Superficial siderosis: comparison of two cases indicates two distinct diagnostic entities. Illustrative cases

Abstract

BACKGROUND

Superficial siderosis is the deposition of hemosiderin in the superficial layers of the central nervous system. It has been described in patients with chronic leakage of blood into the cerebrospinal fluid or with amyloid angiopathy, often associated with Alzheimer’s disease (AD).

OBSERVATIONS

We present two cases of superficial siderosis with vastly different symptomatologies and treatment courses. The patient in case 1 had diffuse superficial siderosis demonstrated on T2-weighted magnetic resonance imaging (MRI), appearing mostly in the inferior cerebellum and extending throughout the neuraxis. He presented with hearing loss, spasticity, gait abnormalities, and urinary incontinence. Ultimately, surgical exploration of the thoracic spinal dura revealed an arteriovenous fistula, which was obliterated. His clinical course stabilized but with persistent deficits. The patient in case 2 had a family history of AD and underwent MRI to evaluate for memory impairment, which demonstrated superficial siderosis of the left occipital lobe. Lumbar puncture demonstrated only traumatic contamination by red blood cells, but tau protein analysis was consistent with the diagnosis of AD.

LESSONS

Superficial siderosis is a diagnostic term prompted by findings on MRI that can arise due to two different pathological entities. The diagnosis in case 1 should be termed diffuse superficial siderosis and in case 2 should be termed lobar cortical siderosis.

Superficial siderosis (SS) is defined as hemosiderin deposition due to chronic bleeding into the subarachnoid space. The clinical manifestation of SS includes a triad of progressive sensorineural hearing loss, cerebellar ataxia, and myelopathy.¹ These are often accompanied by dementia and sphincter disturbances.² In primary SS, the hemorrhage presents from an occult source, whereas secondary SS is due to subarachnoid hemorrhages from known sources, such as arteriovenous malformations, central nervous system neoplasms, or trauma.^2,3 The mechanism of SS is associated with the lysis of erythrocytes during hemorrhage and the release of hemosiderin. The deposition of hemosiderin is associated with gliosis, demyelination, and neuronal loss.¹

SS has also been associated with cerebrospinal fluid (CSF) leaks. After CSF leakage, the probability of developing SS increases in a time-dependent fashion. This has been reported as 0% at 48 months, 4.5% at 56 months, 10.5% at 96 months, and 32.7% at 144 months.⁴

Cortical superficial siderosis (CSS) occurs over the superficial layers of the cerebral cortex and has been an emerging indicator of cerebral amyloid angiopathy (CAA),⁵ which is characterized by progressive deposition of B amyloid protein in the media and adventitia of small cortical and leptomeningeal vessels.⁶ CAA may be associated with Alzheimer’s disease (AD). CAA involves β-amyloid deposition into blood vessels, whereas AD involves β-amyloid deposition as neuritic plaques.⁷ CAA may also contribute to the pathogenesis of AD by affecting perivascular drainage, which is a major route of β-amyloid clearance.

Because SS has been associated with CAA, and CAA may play a part in the origin of AD, this is suggestive of an association between SS and AD.^8,9 In this case comparison, we describe a case of the successful treatment of classic SS and another illustrative case of the potential link with AD.

Illustrative Cases

Case 1

A 57-year-old male with a past medical history of sinus congestion and asthma presented to the clinic in January 2009 with a chief complaint of 5-year progressive bilateral hearing loss. This was sensorineural hearing loss, for which he started using hearing aids. Brain magnetic resonance imaging (MRI) demonstrated SS with hypointense layering over the surface of the brain and spinal cord on T2 imaging (Fig. 1).

FIG. 1.

Case 1. Axial T2-weighted magnetic resonance image of the brain (A) and sagittal T2-weighted magnetic resonance images of the cervical spine (B) and thoracic spine (C) showing diffuse low T2 signal around the surface of the brain, brainstem, cerebellum, and spinal cord, consistent with SS.

His hearing loss was progressive, and he received cochlear implants in both ears. Physical examination was notable for unsteadiness with tandem gait, and the patient noticed that his balance was progressively getting worse, but he denied any falls.

Digital subtraction myelography was performed to assess for a CSF leak. A possible epidural CSF leak was identified in the lower cervical region. Treatment plans sought to address the possible CSF leak, beginning with an anterior cervical discectomy at C5–6 and C6–7. This was performed, and Surgicel, an inert hemostatic material, was placed along the potential leak.

Postoperative MRI showed attenuation but persistence of the ventral epidural fluid collection. Lumbar puncture demonstrated 379 red blood cells (RBCs) per cubic millimeter (RBCs/mm³). The patient was prescribed deferiprone, an iron chelator to assist in the treatment of the siderosis. An epidural blood patch was performed on suspicion of an epidural CSF leak, but a lumbar puncture 1 month later demonstrated 7,089 RBCs/mm³.

Yearly follow-up with neurosurgery continued while the patient remained on iron chelator therapy. In 2019, MRI continued to show hypointensity on the margins of the brain, brainstem, and spinal cord on T2-weighted sequences and appeared as prominent or perhaps slightly more prominent in the spinal segments.

After reviewing the imaging in detail and noting the progression of the symptoms, the patient was offered surgery. A T2–6 laminectomy was performed. Procedure findings included large dilated epidural veins and abnormal appearing arteries exiting the nerve root sleeve at T5–6. Hemosiderin-stained arachnoid as well as pia was also identified. An extensive intradural exploration was performed, and the abnormal vasculature was obliterated with bipolar cautery. When the patient followed up, he reported improvement in steadiness and walking. To confirm the resolution of blood leakage into the CSF, lumbar punctures were performed 2 and 7 months after the surgery. Both demonstrated <1 RBC/mm³ in the CSF.

Case 2

A 73-year-old female with a family history of AD presented with progressive difficulty with word finding, anomia, and speech deficits. On examination, her language was described as fluent but with significant circumlocution, occasional paraphasic errors, and difficulty with naming and repetition. MRI of the brain showed asymmetrical volume loss on the left (Fig. 2).

FIG. 2.

Case 2. Axial T1-weighted image without contrast (A), T1-weighted image with contrast (B), heme sequence (C), and T2-weighted image (D) showing slight asymmetrical volume loss of the left parietal lobe, left temporal lobe, and left occipital lobe with respect to the right, particularly inferiorly. Arrows indicate hypointensity involving the medial occipital lobe, consistent with lobar SS.

Over the next year, the patient exhibited a pattern of cognitive decline indicative of left temporal and perhaps frontal dysfunction with language and executive function impairments. Since the patient reported gradual worsening of speech production and word-finding difficulties, which were also demonstrated on examination, she was sent for head MRI, which showed SS of the left occipital lobe with mild fluid-attenuated inversion recovery hyperintense signal of the subcortical white matter. The siderosis was on the medial margin of the left inferior occipital lobe with extension around into the sulci of the posterior lateral occipital lobe. Because of the identification of SS, the patient was referred to neurosurgery for further investigation of any possible structural cause. A review of the literature demonstrated reports of individuals with SS associated with amyloid angiopathy, often also associated with AD.

Consultation between neurosurgery and neurology led to a plan for lumbar puncture for CSF biomarkers of dementia, which would help to clarify the patient’s diagnosis. Lumbar puncture results demonstrated phosphorylated tau (p-tau) of 114.8 pg/mL, total tau (t-tau) of 930.1 pg/mL, and amyloid β_1–42 (Aβ42) of 390.3 pg/mL, with an Aβ42/t-tau (ATI) of 0.29, which were consistent with AD (p-tau >68 pg/mL, ATI <0.8). The patient and her family were informed of the diagnosis, and since the etiology of her dementia was determined, the treatment plan for AD was started.

Discussion

Superficial siderosis, the deposition of hemosiderin due to chronic subarachnoid hemorrhage, has been an area of study in the pathogenesis of neurodegenerative processes.

Observations

The first case demonstrated the progression of neurological symptoms including sensorineural hearing loss, which progressed bilaterally and required a double cochlear implant, gait and balance issues, as well as incontinence. The siderosis in the first case was shown on MRI to involve the spinal cord, brainstem, cerebellum, and cerebral hemispheres, which were responsible for progressive neurodegeneration. The etiology pointed toward an occult leakage of blood into the CSF, and this was confirmed with CSF results on two occasions before definitive surgical treatment.

After resection of the vascular malformation through the T2–6 laminectomy, the patient did improve in terms of gait and steadiness. Postoperative lumbar punctures on two occasions demonstrated no further RBCs in the CSF. Although the surgery treated the source of bleeding to halt future deposition of hemosiderin, the patient continued iron chelation therapy in an attempt to reverse the hemosiderin deposition.¹⁰ The patient’s course emphasized the role of an aggressive treatment approach to the localization of bleeding in the treatment of SS due to the irreversible course and the progression of symptoms.^11,12 Additionally, while deferiprone, an iron chelator, may reduce the iron burden in hemosiderin deposits, it does not prevent chronic hemorrhage. Thus, surgical treatment of a potential bleeding source will address the underlying cause of the siderosis and normalize the CSF profile.^12,13

The second case was not a typical presentation of diffuse SS, as was seen in the first case. The second case presentation was occipital lobar SS, which is atypical and was an ominous finding. The patient was diagnosed with AD because of the CSF biomarkers such as Aβ42, Aβ40, and tau protein found through lumbar puncture.^14,15 Other signs consistent with AD include MRI indicating cerebral atrophy, which was seen in case 2, especially in the left hemisphere.

Additionally, lobar SS demonstrates a strong correlation between amyloid angiopathy and AD, according to the literature.^7,14,16 This would be the most likely reason for the superficial siderosis in the left occipital lobe and would represent a relatively ominous finding in this patient. The pattern of siderosis in her case does not fit the distribution typically seen in patients with occult leakage of blood into the CSF, in which the spinal cord and cerebellum are usually diffusely coated with siderosis in a relatively symmetrical fashion.

Lessons

Both patients demonstrated superficial siderosis of the central nervous system, but they had different treatment courses and symptoms. The patient in case 1 had a vascular malformation leaking blood into the CSF, which was resected via a T2–6 laminectomy, whereas the patient in case 2 had neurodegeneration indicative of cerebral amyloid angiopathy and was diagnosed with AD. Although both cases were indicative of iron deposition in the brain, the etiologies and clinical presentations were different enough that the diagnoses should be considered separate from one another. To date, SS has been the diagnostic term prompted by findings on MRI, but the pathological entities in both case presentations are different. Therefore, the diagnosis for case 1 should be termed diffuse SS, whereas the diagnosis for case 2 should be termed lobar cortical siderosis. Diffuse SS is associated with occult leakage of blood into the CSF, whereas lobar cortical siderosis is associated with cortical hemorrhage due to amyloid angiopathy, often associated with AD.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Broaddus, Patel, Opalak. Acquisition of data: Krishnakumar, Ghadiyaram, Patel, Dixit Analysis and interpretation of data: all authors. Drafting the article: Krishnakumar, Ghadiyaram, Patel. Critically revising the article: all authors. Reviewed submitted version of manuscript: Broaddus, Krishnakumar, Ghadiyaram, Patel. Approved the final version of the manuscript on behalf of all authors: Broaddus. Administrative/technical/material support: Opalak. Study supervision: Opalak.