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

Abstract

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.

Introduction

Superficial siderosis of the central nervous system (SSCNS) is a rare type of neurological damage caused by excessive iron deposition on the brainstem, cerebellum, spinal cord, and even part of the cranial nerve surface caused by chronic recurrent bleeding into the cerebrospinal fluid. ¹ The typical clinical triad of SSCNS consists of progressive and irreversible sensorineural deafness, cerebellar ataxia, and pyramidal dysfunction, but very few patients exhibit all three symptoms at the same time, which makes timely diagnosis difficult. ² At present, there are many deficiencies in the diagnosis and treatment of the disease, such as late recognition, lack of long-term follow-up data, insufficient attention to the etiological diagnosis, a high missed diagnosis rate, and differences in treatment levels among different regions. ³ Susceptibility-weighted imaging (SWI) is critical for the diagnosis of SSCNS. ⁴ We report a case of SSCNS with an initial symptom of cerebellar ataxia, followed by urinary retention and dysarthria, and review and discuss the etiology, pathogenesis, clinical manifestations, imaging diagnoses, and key points of early identification. This case suggests that the possibility of SSCNS should be considered in patients with progressive cerebellar ataxia, hearing loss, or myelopathy, and the diagnosis should be further confirmed by magnetic resonance imaging (MRI).

Case report

The reporting of this study is in accordance with the CARE guidelines. ⁵ The patient’s personal information has been removed. The patient and their family were informed that the data and images would be submitted for publication, and they signed an informed consent form for publication of this report. This case was approved for publication by the review board of the First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi Province, China (Approval No. GYYFY2022-08-05).

A man in his late 40s with a middle school education level was admitted to the hospital with progressive walking difficulty for 11 years, aggravated by dysphagia for 3 years, on 2 November 2021. The patient exhibited a slightly wide walking gait and impaired mobility and had an 11-year history of dizziness. Tinnitus, hearing loss, hoarseness, dysphagia, and bucking had gradually appeared 3 years prior. The patient sought treatment at our hospital because his unsteady walking gait was gradually aggravated. He had no history of trauma or surgery and denied any family and psycho-social history of relevant conditions.

A physical examination of the nervous system revealed a Mini-Mental State Examination score of 23; vague language; a hoarse voice; a grade of 4 on the Wattan water-drinking test; bilateral hearing loss (Rinne test, +); Weber test results indicating that sound was detected at the midline of the skull without bias; a slightly weakened bilateral pharyngeal reflex; active tendon reflexes of the four limbs (+++); inaccurate bilateral alternating movement test, heel-knee-tibia test, and finger-nose test results; a positive Romberg's sign; difficulty walking in a straight line; and positive bilateral Babinski signs.

Pure tone audiometry indicated severe sensorineural loss on the left side and very severe sensorineural loss on the right side. The acoustic conductance test showed an “A” tympanogram for both ears, and ipsilateral acoustic radiation was not induced, suggesting cochlear acoustic neuropathy. MRI of the head, cervical vertebrae, and thoracic vertebrae showed linear hypointense signals in T2-weighted images of the bilateral surfaces of the temporal lobe, left frontal lobe, bilateral thalamus, anterior pons, medulla oblongata, splenium of the corpus callosum, and cervical spinal cord (see Figure 1 a–f). SWI more clearly showed linear hypointense signals on the surface of the cerebral hemispheres, sulcus gyrus, lateral ventricles, and cerebellum (see Figure 2 a–d). Testing of cerebrospinal fluid from a lumbar puncture showed that routine and biochemical indices were normal, and digital subtraction angiography (DSA) of the cerebrum showed no anomalies.

Figure 1.

Magnetic resonance imaging of the head, cervical vertebrae, and thoracic vertebrae showed linear hypointense signals on the bilateral surface of the temporal lobe, left frontal lobe, bilateral thalamus, anterior pons, medulla oblongata, splenium of the corpus callosum, and cervical spinal cord in T2-weighted images. (a) pons, (b) sulcus gyrus and cerebellum, (c) medulla oblongata, (d) thalamus and (e, f ) cervical spinal cord.

Figure 2.

Susceptibility-weighted magnetic resonance imaging showed linear hypointense signals on the surface of the cerebral hemispheres, anterior pons (a), sulcus gyrus and cerebellum (b), medulla oblongata (c), and thalamus (d).

When the patient was admitted to the hospital because of the clinical manifestation of walking instability, a physical examination indicated cerebellar ataxia. Diagnoses of genetic ataxia, multiple systems atrophy, and other diseases were considered. According to the patient’s history of slow progressive cerebellar ataxia, sensorineural hearing loss, and corticospinal tract symptoms, the finding of hemositin deposits mainly distributed on the brainstem on MRI, and the lack of a clear source of bleeding, the final diagnosis was classical SSCNS. The patient and his family provided consent for treatment with deferiprone, mecobalamin, and vitamin B1. One year later, the patient’s dysphagia and ataxia were not significantly aggravated, and his daily living ability was near normal.

We also reviewed the literature by searching the PubMed database for studies published from database establishment to 31 January 2023 using the following search terms: Superficial siderosis AND subject: central–nervous–system.

Discussion

SSCNS is a rare neurological degenerative disease characterized by deposition of hemosiderin on the brain, spinal cord, and cerebral nerve surface. ¹ The etiology of SSCNS is unknown. At present, it is generally believed that chronic and recurrent subarachnoid hemorrhage of various causes is the main cause of SSCNS. ⁶ SSCNS can be divided into classical and secondary types according to the causes, pathogenesis, and clinical manifestations. Classical SSCNS was first described by Hamill et al. in 1908, mainly affects the subtentorial region (cerebellum, brainstem, cranial nerves, and spinal cord), and is caused by meningeal bleeding or metabolism. Secondary SSCNS is caused by recurrent or persistent subarachnoid hemorrhage. ⁷ SSCNS was classified as cortical superficial siderosis or infratentorial superficial siderosis (iSS) by Wilson et al. ⁸ according to the location of hemosiderin deposition. In cortical superficial siderosis, hemosiderin is mainly deposited on the cerebral cortex surface, while in iSS it is mainly deposited in the brainstem, cerebellum, and spinal cord, which can be accompanied by supratentorial diffusion. The iSS type is subdivided into iSS-1 (no evidence of cerebral hemorrhage in the medical history and imaging results) and iSS-2 (clear spontaneous intracranial hemorrhage or traumatic intracranial hemorrhage on imaging) according to whether cerebral hemorrhage is present. ⁹

The pathogenesis of SSCNS is still unclear, but it is believed to mainly include the following steps: (1) chronic or intermittent subarachnoid hemorrhage and diffusion through the cerebrospinal fluid occur; (2) erythrocytolysis; (3) heme is deposited on the surfaces of the brain, spinal cord, and cranial nerves in contact with the cerebrospinal fluid; (4) glial and microglial cells synthesize heme oxygenase-1 and ferritin, and heme oxygenase-1 breaks down heme into free iron and biliverdin, while ferritin binds to free iron to form hemosiderin; (5) excessive hemosiderin mediates cell apoptosis, oxidative stress, and free radicals, resulting in neurodegenerative injury. ¹⁰

The clinical manifestations of SSCNS are varied, and the symptoms are related to the location, distribution, severity, duration of disease, and individual differences in iron deposits in patients. Progressive and irreversible sensorineural deafness (95%), progressive cerebellar ataxia (88%), and pyramidal dysfunction (76%) comprise the clinical triad of SSCNS, but they occur concomitantly in less than 50% of patients. ² Chan et al. found that cognitive impairment occurred in 50% of patients, and the degree of cognitive dysfunction was significantly correlated with the course of the disease. ¹¹ Other rare symptoms include urinary incontinence or retention (24%), olfactory dysfunction (17%), ¹² paresthesia (13%), sexual dysfunction (<10%), ¹³ and vestibular dysfunction (<10%). ¹⁴ Hearing loss is the most common and earliest symptom of SSCNS and is characterized by prodromal tinnitus, sensorineural hearing loss, and deafness within 15 years. The hearing loss of patients often exceeds the degree of aging, but otolaryngologists are often limited in their diagnosis and only treat the hearing loss. Thus, an imaging examination of the nervous system is not performed, and the cause of such deafness is missed. Although in this case, cerebellar ataxia with progressive walking difficulties was the first symptom, and hearing loss occurred in subsequent years, age-inappropriate hearing loss should be considered by otolaryngologists and neurologists.

Before the introduction of MRI, the diagnosis of SSCNS mainly depended on the pathological, lumbar puncture, and intraoperative findings. The development of imaging has improved the detection rate of SSCNS, and MRI has become an important means of diagnosis. The T2-weighted gradient recalled echo and SWI MRI sequences are very sensitive to hemosiderin deposition, which shows linear “pencil”-like low signals around the brainstem, cerebellum, spinal cord, and cranial nerves. Magnetic resonance angiography, computed tomography angiography, and DSA are helpful in screening for the causes of bleeding, such as vascular malformations. ¹⁵ DSA is still the gold standard for screening for cerebrovascular disease, and its accuracy is superior to that of magnetic resonance angiography and computed tomography angiography. Although not all SSCNS is caused by cerebrovascular diseases, it is highly recommended that all SSCNS patients undergo a DSA examination when the cause cannot be identified by non-invasive examinations because vascular diseases such as vascular malformation may be radically treated by surgery to remove the cause and prevent progressive exacerbation of the disease.

According to the MRI results of this patient, the hemositin deposits were mainly distributed on the brainstem, cerebellar surface, and spinal cord, which is consistent with the clinical signs of cerebellar damage (vague language and gait instability), brainstem damage (hearing loss and hoarse voice), and spinal cord damage (pyramidal tract sign). The patient had no history of trauma or surgery, and no arteriovenous malformations or aneurysms were found in the DSA examination. Brain MRI examination did not show an intracranial tumor or cerebral amyloid vascular disease. No fresh or wrinkled red blood cells were detected in the cerebrospinal fluid samples. Therefore, we suggest that the patient may have classical SSCNS and meet the subententorial imaging characteristics according to the classification criteria of Wilson et al. ⁸ Although previous epidemiological investigations have shown a variety of initial symptoms of SSCNS, the pathological mechanisms are mostly related to bleeding, extravasation, or leakage in the central nervous system. The reasons for many SSCNS cases with unknown causes may include insufficient clinical understanding of the disease; a lack of unified diagnostic criteria; excessive reliance on computed tomography (rather than MRI, which is more sensitive to iron deposits, especially SWI) for follow-up after intracerebral hemorrhage; lack of medical procedures in some patients with asymptomatic recurrent and minor cerebral hemorrhage; the long course (4 months to 30 years) ¹⁶ and mild early symptoms of SSCNS; low initial MRI examination and follow-up rates; and differences in the absorption of hemosiderin in brain tissue among individuals. According to the literature and the diagnosis and treatment process of this case, SSCNS should be highly suspected when the following conditions are present in clinical practice: (1) a previous history of traceable bleeding, trauma, tumor, or inflammation in the central nervous system; (2) recurrent headache of unknown cause, especially headache with sudden onset and throbbing, accompanied by bilateral non-acute sensorial deafness and cerebellar ataxia, or symptoms suggestive of progressive damage to the central nervous system and cranial nerves in the posterior fossa and spinal cord; (3) unexplained impairment of cognitive function, especially rapidly progressive dementia; (4) long-term use of antiplatelet drugs and/or anticoagulants for various reasons, during which time symptoms localized to the central nervous system occur. For highly suspected cases without a clear history of cerebral hemorrhage, etiological tests including cerebrospinal fluid examination, cerebrovascular angiography, genetic screening of cerebrovascular diseases, and even skin biopsy pathology should be performed. Once diagnosed, treatment should be timely to provide accurate and effective intervention.

Treatment of SSCNS mainly consists of surgical and drug therapy. The surgical procedure is performed to remove potential bleeding sources of subarachnoid hemorrhages and is applicable to dural defects, vascular malformations, and tumors. However, surgical treatment is usually considered ineffective because of the irreversible damage to the nervous system caused by hemosiderin. Drug treatment mainly consists of iron chelating agents to reverse iron deposition, and the most commonly used drug is deferiprone. Kessler et al. conducted a 2-year prospective study on 38 patients with SSCNS treated with deferiprone. The results showed that deferiprone reduced the degree of iron deposition in more than 50% of patients and stabilized or improved the course of the disease in at least one neurological area, most commonly hearing and balance disorders. ¹⁷ In a clinical trial by Cossu, four SSCNS patients received long-term treatment with deferiprone (average 3.7 years), and follow-up MRI showed a reduction of abnormal iron deposition in all patients. ¹⁸ In the present case, the patient’s symptoms also improved with deferiprone treatment.

Conclusions

This case suggests that the possibility of SSCNS should be considered in patients with progressive cerebellar ataxia, hearing loss, or myelopathy, and the diagnosis should be further confirmed by MRI. For confirmed patients, it is necessary to actively search for the cause of the disease. The disease can be treated with iron chelating agents and symptomatic drugs.