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Superficial Siderosis
Superficial siderosis of the central nervous system is
characterized by an insidiously progressive cerebellar
ataxia and sensorineural deafness. Later in the illness,
a spastic myelopathy and dementia develop in some
patients. The condition has been recognized chiefly at
autopsy by the rust-colored appearance of the involved
structures. Computed tomography and magnetic resonance imaging (MR) have shown that the diagnosis is
far more frequent than previously suspected [l]. MR
has greater sensitivity because the strong paramagnetic
effect of iron-containing compounds allows visualization in T2-weighted images of striking hypointensities
overlying the vermis and adjacent cerebellum, the
brainstem, basal cisterns, spinal cord, and in some cases
the surfaces of the cerebral cortex, particularly the intrahemispheric and sylvian sulci. Hypointensities are
also observed along the 8th cranial nerves and the optic
chiasm with relative sparing of the other cranial nerves,
the spinal roots, and the cauda equina. There is atrophy
of the adjacent neural tissue, often most pronounced in
the folia of the superior vermis with striking microglial
proliferation in the involved subpial parenchyma. Ferritin accumulates both in microglia and in the radially
oriented Bergmann glia of the cerebellum.
Superficial siderosis occurs as a consequence of the
chronic or recurrent oozing of blood into the subarachnoid space. It has been reported as a consequence of
hemispherectomy, aneurysms, vascular malformations,
and spinal tumors, notably ependymomas of the conus
medullaris. In some reports, a source of bleeding has
not been identified at autopsy. Moreover, a welldefined history of recurrent subarachnoid hemorrhage
is not always obtained. In such cases, insidiously progressive superficial siderosis may develop in patients
without any history whatsoever of headache or back
or neck pain that heralds a typical subarachnoid hemorrhage. Thus, the chronic or episodic introduction of
small amounts of blood into the cerebrospinal fluid
(CSF) can occur without symptoms of a meningeal response. A history of 5 to 10 years of a slowly progressive cerebellar ataxia affecting the trunk more than the
limbs, with nerve deafness, suggests the diagnosis of
a heredodegenerative disorder until MR reveals the
findings typical of superficial siderosis.
In a series of papers, Koeppen and colleagues 12-51
have delineated the clinical, pathological, and biochemical features of the disorder. The special vulnerability
of the eighth cranial nerve has been attributed to the
presence of central nervous system (CNS) myelin surrounding the axons within the subarachnoid space extending to the internal auditory meatus. CNS myelin
appears to favor the deposition of hemosiderin, unlike
the peripheral nervous system myelin that covers the
other cranial nerves as they exit from the brainstem.
The mechanism whereby Schwann cells have such a
protective effect is not clear. Koeppen and Dentinger
121 suggested that the special vulnerability of the Bergmann glia of the cerebellum and of the glial sheath of
the eighth nerve may be explained by their ability to
synthesize ferritin, a precursor of hemosiderin, more
readily than other neural cells. The affected glia are
accessible to the presence of increased amounts of hemoglobin, heme, and its products in the adjacent CSF.
These cells appear to sequester iron and to limit its
toxic effects on the neuropil. The glia and microglia
appear damaged as ferritin is accumulated. Ferric ions
are toxic in part because they are potent generators of
oxygen-derived free radicals. Superficial siderosis is a
dramatic example of the selective regional and cellular
vulnerability in the nervous system. Better understanding of the cellular and molecular basis of the cerebellar
injury in siderosis promises to help explain other forms
of cerebellar degeneration.
In this issue of the Annuls, Koeppen and colleagues
[ S } have explored further the mechanisms of cellular
injury in the rabbit cerebellum and cerebral cortex following the intracisternal injection of autologous blood
at weekly intervals. The conversion of hemoglobin in
the CSF to heme, iron, ferritin, and the hemosiderins
takes place in the microglia. Bergmann glia are a source
of ferritin-repressor protein that facilitates the conversion of heme to ferritin and ultimately hemosiderin.
These observations indicate that the injury of the involved neural elements is an intracellular process. Preliminary studies using an iron-chelating agent have
been ineffective. The authors conclude that chelation
therapy is unlikely to remove hemosiderin selectively
without attacking normal brain iron.
Thus, the treatment of superficial siderosis depends
upon finding and treating the bleeding source, obvious
enough in patients with aneurysms, vascular malformations, and tumors. It is frustrating to diagnose superficial siderosis and then to be unable to establish the
origin of the blood. It is of special interest that Bracchi
and colleagues [ 11 have recently reported 2 patients
with siderosis in whom traumatic cervical root avulsions preceded the onset of hearing loss by many years.
I too have seen 2 patients with idiopathic siderosis that
developed long after dural injury. One patient had
multiple cervical root avulsions 8 years prior to the
onset of deafness and ataxia, and another patient had
a pseudomeningocele that developed following lumbar
laminectomy 15 years prior to the onset of ataxia. In
the latter patient, the CSF aspirated from the cavity of
the meningocele was slightly xanthochromic despite a
normal protein content. This observation suggests that
such spinal meningeal defects may be the source of
the cryptic, asymptomatic, and intermittent bleeding
Copyright 0 1993 by the American Neurological Association
responsible for superficial siderosis. Closing such dural
defects may prove effective in arresting the progressive
neurological injury that characterizes superficial siderosis.
Robert A. Fishman, MD
Department of Nearology
University of California, San Francisco
1. Bracchi M, Savoiardo hi, Triulzi F, et al. Superficial siderosis of
the CNS: MR diagnosis and clinical findings. AJNR 1993;14:
2. Koeppen AH, Denringer MP. Brain hemosiderin and superficial
siderosis of the central nervous system. J Neuropathol Exp Neurol 1988;47:249-270
3. Koeppen AH, Borke RC. Experimental superficial siderosis of
the central nervous system I. Morphological observations. J Neuroparhol Exp Neurol 1991;50:579-534
4. Koeppen AH, Hurwitt CG, Dearborn RE, et al. Experimental
superficial siderosis of the central nervous system: biochemical
correlates. J Neurol Sci 1992;112:38-45
5 . Koeppen AH, Dickson AC, Chu RC, Thach RE. The pathogenesis of superficial siderosis of the central nervous system. Ann
Neurol 1993;34:646-653
Experimental Allergic
as a Guide to the
Understanding and
Treatment of Multiple
Since the initial description by Rivers and colleagues
in the 1930s that monkeys injected with normal central
nervous system (CNS) tissue develop organ-specific
inflammation of the CNS (reviewed in [lf),the disease induced-experimental allergic encephalomyelitis
(EAE)-has had a profound influence on the direction
and design of basic and clinical research aimed at
understanding and treating multiple sclerosis (MS).
Clearly, EAE is an autoimmune disease, initiated with
at least two CNS myelin antigens, myelin basic protein
and proteolipid protein. These work through an immunogenetically restricted recognition system involving
the major histocompatibility complex and the T cell
receptor. Thereafter a cascade of events ensues
prompted by specific CD4 positive lymphocytes that
attach to endothelial cells and infiltrate the CNS. The
recruitment of a variety of lymphoid cells and the activation of resident astrocytes and rnicroglia convert an
initial, specific immune event into a broad-based process with synthesis and release of chemical mediators,
including cytokines and antibodies that produce or increase inflammation and demyelination.
The pathogenesis of MS is usually considered to depend on similar mechanisms. Since the recognition of
MS in a genetically outbred species, i.e., humans, always occurs after onset and amplification of the disease
process, the identification of the initial event and the
distinguishing of primary from secondary mechanisms
become almost insurmountable tasks. Thus, investigators have taken different positions regarding the processes that are most important to understand and modify, in order to improve, the treatment of MS. There
is certainly something awry with the immune system
in MS [2], but whether some or all of the steps established for EAE apply to MS remains to be determined.
The current status of our understanding of MS underscores the word maltiple in the naming of this disorder.
From studies of CNS histopathology, serial cranial
magnetic resonance imaging [ 3 ] , immunogenetics [4],
and immune profiles [23 in MS, it is likely that multiple
processes occur independently in patients with a polygenic background modified by as yet undetermined environmental factors. A host of immune reactivities are
induced that are directed at different epitopes. Given
this complex situation, studies of EAE come as a relief
in the face of the unremitting or slowly yielding confusion surrounding MS.
Over the years, procedures for the production of
EAE have been modified in a number of ways. Now,
rather than being limited to an experimental model
that produces a single episode of acute EAE simulating
the human disease acute disseminated encephalomyelitis, there are models that can be induced with active
immunization or by passive transfer of sensitized cells
that result in chronic relapsing EAE in which the occurrence of CNS inflammation and demyelination are similar to that observed in MS [l]. It may be relevant
that some of the amplification and diversity of immune
reactivities noted in MS occur in chronic EAE. These
circumstances have earned for EAE a premier position
for studies of therapy that might be beneficial in MS.
Numerous immunosuppressive agents (reviewed in
[l}) and more sophisticated immunotherapeutic approaches [ 5 ] applied to EAE have been used subsequently in MS. Thus, cyclophosphamide, cyclosporine
A, copolymer 1, antibodies to specific lymphocyte subsets, and immunization with T cell receptor peptides
have been used in previous therapeutic trials or are
being tested currently [I, 5 , 61. These and other therapeutic efforts for EAE and MS do not necessarily have
the same outcome. For example, cyclosporine A and
cyclophosphamide have a beneficial effect on EAE but
636 Copyright 0 1993 by the American Neurological Association
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