels that might have otherwise been missed; 28.8% of this group had PA for whom long-term B12 replacement is indicated. As treatment for B12 deficiency is inexpensive, non-toxic, and non-invasive, it is reasonable to evaluate B12 status by cascade testing which may provide additional diagnostic data beyond B12 level. Notable clinical practice findings from this study include the lack of B12 results in 173 of 326 discharge summaries, and no record of B12 supplementation in 22 of 59 patients with B12 deficiency. These gaps in documentation and follow-up may be associated with the relatively long turnaround time of MMA testing. Efforts at improving documentation, communication, and treatment of B12 deficiency are ongoing. Disclosures No relevant conflicts of interest to declare.

The authors report on a patient with craniospinal hypovolemia and inferior vena cava obstruction, and describe how the two conditions may be linked. This unique report further advances the emerging literature on spinal CSF venous fistulae.

Background and Purpose— Superficial siderosis (SS) is characterized by hemosiderin deposition in the superficial layers of the central nervous system and can be seen during postmortem examination or with iron-sensitive magnetic resonance imaging techniques. The distribution of SS may predict the probable underlying cause. This study aimed to report the prevalence and natural history of SS in a population-based study. Methods— Brain magnetic resonance imaging scans from the MCSA (Mayo Clinic Study of Aging), a population-based study of residents 50 to 89 years of age in Olmsted County, Minnesota, were reviewed. Participants with imaging consistent with SS were identified from 2011 through 2016. An inverse probability weighting approach was used to convert our observed frequencies to population prevalence of SS. Additional data abstracted included amyloid positron emission tomography, Apolipoprotein E genotype, coexisting cerebral microbleeds, and extent of SS. Results— A total of 1412 participants had eligible magnetic resonance imaging scans. Two participants had infratentorial SS, restricted to the posterior fossa. Thirteen participants had cortical SS involving the cerebral convexities (7 focal and 6 disseminated). Only 3 of the participants with cortical SS (23%) also had cerebral microbleeds. The population prevalence of SS was 0.21% (95% confidence interval, 0–0.45) in those 50 to 69 years old and 1.43% (confidence interval, 0.53–2.34) in those over 69 years old. Apolipoprotein E ε2 allele was more common in those with SS (57.1% versus 15.0%; P <0.001). Compared with participants without SS, those with SS were also more likely to have a positive amyloid positron emission tomographic scan (76.9% versus 29.8%; P <0.001). Conclusions— SS may be encountered in the general elderly population. The association with increased amyloid burden and Apolipoprotein E ε2 genotype supports cerebral amyloid angiopathy as the most common mechanism. Longitudinal follow-up is needed to evaluate the risk of subsequent hemorrhage in cases of incidentally discovered SS.