CSF t au prot ei n i s a usef ul  marker f oref f ect i ve t reat ment  of  superf i ci al  si derosi sof  t he cent ral  nervous syst em:  Two casereport s
著者I keda Tokuhei ,  Not o Dai suke,  Noguchi - Shi noharaMoeko,  Ono Kenj i ro,  Takahashi  Kazuya,  I shi daChi ho,  Yoshi t a Mi t suhi ro,  Kawaguchi  Masahi t o,Kawahara Nori o,  I wasa Kazuo,  Tomi t a Kat suro,Yamada Masahi t o
j ournal  orpubl i cat i on t i t l e
Cl i ni cal  Neurol ogy and Neurosurgery
vol ume112
number1
page range62- 64
year2010- 01- 01
URLht t p: //hdl . handl e. net /2297/19435
doi: 10.1016/j.clineuro.2009.08.020
Case report:  
CSF tau protein is a useful marker for effective treatment of superficial 
siderosis of the central nervous system: two case reports 
Word count: 1,264 words 
Key words: cerebrospinal fluid, superficial siderosis, tau protein, ferritin, iron, marker, 
phosphorylated tau protein,  
Tokuhei Ikeda 1, Daisuke Noto 1, Moeko Noguchi-Shinohara 2,3, Kenjiro Ono1, Kazuya 
Takahashi1,2, Chiho Ishida 1,2, Mitsuhiro Yoshita 1, Masahito Kawaguchi 4, Norio Kawahara 4, 
Kazuo Iwasa 1, Katsurou Tomita 4, Masahito Yamada 1
Authors’ affiliations:  
1Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of 
Medical Science, Kanazawa, Japan  
2Department of Neurology, Iou Hospital, Kanazawa, Japan  
3Department of Neurology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan  
4Department of Orthopaedic Surgery, Kanazawa University Graduate School of Medical 
Science, 13-1, Takara-machi, Kanazawa 920-8640, Japan 
Correspondence to: Tokuhei Ikeda 
13-1 Takara-machi, Kanazawa 920-8640, JAPAN  Tel: +81-76-265-2292  
Fax: +81-76-234-4253  E-mail: tokuhei@med.kanazawa-u.ac.jp 
 CSF tau protein in superficial siderosis 
ABSTRACT 
We report two cases of superficial siderosis (SS) of the central nervous system (CNS), 
which is caused by chronic haemorrhaging into the subarachnoid space with haemosiderin 
deposition in the superficial portion of the CNS. Patient 1 had fluid collection in the spinal canal, 
which was reported as the source of the chronic bleeding. Patient 2 was bleeding from thickened 
dura at the level of the sacral vertebrae. Both of the patients had xanthochromic cerebrospinal 
fluid. We surgically repaired the sources of bleeding. Subsequently the cerebrospinal fluid (CSF) 
cleared and their symptoms were not aggravated for about one year. We measured several CSF 
markers of SS before and after surgery. Total tau protein (CSF-t-tau), phosphorylated tau protein 
(CSF-p-tau), iron (CSF-iron) and ferritin (CSF-ferritin) in the CSF were highly elevated at 
diagnosis. After surgery, the levels of CSF-t-tau and CSF-p-tau were markedly reduced while 
CSF-iron and CSF-ferritin had not decreased. It is suggested that CSF-t-tau and CSF-p-tau 
reflected the neural damage in SS and were useful to evaluate the effectiveness of SS therapies. 
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 CSF tau protein in superficial siderosis 
1. Introduction 
Superficial siderosis (SS) of the central nervous system (CNS) is a rare disease that 
produces haemosiderin deposition in the subpial layers of the brain and spinal cord due to 
chronic and repeated haemorrhaging into the subarachnoid space, leading to progressive and 
irreversible cerebellar ataxia, auditory disturbance and dementia [1–8]. The causes of SS include 
a prior intradural surgery, carcinoma, arteriovenous malformation, amyloid angiopathy and fluid 
collection in the spinal canal [1–3,8].  
MR T2-weighted images are characterised by hypointensity around the surfaces of the 
brainstem, cerebellum, cortical fissures and spinal cord, which allows the diagnosis of SS without 
the need for either biopsy or autopsy. Although MRI is useful for detecting haemosiderin 
deposition in SS, it cannot show disease activity. Several lumbar punctures are necessary to 
identify the bleeding in SS because some patients have intermitted bleeding sources, and 25% 
of SS patients do not show haemorrhagic and/or xanthochromic cerebrospinal fluid (CSF) [1]. 
The only effective treatment for SS is the repair of the bleeding site by surgery [1,4,5]. The 
slowly progressive course of SS makes it difficult to confirm the effect of treatment and requires a 
long follow-up period and several lumbar punctures to ensure that the surgery has successfully 
prevented progression of the disease. We encountered two patients with SS, whose bleeding 
points were repaired and who underwent CSF analysis before and after surgery. In SS, iron is 
released from red blood cells (RBCs) to the subarachnoid space and stored as ferritin, and 
CSF-t-tau and CSF-p-tau are elevated [6]. Therefore, CSF levels of CSF-t-tau, CSF-p-tau, iron 
(CSF-iron) and ferritin (CSF-ferritin) could be CSF markers for SS to evaluate the effects of 
surgery. We found CSF-t-tau and CSF-p-tau were reduced after the surgery despite high levels 
of CSF-iron and CSF-ferritin. Here, we report the clinical courses of two patients with SS and the 
utility of CSF-t-tau, CSF-p-tau, CSF-iron and CSF-ferritin as CSF markers for SS.  
2. Case reports  
Patient 1 
A 71-year-old woman was admitted to our hospital with a 7-year history of progressive gait 
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 CSF tau protein in superficial siderosis 
difficulties and auditory disturbance. A neurological examination revealed right dominant 
deafness and mild truncal ataxia. Muscle tonus, motor strength, sensory examination, tendon 
reflexes and cognitive function were normal. She could walk without a cane despite her ataxic 
gait. T2-weighted MRI revealed hypointensity in the superficial areas of the CNS, suggestive of 
haemosiderin deposition involving the brain and spinal cord (Fig. 1 A). The initial lumbar 
puncture revealed a watery clear CSF and slightly elevated levels of CSF protein (47 mg/dl). We 
determined the levels of the four CSF markers, all of which were elevated (Table 1). The next 
month, she underwent CSF analysis once more, which showed xanthochromia.  
Spinal MRI demonstrated an unusual fluid collection in the ventral portion of the vertebral 
canal ranging from C7 to T12 (Fig. 1 B and C). At surgery, a dural defect involving the arachnoid 
membrane at the level of T2–3 was detected (Fig. 1 D) and repaired. 
One year after the surgery, the clinical manifestations were not aggravated. The CSF had 
become clear, and levels of CSF-t-tau and CSF-p-tau had rapidly decreased, whereas the 
concentrations of CSF-ferritin and CSF-iron remained high (Table 1).  
Patient 2 
A 67-year-old woman presented with an 8-year history of progressive gait disturbance, 
dysarthria and hearing loss. She had been diagnosed with spinocerebellar degeneration and 
medicated with protirelin tartrate since the age of 61. On admission, a neurological examination 
revealed mild dementia, deafness, dysarthria, severe ataxia and hyperactive tendon reflexes in 
all extremities. She could not walk by herself. She showed no meningeal signs, sensory 
impairment or orthostatic hypotension. T2-weighted MRI images of the brain demonstrated 
hypointensity around the surface of the brainstem, cerebellum and perisylvian areas and at the 
base of the cerebrum (Fig. 2 A and B). A CSF analysis revealed xanthochromia with an increase 
in RBC count (595/μl) and elevated levels of protein (79 mg/dl), CSF-t-tau, CSF-p-tau, CSF-iron 
and CSF-ferritin (Table 1). 
A spinal MRI demonstrated marked thickening of the meninges with mild gadolinium 
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 CSF tau protein in superficial siderosis 
enhancement at the level of the sacral vertebrae (Fig. 2 C). At surgery, the sacral arachnoid 
membrane presented with tremendous thickening and bleeding (Fig. 2 D); therefore, we resected 
it with the surrounding dura. The pathological examination revealed no neoplasm and that the 
thickening of the dura was just a reaction to the bleeding.  
Eight months after the surgery, a CSF analysis showed reduced levels of CSF-t-tau and 
CSF-p-tau without significant changes in CSF-iron or CSF-ferritin and no xanthochromia (Table 
1). There was no aggravation in the clinical manifestations after surgery.  
3. Discussion 
We report two patients with SS who underwent surgery for the repair of the bleeding site. 
Patient 1 had fluid collection in the spinal canal, which was related to chronic bleeding [2]. In 
Patient 2, we detected the bleeding point in the thickened dura at the level of the sacral vertebrae 
and resected it with the surrounding dura. Chronic and repeated bleeding stopped in both 
patients because there were no xanthochromia or RBCs in the CSF of several lumbar punctures 
after surgery. We measured CSF-t-tau, CSF-p-tau, CSF-iron and CSF-ferritin as CSF markers of 
SS. Sandwich enzyme linked immunosorbent assays were used to determine CSF levels of total 
tau protein (CSF-t-tau; Innotest hTAU-Ag; Innogenetics, Gent Belgium) and phosphorylated tau 
protein (CSF-ptau; Innotest Phospho-tau (181p); Innogenetics) [9,10]. CSF- iron was measured 
using a colorimetric method, and CSF-ferritin was measured using a chemiluminescent 
immunoassay. Their levels were significantly elevated before surgery, and surgical treatment 
resulted in a significant reduction of CSF-t-tau and CSF-p-tau despite the high levels of CSF-iron 
and CSF-ferritin. 
Kondziella et al.[6] reported a 37-year old man with SS, who had gait ataxia, mild sensory 
hearing loss, spastic paresis of the right arm and both legs, mild dysarthria and urge 
incontinence. T2-weighted MRI showed hypodense layers around the brain and spinal cord, and 
a lumbar puncture confirmed chronic subarachnoidal bleeding. In this patient, CSF-t-tau and 
CSF-p-tau were elevated (CSF-t-tau: 1070 pg/ml; CSF-p-tau: 127 pg/ml) as observed in our 
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 CSF tau protein in superficial siderosis 
patients. To our knowledge, this is the only report of an elevation in the CSF level of a tau protein 
in an SS patient, and none has reported a change in the CSF level of the tau protein after 
surgical treatment.  
Tau protein is a microtubule-associated protein primarily localised in neuronal cells [11]. 
Elevated CSF-t-tau levels have been reported in a variety of neurodegenerative diseases, such 
as Alzheimer’s disease, corticobasal degeneration, dementia with Lewy bodies and 
Creutzfeldt-Jakob disease as well as in the acute phases of stroke and encephalitis [9–13]. 
These reports indicate that increased CSF tau protein is associated with neuronal damage, 
during which intracellular tau protein is released into the extracellular space and CSF. Iron 
toxicity and oxidative stress in SS lead to the progressive death of neurons and provoke the high 
levels of CSF-t-tau and CSF-p-tau [6]. The finding that two proteins had decreased following 
surgery in Patients 1 and 2 indicated that the surgical treatments successfully prevented further 
neural damage. 
In our patients, the levels of CSF-t-tau and CSF-p-tau were significantly lower after surgery, 
whereas the CSF-iron and CSF-ferritin levels showed little or no reduction. This discrepancy 
suggests that although haemostasis of the new bleeding point corrected iron exposure against 
the neural tissue, iron and ferritin were continuously released into the CSF from the 
haemosiderin deposited surface. Another possibility is that other blood components were 
causative agents of the neuronal damage as well as iron.  
In conclusion, SS is associated with elevated CSF-t-tau, CSF-p-tau, CSF-iron and 
CSF-ferritin levels. Measuring CSF-t-tau and CSF-p-tau was useful for evaluating the 
effectiveness of SS treatment. 
Acknowledgement 
The authors thank Ms. Yukari Yamaguchi for technical assistance.[14]  
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 CSF tau protein in superficial siderosis 
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 CSF tau protein in superficial siderosis 
FIGURE LEGENDS 
Figure 1. (A) Axial T2-weighted brain MRI in Patient 1. Signal hypointensity is observed on the 
surface of the cerebellum (arrows) and pons (arrowheads). (B and C) Sagittal and axial 
T2-weighted spine MRI in Patient 1. Surface of the spinal cord shows hypointensity, and there is 
fluid collection along the dorsal surface of the vertebrae (arrows). (D) Operative findings in 
Patient 1 (bar = 1 cm). A C2-T5 laminectomy was performed. There was a dural defect (arrow) 
involving the arachnoid membrane (arrowheads) at the level of T2–3.  
Figure 2. (A and B) Axial T2-weighted brain MRI in Patient 2. Signal hypointensity is observed 
on the surface of the medulla oblongata, cerebellar hemisphere and bilateral perisylvian fissures 
(arrows). (C) Sagittal T1-weighted MRI of the spine with gadolinium enhancement (inset) in 
Patient 2. Thickening of the meninges with slight enhancement is seen at the level of the sacral 
vertebrae (arrow). (D) Operative findings in Patient 2 (bar = 1 cm). On L4-S3 laminectomy, a 
bleeding point (arrow) with thickened dura (arrowheads) was detected. 
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