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Autoimmune Neurological

Autoimmune Neurological

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In organ-specific autoimmune disease, immune destruction is focused on a
limited range of tissues or cells, and the autoimmune response must persist
to produce disease
In organ-specific autoimmune disease, immune destruction is focused on a
limited range of tissues or cells, and the autoimmune response must persist
to produce disease

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MICHAEL P. PENDER

Introduction

Paraneoplastic neurological disorders are diseases of the nervous system
that occur as a remote effect of malignant neoplasms and that are not due to
infiltration of the nervous system by neoplastic tissue. These disorders have
been described in association with a wide variety of neoplasms, with the
lung, ovary and breast being common sites of origin. There is increasing
evidence that paraneoplastic neurological disorders are due to an auto-
immune attack on specific regions of the nervous system triggered by the
aberrant expression of neuronal antigens by the neoplasm (Posner, 1992).
Many regions of the nervous system can be involved, either in isolation or in
combination, and this involvement determines the clinical features. The
following paraneoplastic neurological syndromes have been described:
subacute sensory neuronopathy (Denny-Brown, 1948), the Lambert-Eaton
myasthenic syndrome (Eaton & Lambert, 1957), subacute cerebellar de-
generation (Brain & Wilkinson, 1965), paraneoplastic motor neurone
disease (Brain, Croft & Wilkinson, 1965; Henson, Hoffman & Urich, 1965),
brainstem encephalitis (Henson etal., 1965), limbic encephalitis (Corsellis,
Goldberg & Norton, 1968), opsoclonus and myoclonus (Brandt etal., 1974),
the visual paraneoplastic syndrome (Grunwald et al., 1987), dysautonomia
(Veilleux, Bernier & Lamarche, 1990), the stiff-man syndrome (Ferrari et
al.
, 1990; Folli etal, 1993) and cochleovestibular dysfunction (Gulya, 1993).
At least some of these syndromes can occur on an autoimmune basis in the
absence of any detectable neoplasm. As the Lambert-Eaton myasthenic
syndrome and the stiff-man syndrome commonly occur in the absence of an
associated neoplasm, they are dealt with in separate specific chapters
(Chapters 10 and 6, respectively).

328

AUTOIMMUNE NEUROLOGICAL DISEASE

Clinical features

Because of the diversity of clinical syndromes, the clinical features of the
paraneoplastic neurological disorders will be discussed separately for each
syndrome.

Subacute sensory neuronopathy

This disorder is most commonly seen in association with small cell carcinoma
of the lung, but may also occur with a wide variety of other neoplasms,
including breast cancer (Horwich et aL, 1911 \ Chalk et aL, 1992). The
incidence of subacute sensory neuronopathy in small cell lung cancer is
about 1% (Elrington et aL, 1991). A similar disorder can develop in
association with primary Sjogren's syndrome (Malinow et aL, 1986; Griffin
et aL, 1990; see Chapter 13) or may occur in the absence of any detectable
associated disease (Kaufman, Hopkins & Hurwitz, 1981). Paraneoplastic
subacute sensory neuronopathy may become manifest before or after the
diagnosis of the associated neoplasm. Typically the syndrome comprises the
subacute onset of pain, paraesthesiae, dysaesthesiae and numbness in the
limbs commencing distally and spreading proximally and sometimes involv-
ing the trunk and face (Denny-Brown, 1948; Horwich etaL, 1911 \ Chalk et
aL,
1992). Physical examination reveals loss of light touch, pain and
temperature sensation, and severe impairment of joint position sense and
vibration sense. Sensory ataxia and areflexia are also characteristic features.
Strength is preserved. In one series, about half of the patients had associated
autonomic, cerebellar or cerebral abnormalities (Chalk et aL, 1992).
Electrophysiological studies are useful in confirming the selective sensory
involvement. Examination of the cerebrospinal fluid (CSF) usually reveals
an elevated protein level and sometimes a mononuclear pleocytosis (Hor-
wich etaL, 1977).

Subacute cerebellar degeneration

Subacute cerebellar degeneration is most commonly seen in association with
small cell carcinoma of the lung, gynaecological cancers (especially of the
ovary or breast) and Hodgkin's disease (Brain & Wilkinson, 1965; Ham-
mack et aL, 1992), but may also occur with other malignancies, including
carcinoma of the colon (Tsukamoto et aL, 1993). When it occurs in
Hodgkin's disease, it is more common in men and has a younger age of onset
than when associated with other malignancies (Hammack et aL, 1992).
Paraneoplastic subacute cerebellar degeneration may become clinically
evident either before or after detection of the malignancy. The typical

PARANEOPLASTIC NEUROLOGICAL DISORDERS

329

clinical pattern is the subacute evolution (over weeks to months) of truncal
and limb ataxia and dysarthria (Brain & Wilkinson, 1965; Hammack et al.,
1992). The ataxia can become so severe that the patient has difficulty sitting
up in bed. Nystagmus, particularly downbeat nystagmus, may occur, but is
often absent. Subacute cerebellar degeneration is often accompanied by
evidence of involvement of other regions of the nervous system (Brain &
Wilkinson, 1965). Examination of the CSF often reveals an elevated protein
level and a lymphocytic pleocytosis (Peterson et al., 1992). Computerized
tomography or magnetic resonance imaging may reveal cerebellar atrophy,
particularly in the later stages (Peterson etal., 1992). Although spontaneous
improvement may occur (Hammack et al., 1992), the disorder is usually
irreversible.

Paraneoplastic motor neurone disease

A lower motor neurone syndrome with or without upper motor neurone
involvement may occur in association with malignancy, particularly that of
the lung (Brain etal., 1965; Dhib Jalbut & Liwnicz, 1986). This paraneoplas-
tic disorder may also be accompanied by clinical evidence of involvement of
other regions of the nervous system (Henson et al., 1965), but when it occurs
in the absence of such involvement it resembles idiopathic motor neurone
disease. There is evidence that the latter may sometimes have an auto-
immune basis (see Chapter 10).

Brainstem encephalitis

Paraneoplastic brainstem encephalitis occurs particularly in association with
lung cancer and manifests itself in ophthalmoplegia, bulbar palsy, vertigo
and nystagmus (Henson et al., 1965). It may also be accompanied by clinical
involvement of other regions of the nervous system. Baloh etal. (1993) have
recently reported a novel brainstem syndrome occurring in patients with
prostatic carcinoma and consisting of a loss of voluntary horizontal saccadic
eye movements and severe persistent muscle spasms of the face, jaw and
pharynx together with mild unsteadiness of gait.

Limbic encephalitis

Limbic encephalitis occurs particularly in conjunction with small cell carci-
noma of the lung (Brierley et al., 1960; Corsellis et al., 1968; Bakheit,
Kennedy & Behan, 1990), but also with other tumours, such as thymoma
(McArdle & Millingen, 1988; Ingenito etal., 1990), carcinoma of the testis
(Burton et al., 1988) and carcinoma of the colon (Tsukamoto et al., 1993).
Characteristically, the disorder is manifested by the onset over several

330

AUTOIMMUNE NEUROLOGICAL DISEASE

months of a marked disturbance of affect, such as severe anxiety or
depression, and of a selective impairment of recent memory (Corsellis et al.,
1968;Bakheitefa/., 1990). Hallucinations and epilepsy may also occur. The
clinical picture may resemble that of schizophrenia (Frommer et al., 1993).
Clinical involvement of other regions of the nervous system may accompany
the picture of limbic encephalitis (Tsukamoto et al., 1993). Examination of
the CSF often reveals a mononuclear pleocytosis and an elevated protein
level, while electroencephalography may demonstrate paroxysmal activity
and/or slow waves over one or both temporal lobes (Corsellis et al., 1968).
On magnetic resonance imaging there may be abnormal high-signal inten-
sity in the medial temporal lobes on T2-weighted scans followed by the
development of temporal lobe atrophy on Trweighted scans (Dirr et al.,
1990; Kodama etal, 1991).

Opsoclonus and myoclonus

A syndrome of opsoclonus ('dancing eyes'), truncal and limb myoclonus,
and ataxia may occur in children with neuroblastoma (Brandt et al., 1974),
and in adults with cancer, particularly small cell carcinoma of the lung
(Anderson et al., 1988a). Opsoclonus is defined as the occurrence of
involuntary, arrhythmic, large-amplitude, multidirectional, conjugate
saccadic eye movements without an intersaccadic interval. The syndrome is
characterized by the acute onset of vertigo, nausea, vomiting, opsoclonus,
truncal and limb myoclonus, truncal and (to a lesser extent) limb ataxia, and
encephalopathy (Brandt et al., 191 A; Anderson et al., 1988a). The truncal
ataxia often becomes so severe that the patient is unable to stand or sit
without support. The encephalopathy is manifested by apathy, lethargy and
confusion, and may progress to stupor or coma. Unlike most other para-
neoplastic neurological syndromes, the course is often remitting and relaps-
ing (Anderson et al., 1988a). CSF examination may reveal a lymphocytic
pleocytosis, a mild elevation of the protein level, and the presence of
oligoclonal immunoglobulin (Ig) bands. Electro-oculography allows accu-
rate definition of the involuntary eye movements. Patients with this syn-
drome differ clinically from those with the more common paraneoplastic
cerebellar degeneration by the predominance of truncal over limb ataxia,
the presence of opsoclonus and myoclonus, the absence of severe dysarthria
and a tendency for remission (Anderson et al., 1988a). A similar
opsoclonus-myoclonus syndrome can occur in children without detectable
neuroblastoma (Kinsbourne, 1962) and can occur in adults without malig-
nancy as an acute self-limited disorder following a respiratory or gastro-
intestinal infection (Baringer, Sweeney & Winkler, 1968).

PARANEOPLASTIC NEUROLOGICAL DISORDERS

331

Other paraneoplastic neurological syndromes

The Lambert-Eaton myasthenic syndrome, which can occur in association
with small cell carcinoma of the lung (Eaton & Lambert, 1957), and the stiff-
man syndrome, which can occur with Hodgkin's disease (Ferrari etal., 1990)
and breast cancer (Folli et aL, 1993), are discussed in detail in Chapters 10
and 6, respectively. Other paraneoplastic neurological syndromes include:
the visual paraneoplastic syndrome, which occurs in association with small
cell carcinoma of the lung and results in binocular visual loss (Grunwald et
al.,
1987); cochleovestibular dysfunction, which has been observed accom-
panying other paraneoplastic neurological syndromes (Gulya, 1993); and
dysautonomia manifested by orthostatic hypotension, abnormal pupillary
reflexes, hyperhidrosis, urinary retention, constipation, impotence, cardiac
arrhythmias, hypothermia and sleep apnoea (Veilleux etal., 1990; Dalmau
et aL, 19926). Posterior uveitis may also occur in association with paraneo-
plastic neurological involvement (Antoine et aL, 1993). A severe impair-
ment of gastrointestinal motility with intestinal pseudo-obstruction,
gastroparesis and oesophageal dysmotility can occur in patients with small
cell lung cancer with or without other autonomic dysfunction (Chinn &
Schuffler, 1988; Sodhi etal., 1989; Lennon etal., 1991). Turner etal. (1993)
found subclinical cardiovascular autonomic dysfunction in 80% of patients
with Hodgkin's disease or non-Hodgkin's lymphoma at the time of presen-
tation, and suggested that this was due to a paraneoplastic syndrome.

Neuropathology

The typical neuropathological features of the paraneoplastic neurological
disorders are neuronal loss, neuronal pyknosis, neuronophagia, microglial
nodules (or nodules of Nageotte in the dorsal root ganglia), meningeal
lymphocytic infiltration, perivascular lymphocytic cuffing, parenchymal
infiltration with lymphocytes and macrophages, and astrocytic gliosis
(Denny-Brown, 1948; Henson et aL, 1965; Brain & Wilkinson, 1965;
Corsellis et al., 1968; Horwich etal., 1977). The distribution of these changes
varies with the clinical syndrome. Thus, the dorsal root ganglion is the main
site in subacute sensory neuronopathy (Denny-Brown, 1948; Horwich etal.,
1977); the cerebellar Purkinje cell layer in subacute cerebellar degeneration
(Brain & Wilkinson, 1965); the anterior horn cells of the spinal cord in
paraneoplastic motor neurone syndromes (Henson et al., 1965; Brain et al.,
1965); the lower brainstem nuclei in brainstem encephalitis (Henson et aL,
1965; Baloh et al., 1993); the limbic grey matter (hippocampal formation,

332

AUTOIMMUNE NEUROLOGICAL DISEASE

amygdaloid nucleus, and the cingulate and orbital cortex) in limbic encepha-
litis (Corsellis et al., 1968); and the retinal ganglion cell layer in the visual
paraneoplastic syndrome (Grunwald et al., 1987). The paravertebral sym-
pathetic ganglia, brainstem grey matter and spinal cord are among the sites
of involvement in dysautonomia (Veilleux et al., 1990; Dalmau et al.,
19926). In intestinal pseudo-obstruction and gastroparesis the pathological
changes are found in the myenteric plexus (Chinn & Schuffler, 1988; Chu et
al.,
1993). The neuropathological basis of the opsoclonus-myoclonus syn-
drome is unknown (Anderson et al., 1988a). Involvement of the limbic grey
matter, the lower brainstem nuclei, the anterior horn cells of the spinal cord
and the dorsal root ganglia often occur together in various combinations
(Henson etal., 1965); these combinations are often referred to as 'paraneop-
lastic encephalomyelitis'.

Immunopathology of the lesions in the nervous system

Characteristics of the inflammatory infiltrate in the nervous
system

Immunohistochemical studies in patients with paraneoplastic encephalomy-
elitis and sensory neuronopathy have shown that the perivascular inflamma-
tory infiltrates are composed mainly of B cells and CD4+

T cells with some

CD8+

T cells and macrophages, while the interstitial inflammatory infil-
trates consist predominantly of CD8+

CDllb~ (reportedly cytotoxic) T

cells, although CD4+

T cells, macrophages and occasional B cells are also
present (Graus et al., 1990; Yoshioka et al., 1992; Jean et al., 1994).
Neurones do not express class I or class II major histocompatibility complex
(MHC) antigens, although satellite cells in the dorsal root ganglia express
HLA-DR in both patients and controls (Graus et al., 1990; Yoshioka et al.,
1992). By incubating tissue sections with biotinylated HuD neuronal antigen
(see below), Szabo etal. (1991) have demonstrated HuD-reactive B lympho-
cytes in the brain of a patient with a paraneoplastic neurological disorder.
Interestingly, a predominance of CD8+

T cells has also been observed in the
dorsal root ganglion inflammatory infiltrate of a patient with subacute
sensory neuronopathy due to primary Sjogren's syndrome (Griffin et al.,
1990), suggesting that a similar mechanism may be responsible for the
neuronal destruction in this syndrome and in the paraneoplastic one.

Localization of antibody in the nervous system

IgG bound to neurones has been demonstrated in situ in patients with
paraneoplastic neurological disorders and with circulating anti-Hu anti-

PARANEOPLASTIC NEUROLOGICAL DISORDERS

333

bodies (Graus et al, 1990; Brashear et al, 1991; Dalmau et al, 1991).
Dalmau et al (1991) found that the amount of anti-Hu IgG relative to total
IgG was higher in some areas of the brain than in the serum and CSF. The
anti-Hu IgG within the nervous system is predominantly of the IgGl isotype
and to a lesser extent of the IgG2 and IgG3 isotypes (Jean et al,, 1994). There
is also a minor degree of complement deposition within the nervous system
parenchyma (Jean et al., 1994). Binding of Ig to neurones in situ has been
demonstrated in patients with small cell lung cancer and circulating anti-
neuronal antibodies in the absence of clinical evidence of a paraneoplastic
neurological disorder, but not in cancer patients without circulating anti-
neuronal antibodies (Drlicek etal, 1992). Immune deposits have also been
found in the retina of a patient with the visual paraneoplastic syndrome
(Grunwaldeffl/., 1987).

Immunological findings in the peripheral blood

Anti-neuronal antibodies can be demonstrated in the sera of patients with
paraneoplastic neurological disorders. Different antibodies have been de-
fined according to their specificities and will be discussed separately below.
The antibodies have been called 'anti-Yo', 'anti-Hu' and 'anti-Ri' after the
first two letters of the last names of patients with the respective antibodies.

Antibodies against Purkinje cell cytoplasm (anti-Yo
antibodies)

Antibodies against Purkinje cell cytoplasm (anti-Yo antibodies) are present
in the sera of patients with subacute cerebellar degeneration and gynaecolo-
gical cancer (mainly ovarian and breast) but not in normal healthy controls
or patients with other paraneoplastic neurological disorders or other neuro-
logical diseases (Greenlee & Brashear, 1983; Jaeckle etal., 1985; Peterson et
al.,
1992). Generally, they are not present in patients with subacute
cerebellar degeneration associated with other malignancies. These anti-
bodies are also present in some patients with gynaecological cancer without
clinical evidence of cerebellar degeneration, although they are absent in the
majority of such patients (Greenlee & Brashear, 1983; Brashear et al.,
1989). Therefore, serum anti-Yo antibodies are a specific marker for
gynaecological cancer (Peterson etal., 1992). Their presence in patients with
cerebellar dysfunction should prompt a careful search for such an underlying
malignancy.

Western blot analysis of purified Purkinje neurones has shown that the
autoantibodies recognize at least two proteins: a major antigen of 62 kDa
(CDR 62, cerebellar degeneration-related 62-kDa protein) and a minor

334

AUTOIMMUNE NEUROLOGICAL DISEASE

antigen of 34 kDa (CDR 34) (Cunningham etal, 1986). The gene encoding
CDR 34 has been isolated and characterized and found to reside on the X
chromosome (Dvopcho et al, 1987; Furneaux ef a/., 1989; Chen etal, 1990).
It is uniquely expressed in Purkinje cells of the cerebellum and has also been
detected in tumour tissue from a patient with paraneoplastic cerebellar
degeneration (Furneaux et al, 1989). Screening of a human expression
library has also resulted in the isolation of cDNA clones encoding the major
CDR 62 antigen (Fathallah Shaykh etal., 1991). Sequence analysis revealed
the presence of leucine-zipper and zinc-fingers motifs in the predicted open
reading frame, suggesting that the CDR 62 protein plays a role in the
regulation of gene expression. In contrast to the minor antigen CDR 34, the
recombinant CDR 62 antigen is highly reactive with anti-Yo sera and
provides the basis for a simple diagnostic enzyme-linked immunosorbent
assay for the presence of anti-Yo antibodies (Fathallah Shaykh et al., 1991).
Interestingly, H.M. Furneaux et al. (1990) have found that the CDR 62
protein is expressed by gynaecological tumours from patients with para-
neoplastic cerebellar degeneration but not by gynaecological tumours from
patients without this neurological complication. They hypothesize that
paraneoplastic cerebellar degeneration is a result of an immunological
response directed against the Purkinje cell but provoked by the tumour-
induced expression of the Yo antigen.
An antibody specifically reacting against Purkinje cell cytoplasm, but in a
different, more diffuse pattern than that obtained with anti-Yo antibodies,
has been found in the sera of some patients with paraneoplastic cerebellar
degeneration and Hodgkin's disease, but Western blotting has not identified
a discrete Purkinje cell antigen (Hammack etal., 1992). Furthermore, non-
anti-Yo antibodies reacting with Purkinje cell cytoplasm and recognizing
62-kDa or 110-kDa neuronal antigens have been detected in the sera of men
with subacute sensory neuronopathy without tumours (Nemni et al., 1993).

Antibodies against neuronal nuclei (anti-Hu antibodies)

Antibodies specifically reactive against neuronal nuclei, but not the nuclei of
most other cells, (anti-Hu antibodies) are present in the sera of patients with
subacute sensory neuronopathy, or paraneoplastic encephalomyelitis (in-
cluding limbic encephalitis, motor neurone dysfunction, cerebellar dysfunc-
tion, brainstem encephalitis and dysautonomia) and small cell lung cancer
(Graus, Cordon-Cardo & Posner, 1985; Dick et al, 1988; Anderson et al,
19886; Moll et al, 1990; Dalmau et al, 1990, 19926; Lennon et al, 1991).
They are predominantly of the IgGl isotype and to a lesser extent of the
IgG2 and IgG3 isotypes (Jean et al., 1994). The antibodies are also present,
although at lower titre, in the sera of a minority of patients with small cell
lung cancer without clinical evidence of a paraneoplastic neurological

PARANEOPLASTIC NEUROLOGICAL DISORDERS

335

disorder. They are not present in normal healthy individuals. Furthermore,
they are not usually present in cases of subacute sensory neuronopathy
associated with other cancers or occurring without malignancy (Anderson et
al.,
19886) although they can be detected in some patients with primary
Sjogren's syndrome with or without sensory neuronopathy (Moll et al.,
1993). With the latter exception, the anti-Hu antibody is a specific marker
for the paraneoplastic syndromes associated with small cell lung cancer; its
detection in a patient not known to have cancer should prompt a careful
search for this malignancy.
The antibodies stain predominantly the neuronal nuclei, with sparing of
the nucleoli, and with weaker staining of the neuronal cytoplasm. Western
blot analysis of nuclear extracts of human and rat brain has revealed that the
antibodies react with a closely arranged set of protein bands of 35^0 kDa
(Graus et al., 1986; Dalmau et al., 1990). Using immunohistochemistry or
Western blot analysis, Dalmau et al. (1992a) studied the expression of the
Hu antigen in normal human tissues and in tumours of different histological
types. They found that in normal tissues the Hu antigen was restricted to
neurones (including those of the myenteric plexus), adrenal chromaffin cells
and ganglion cells of the bronchus. With regard to tumours, the antigen was
present in all small cell lung cancers, but not other lung cancers; it was not
present in most other cancers, except for neuroendocrine-related cancers,
especially neuroblastoma. Given that all small cell lung cancers express the
Hu antigen, it is unclear why only a minority of patients with this cancer
develop anti-Hu antibodies.
By screening a phage lambda cerebellar expression library, Szabo et al.
(1991) have isolated a recombinant neuronal antigen (HuD) that is recog-
nized by anti-Hu antibodies and that can be used to provide an unambiguous
assay for these antibodies. In normal tissues, HuD mRNA is uniquely
expressed in the nervous system. The HuD antigen is homologous to the
Drosophila proteins Elav (embryonic lethal abnormal vision) and couch
potato, which are essential RNA-binding proteins expressed early during
neuronal development (Szabo et al., 1991; Bellen et al., 1992). In view of this
homology it is likely that HuD plays a role in neurone-specific RNA
processing. Sakai etal. (1994) have isolated a hippocampal 38-kDa antigen
(PLE21) that is also recognized by anti-Hu antibodies. This protein contains
RNA recognition motifs and is highly homologous to the HuC antigen
isolated by Szabo et al. (1991).

Anti-Ri antibodies

Patients with opsoclonus, ataxia and breast cancer have serum antibodies
specifically directed against neuronal nuclei (Luque et al., 1991). Histo-
chemically these antibodies appear identical to anti-Hu antibodies, but

336

AUTOIMMUNE NEUROLOGICAL DISEASE

Western blot analysis with cerebral cortex neuronal extracts reveals that the
protein antigens have a different molecular mass (55 kDa and 80 kDa) than
the antigens recognized by anti-Hu antibodies (35-40 kDa) (Luque et al.,
1991). Serum anti-Ri antibodies are not present in normal individuals.
Generally they are not detected in patients with breast cancer without
opsoclonus, although they have been found in some patients with breast
cancer and ataxia in the absence of opsoclonus (Luque et al., 1991; Escudero
et al., 1993). Furthermore, these antibodies have not been detected in the
sera of patients with paraneoplastic opsoclonus associated with small cell
lung cancer or neuroblastoma. While they are generally absent in patients
with non-paraneoplastic opsoclonus (Luque et al., 1991), they have been
detected in a patient with steroid-responsive opsoclonus-myoclonus in the
absence of tumour (Dropcho, Kline & Riser, 1993). Anti-Ri antibodies
react with the tumours of patients with the respective antibodies and
opsoclonus, but do not react with the breast cancers of those without anti-Ri
antibodies (Luque et al., 1991). Therefore, the situation in anti-Ri para-
neoplastic opsoclonus is similar to that in anti-Yo paraneoplastic cerebellar
degeneration, where the antigen is present only in the tumours of those
patients who develop the antibody response. It is different from the situation
with anti-Hu antibodies and from the paraneoplastic Lambert-Eaton myas-
thenic syndrome, where the antigen appears to be present in all small cell
lung cancers but where only a small proportion of patients mount an
antibody response.

Immunological findings in the cerebrospinal fluid

Furneaux, Reich & Posner (1990) quantified the activity of anti-Yo and
anti-Hu antibodies in simultaneously obtained samples of serum and CSF of
patients with paraneoplastic neurological disorders. In the majority of
patients the autoantibody activity per milligram of total IgG was substan-
tially greater in the CSF than in the serum, indicating intrathecal production
of these autoantibodies in the paraneoplastic syndromes. Plasmapheresis
reduced the level of antibody in the serum without affecting that in the CSF
in five of six patients. In patients with the anti-Ri paraneoplastic syndrome
there is also evidence of intrathecal production of the anti-Ri antibodies
(Luque etal., 1991).

Mechanism of neuronal destruction and/or dysfunction

It is likely that the anti-neuronal antibodies that are present in the serum,
CSF and nervous tissue in the paraneoplastic disorders play a role in the
neuronal destruction that is characteristic of these disorders; however, this

PARANEOPLASTIC NEUROLOGICAL DISORDERS

337

has not yet been definitely established. Greenlee, Parks & Jaeckle (1993)
found that anti-Hu antibodies from patients with paraneoplastic disorders
produced specific lysis of rat cerebellar granule neurones in vitro in the
presence of complement, as compared with controls using normal serum or
heat-inactivated complement. More prolonged incubation of cultures with
anti-Hu antibodies without complement also resulted in specific lysis,
whereas incubation with normal serum or serum from neurologically normal
patients with small cell lung cancer did not. These results indicate that anti-
Hu antibodies may cause neuronal destruction in the absence of lympho-
cytes. On the other hand, attempts to transfer the neurological disorder by
injecting anti-Hu antibodies into experimental animals have so far been
unsuccessful (Dick etal, 1988; Szabo etal, 1991). Repeated intraventricu-
lar injections of anti-Yo IgG from a patient with paraneoplastic cerebellar
degeneration into guinea pigs have failed to produce either clinical or
histological evidence of cerebellar disease, despite the presence of IgG in
the Purkinje cell cytoplasm of the recipients (Graus et al, 1991).
The CD8+

lymphocytes infiltrating the nervous system (Graus et al,
1990; Yoshioka et al., 1992) may also contribute to the neuronal elimination
by acting as cytotoxic T cells. However, as neurones do not express class I
MHC antigens (Graus et al, 1990; Yoshioka et al, 1992), it is difficult to
explain how CD8+

cytotoxic T cells, which recognize antigen in the context
of these MHC antigens, could specifically interact with the neurones. An
alternative explanation is that some of the infiltrating CD8+

cells represent
natural killer cells which might be targeted by their Fc receptors to antibody-
binding neurones. Natural killer cells have been shown to mediate the
destruction of sympathetic neurones in the superior cervical ganglia of rats
treated with guanethidine (Hickey et al, 1992). However, Jean et al. (1994)
did not find natural killer cells in the inflammatory infiltrates of patients with
paraneoplastic encephalomyelitis.
While neuronal death is the cause of the clinical deficit in most of the
paraneoplastic disorders, antibody-mediated dysfunction without neuronal
death may be responsible for the manifestations of reversible central
nervous system syndromes, for example opsoclonus-myoclonus, as in the
case of the Lambert-Eaton myasthenic syndrome (see Chapter 10). The
availability of recombinant neuronal antigens such as Yo and Hu may allow
the production of animal models that will facilitate studies on the patho-
genesis of the paraneoplastic neurological disorders.

Effect of the immune response on the tumour

Altman & Baehner (1976) observed that children with coincident
opsoclonus-myoclonus and neuroblastoma had a much better prognosis for

338

AUTOIMMUNE NEUROLOGICAL DISEASE

survival than those without opsoclonus-myoclonus. They acknowledged
that this might be partly explained by earlier tumour detection in the former
group, because of the striking neurological symptomatology. However, as
five of the seven patients with opsoclonus-myoclonus and advanced malig-
nancy also exhibited long-term survival, they suggested that an immune
response might be responsible for controlling the growth and spread of the
tumour, as well as being responsible for the neurological syndrome. This
hypothesis has been supported by the observation that patients with small
cell lung cancer who have low-titre anti-Hu antibodies and no paraneo-
plastic neurological syndrome are more likely to have their tumour limited
to the chest than patients without anti-Hu antibodies (Dalmau et al., 1990).
Despite the fact that the presence of anti-Hu antibody appears to protect
against death from the tumour, the median survival of patients with the
associated paraneoplastic syndrome is similar to that of small cell lung
cancer patients without the syndrome, because of the severity of the
neurological disorder (Dalmau et al., 19926). Interestingly, spontaneous
tumour regression can occur in patients with small cell lung carcinoma,
paraneoplastic neurological disease and anti-neuronal antibodies (Darnell
& DeAngelis, 1993). This raises the possibility that the absence of identifi-
able tumour in some patients with 'paraneoplastic' neurological syndromes
may be explained by immune-mediated elimination of the tumour cells.
Anti-Hu IgG and anti-Hu B lymphocytes have been demonstrated in the
tumour as well as in the brain in patients with paraneoplastic neurological
disorders (Dalmau etal., 1991; Szabo etal, 1991).

Therapy

In general, the clinical deficits in patients with the paraneoplastic neurologi-
cal syndromes with underlying neuronal loss are irreversible, whereas
syndromes without demonstrable neuronal loss such as paraneoplastic
opsoclonus-myoclonus may spontaneously remit. In some instances of
limbic encephalitis, clinical improvement has occurred following antineo-
plastic therapy or surgical removal of the tumour (Burton et al., 1988;
Kaniecki & Morris, 1993; Tsukamoto et al., 1993), indicating either that
neuronal loss was not responsible for the clinical manifestations or that any
neuronal loss had been compensated for, perhaps by axonal sprouting. In
some patients with paraneoplastic sensory neuronopathy, treatment of the
neoplasm may halt progression of the neuronopathy but neurological
improvement does not occur and most patients continue to worsen even
when the tumour responds well to therapy (Chalk et al., 1992).
With the exception of the paraneoplastic Lambert-Eaton myasthenic
syndrome (see Chapter 10), the paraneoplastic neurological disorders do

PARANEOPLASTIC NEUROLOGICAL DISORDERS

339

not respond to plasmapheresis, corticosteroid or other immunosuppressant
therapy (Peterson^al., 1992; HammacketaL, 1992; Dalmauetal., 1992fo).
Given the underlying neuronal loss, the most that could be expected from
such therapy would be prevention of progression. By inhibiting the immune
response against the tumour, immunosuppressive treatment may also allow
the tumour to progress unless it is controlled by other therapy.

Conclusions

The hypothesis that paraneoplastic neurological syndromes are due to an
autoimmune attack on the nervous system triggered by the aberrant ex-
pression of neuronal antigens by the neoplasm is supported by the following
observations: lymphocytic pleocytosis in the CSF; lymphocytic infiltrate in
the nervous system; circulating anti-neuronal antibodies that also react with
the underlying tumour; intrathecal synthesis and localization of these
autoantibodies in nervous tissue parenchyma; and (in one study) the lytic
effect of anti-neuronal antibodies on neurones in vitro. Further studies are
needed to determine the relative roles of T cells and antibodies in the
pathogenesis of these disorders. At least some, and perhaps all, of these
syndromes may occur on an autoimmune basis in the absence of any
triggering neoplasm. Studies on the pathogenesis of the paraneoplastic
neurological disorders may shed light on the pathogenesis of the corre-
sponding non-paraneoplastic disorders. The availability of recombinant
neuronal antigens should allow the development of animal models that will
facilitate these studies.

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-13-

Neurological complications of
connective tissue diseases and
vasculitis

PAMELA A. McCOMBE

Connective tissue diseases such as systemic lupus erythematosus can have
neurological manifestations. Furthermore, systemic vasculitides can result
in neurological disease (Sigal, 1987; Moore, 1989fo) and some vasculitides
are restricted to the nervous system (Dyck et al., 1987; Moore, 1989a;
Crane, Kerr & Spiera, 1991). There are three possible means by which
connective tissue diseases and vasculitides could be associated with neuro-
logical disorders. Firstly, the neurological complications of these conditions
could be due to ischaemia secondary to vascular occlusion. Secondly,
neurological complications could be due to a specific immune response
directed against antigens in the parenchyma of the nervous system. Thirdly,
neurological disturbance could result from a separate autoimmune neuro-
logical disorder occurring in an individual predisposed to autoimmune
disease. This chapter reviews central nervous system (CNS) and peripheral
nervous system (PNS) manifestations of connective tissue diseases and
vasculitides, but does not attempt a comprehensive review of these systemic
disorders.

Clinical features

Systemic lupus erythematosus

The neurological manifestations of systemic lupus erythematosus (SLE) are
manifold (Johnson & Richardson, 1968; Feinglass et al.y 1976; Futrell,
Schultz & Millikan, 1992). There are strict criteria for the diagnosis of SLE
(Tan et al., 1982) and these include the presence of neurological signs. In
some patients, neurological symptoms and signs are the first manifestation
of SLE (Tola et al., 1992). SLE is associated with a wide range of

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AUTOIMMUNE NEUROLOGICAL DISEASE

neuropsychiatric abnormalities including psychosis and cognitive impair-
ment (Feinglass et al., 1976). In one series, 21% of SLE patients had
cognitive impairment (Hanly etal., 1992a). SLE can also be associated with
encephalomyelitis, which sometimes has clinical and radiological features
similar to those of multiple sclerosis (MS) (Penn & Rowan, 1968; Pender &
Chalk, 1989; Tola et al., 1992). In the PNS, SLE can occur in association
with a chronic sensorimotor neuropathy (McCombe et al., 1987). SLE can
also occur in association with syndromes typical of the Guillain-Barre
syndrome (Chaudhuri et al., 1989) and chronic inflammatory demyelinating
polyradiculoneuropathy (Rechthand et al., 1984; Sindern et al., 1991),
although it is not clear whether this is an association of different diseases or
whether these syndromes are a direct complication of SLE. SLE may occur
in association with myositis (see Chapter 11), myasthenia gravis (Ben
Chetrit et al., 1990) and the Lambert-Eaton myasthenic syndrome (Brom-
berg, Albers & McCune, 1989). Modern imaging techniques have led to
significant advances in the understanding of the CNS manifestations of
connective tissue diseases. Magnetic resonance imaging (MRI) of the brain
has demonstrated increased signal intensity in the periventricular regions in
some patients with neuropsychiatric features of SLE (Stimmler, Coletti &
Quismorio, 1993; Baum etal., 1993). Single photon emission computerized
tomography (SPECT) studies have found areas of reduced cerebral blood
flow in patients with CNS complications of SLE (Emmi et al., 1993).
Positron emission tomography (PET) has shown deficiencies in cerebral
glucose metabolism in patients with cognitive defects and SLE (Carbotte et
al.,
1992).

Primary Sjogren's syndrome

Sjogren's syndrome (sicca syndrome) was named after Henrik Sjogren (see
Mutlu & Scully, 1993). Sjogren's syndrome is characterized by dry eyes
(xerophthalmia), dry mouth (xerostomia), lacrimal and salivary gland
enlargement and punctate keratitis. The diagnosis of Sjogren's syndrome
rests on the finding of xerophthalmia confirmed by a Schirmer's test and a lip
biopsy showing lymphocytic infiltration of the salivary glands (Greenspan et
al.,
1974). Sjogren's syndrome can be a primary disorder or may be
secondary to other diseases such as rheumatoid arthritis. Patients with
primary Sjogren's syndrome often have extraglandular involvement and in
particular may have disease of the CNS or PNS. CNS disturbances, such as
seizures, encephalopathy, cognitive impairment and focal deficits have been
reported to occur in up to 25% of patients with primary Sjogren's syndrome
(Alexander etal, 1986«; Alexander, 1986; Spezialetti etal., 1993) and often
occur in patients with widespread cutaneous vasculitis (Alexander &
Provost, 1987). However, others have found that the incidence of CNS

CONNECTIVE TISSUE DISEASES AND VASCULITIS

347

abnormalities is much lower (Binder, Snaith & Isenberg, 1988; Mellgren et
al,
1989; Andonopoulos et al, 1990). It has been reported that CNS
involvement in primary Sjogren's syndrome can lead to widespread neuro-
logical abnormalities that mimic multiple sclerosis (Alexander etal., 19866).
MRI has been reported to show patchy cerebral lesions in patients with CNS
complications of primary Sjogren's syndrome (Alexander et al., 1988a).
However, others have found little evidence of MRI abnormalities in primary
Sjogren's syndrome (Manthorpe, Manthorpe & Sjoberg, 1992). There is less
controversy about the involvement of the PNS in primary Sjogren's syn-
drome. PNS involvement is frequently present (Mellgren et al., 1989;
Andonopoulos et al., 1990; Mauch et al., 1994) and includes trigeminal
sensory neuropathy (Kaltreider & Talal, 1969), peripheral sensorimotor
neuropathy, subacute sensory neuronopathy resembling that which occurs
as a paraneoplastic syndrome (Graus et al., 1988; Griffin et al., 1990;
McCombe etal., 1992) and mononeuritis multiplex (Kaplan etal., 1990).

Rheumatoid arthritis

Rheumatoid arthritis (RA) is a destructive arthritis associated with the
presence in the serum of rheumatoid factor. In RA, the spinal cord and
peripheral nerves may be subjected to physical compression secondary to
disease of the cervical spine or disorders such as carpal tunnel syndrome.
Peripheral neuropathy is frequently present and includes mild sensory or
sensorimotor neuropathies as well as more severe sensorimotor neuropath-
ies in association with vasculitis (Good et al., 1965; Chamberlain &
Bruckner, 1970). Patients with RA may also develop chronic inflammatory
demyelinating polyradiculoneuropathy, although it is not clear whether this
represents the simultaneous development of two conditions or whether RA
can more directly cause the development of a demyelinating neuropathy
(McCombe et al., 1991). CNS abnormalities such as confusional states,
seizures and focal neurological signs have occasionally been reported in RA
(Skowronski & Gatter, 1974; Ramos & Mandybur, 1975; Gupta & Ehrlich,
1976; Kim, 1980).

Isolated angiitis of the CNS or PNS

Primary angiitis of the CNS

Vasculitis confined to the intracranial cerebral circulation was first described
as granulomatous angiitis of the nervous system. More recently the terms
'isolated angiitis of the nervous system' (Moore, 1989a; Crane etal., 1991) or
'primary angiitis of the CNS' (Calabrese et al., 1992) have been adopted.
Calabrese etal. (1992) reported that the symptoms of this condition included

348

AUTOIMMUNE NEUROLOGICAL DISEASE

headache (62%), weakness (55%), cognitive impairment (51%) and
impaired consciousness (29%). Other symptoms include seizures, cerebral
haemorrhage and spinal cord disease. Diagnosis requires proof of vasculitis
by cerebral angiography or biopsy.

Non-systemic vasculitic neuropathy

Dyck et al. (1987) have described peripheral neuropathy associated with
vasculitis that, on clinical testing, was confined to the PNS, and remained
confined to the PNS after lengthy follow-up. Most of their patients exhibited
mononeuritis multiplex, while others had asymmetrical or symmetrical
poly neuropathy. Torvik & Berntzen (1968) reported patients with vasculitis
affecting nerves and muscles but without visceral involvement. Kissel et al.
(1985) reported that four of 16 patients with necrotizing vasculitic neuro-
pathy had no systemic involvement.

Other vasculitides

Other generalized vasculitides such as polyarteritis nodosa and Wegener's
granulomatosus can cause neurological abnormalities. Mononeuritis mul-
tiplex is frequently associated with vasculitis (Cohen Tervaert & Kallen-
berg, 1993). Giant cell arteritis is a large vessel vasculitis that is restricted to
the aortic arch and its branches and that can cause headache, loss of vision
and occasionally cognitive impairment (Caselli & Hunder, 1993). Giant cell
arteritis is diagnosed by elevation of the erythrocyte sedimentation rate and
abnormalities on superficial temporal artery biopsy and is treated with
corticosteroids. Behget's disease, which may be an autoimmune vasculitis,
can have relapsing and remitting neurological manifestations (Allen, 1993).
In Behqet's disease MRI brain scans may show widespread white matter
abnormalities and evidence of intracranial venous thrombosis (Morrissey et
al,
1993; Wechsler etal., 1993). The cerebrospinal fluid (CSF) protein may
be elevated (Hatzinikolaou etal., 1993). Eales' disease is a vasculitis of the
retina that can be associated with more widespread neurological involve-
ment (Katz et al., 1991).

Neuropathology

Systemic lupus erythematosus

Ischaemia secondary to vasculitis is one possible cause of the neurological
disturbance in cerebral SLE, and is likely to be due to vascular changes

CONNECTIVE TISSUE DISEASES AND VASCULITIS

349

affecting small blood vessels. Hanly, Walsh & Sangalang (19926) found
small-vessel damage and cerebral microinfarcts in the brain of patients with
SLE. Others have found small-vessel hyalinization and platelet deposition
in the walls of blood vessels (Ellison et al., 1993). In a post-mortem study,
Johnson & Richardson (1968) found destructive and proliferative changes of
the small blood vessels of the brain of patients with neurological manifes-
tations of SLE. They found no evidence of vasculitis of larger vessels.
Devinsky, Petito and Alonso (1988) also found that there was no evidence of
large-vessel vasculitis in patients with neurological complications of SLE.
Immune complexes have been found in the choroid plexus of patients with
confusional states associated with SLE (Atkins et aL, 1972). Sural nerve
biopsies from patients with sensorimotor neuropathy associated with SLE
showed axonal degeneration with little evidence of abnormalities of blood
vessels (McCombe et aL, 1987), although this is not conclusive, because of
the sampling problems of peripheral nerve biopsy.

Sjogren's syndrome

In the CNS in primary Sjogren's syndrome there may be vasculitis often
associated with meningitis (Alexander, 1992). Aseptic meningitis without
vasculitis has also been reported (Gerraty, McKelvie & Byrne, 1993), as has
venous sinus thrombosis (Urban, Jabbari & Robles, 1994). In patients with
subacute sensory neuronopathy associated with primary Sjogren's syn-
drome there is lymphocytic infiltration of the dorsal root ganglia (Griffin et
al.
, 1990). Peripheral nerve biopsies may show evidence of axonal degener-
ation and vasculitis (Peyronnard etal., 1982; Mellgren et aL, 1989), although
some studies have found little evidence of vasculitis (Gemignani et aL,
1994). One study of peripheral nerve from a patient with sensory neurono-
pathy and primary Sjogren's syndrome did not demonstrate antibody bound
to peripheral nerve (Graus et aL, 1988), although such deposition would not
be expected if the pathology was confined to the dorsal root ganglia.

Rheumatoid arthritis

Beckett & Dinn (1972) found that in sural nerves from RA patients with
clinically mild neuropathy there was segmental demyelination and no
vascular damage. They found that nerves from patients with more severe
neuropathy showed evidence of vascular damage and axonal degeneration.
Conn, McDuffie & Dyck (1972) found immunoglobulin deposition in the
wall of a neural blood vessel in a patient with vasculitic neuropathy and RA,
but there was no such deposition in the nerves of patients with chronic
neuropathy associated with RA. In one patient studied by van Lis &
Jennekens (1977) there was inflammation of the epineural arterioles and

350

AUTOIMMUNE NEUROLOGICAL DISEASE

deposition of immunoglobulin. In the brains of patients with CNS manifes-
tations of RA there may be severe necrotizing vasculitis, the presence of
rheumatoid nodules, meningeal involvement or choroid plexus involvement
(Ramos & Mandybur, 1975; Kim, 1980; Kim & Collins, 1981). IgM deposits
have been found in the choroid plexus in one patient with RA and organic
brain syndrome (Gupta & Ehrlich, 1976). Clearly, further clinicopatho-
logical correlation is needed to define the neurological complications of RA.

Isolated angiitis of the CNS and PNS

In primary angiitis of the CNS there is inflammation of the small veins and
arterioles, with prominent involvement of the leptomeninges (Calabrese et
al.
, 1992). The infiltrate is usually granulomatous. In non-systemic vasculitic
neuropathy, the pathological features are those of an ischaemic neuropathy
associated with necrotizing vasculitis affecting small arterioles (Dyck et al.,
1987).

Immunological findings in the peripheral blood and
cerebrospinal fluid

Systemic lupus erythematosus

SLE is characterized by the presence of increased levels of serum anti-
nuclear antibodies (Warner, 1994). Anti-cardiolipin antibodies may be
increased in the serum and CSF of patients with CNS manifestations of SLE
(Lolli et al., 1991) and are associated with ischaemia and thrombotic CNS
disease (Brey, Gharavi & Lockshin, 1993). Increased levels of antibodies to
brain antigens are also found in SLE (Klein, Richter & Berg, 1991; Hanly,
Hong & White, 1993; Khin & Hoffman, 1993; Teh etal, 1993). Correlation
between the presence of anti-neuronal antibodies and cognitive impairment
has been reported (Denburg, Carbotte & Denburg, 1987). It has been
suggested that antibodies to synaptosomal particles may contribute to
neurological complications of SLE (Hanly et al., 1993). Such antibodies
react with a 50-kDa membrane protein (Hanson et al., 1992). SLE sera also
contain antibodies reactive with ribosomal P proteins (Bonfa et al., 1987).
The anti-P antibodies react with a 38-kDa membrane protein (Koren et al.,
1992). Antibodies to a cytoskeletal protein L-fimbrin are present in the sera
of patients with SLE and correlate with CNS complications (De Mendonca
Neto et al., 1992). CSF examination in patients with neurological compli-
cations of SLE may reveal intrathecal antibody synthesis (Hirohata &
Miyamoto, 1986), intrathecal synthesis of the fourth component of com-
plement (Jongen etal., 1990) or elevated levels of interleukin-6 (Hirohata &
Miyamoto, 1990).

CONNECTIVE TISSUE DISEASES AND VASCULITIS

351

Primary Sjogren's syndrome

Primary Sjogren's syndrome patients with circulating anti-Ro antibodies
have a higher incidence of serious CNS disease than those without these
antibodies (Alexander, 1992; Alexander et al, 1994). Spezialetti et al.
(1993) found that patients with CNS manifestations do not have increased
levels of serum anti-ribosomal P proteins or anti-neuronal antibodies.
However, Moll etal. (1993) have shown that some patients with neurological
complications of primary Sjogren's syndrome have anti-neuronal antibodies
including the anti-Hu antibodies found in patients with paraneoplastic
syndromes (see Chapter 12). In the CSF in patients with neurological
disease associated with primary Sjogren's syndrome, there are increased
immunoglobulin levels and the presence of oligoclonal bands (Alexander et
al,
1986a; Vrethem etal., 1990). Activated complement can be detected in
the serum and CSF of patients with CNS disease associated with primary
Sjogren's syndrome (Sanders et al, 1987; Alexander et al., 1988&).

Rheumatoid arthritis

Reduced levels of CSF complement have been reported in a patient with a
confusional state associated with RA (Kim, 1980).

Isolated angiitis of the nervous system

There is no evidence of any immunological abnormality specific for primary
angiitis of the CNS. It might be expected that primary angiitis of the CNS
would be associated with inflammation directed against antigens specific for
CNS blood vessel antigens. One antigen that is found on CNS endothelium
but not other endothelium is HT7 (Unger et al., 1993), which is also known
as neurothelin or basigin (Seulberger, Unger & Risau, 1992) and which is a
member of the immunoglobulin superfamily (Miyauchi, Masuzawa & Mura-
matsu, 1991; Seulberger et al., 1991; Kasinrerk etal, 1992). Similarly, it can
be postulated that isolated angiitis of the PNS might be associated with an
immune attack directed against antigens that are unique to vessels of the
PNS.

Other vasculitides

The finding of elevated levels of serum anti-neutrophil cytoplasmic anti-
bodies is an important part of the diagnosis of the systemic vasculitides
(Kallenberg, Mulder & Tervaert, 1992; Geffriaud Ricouard et al, 1993;
Warner, 1994), but these antibodies are not likely to have a direct involve-

352

AUTOIMMUNE NEUROLOGICAL DISEASE

ment in the development of neurological complications. In Behqet's disease,
elevated serum anti-cardiolipin antibodies have been found (al Dalaan etal.,
1993). Elevated levels of anti-endothelial antibodies have also been
reported in Behqet's disease (Aydintug etal., 1993).

Pathogenesis

There is considerable evidence that ischaemia plays a major role in the
neurological complications of connective tissue diseases and vasculitis. The
consequences of ischaemia have been studied by Nukada & Dyck (1987),
who showed that occlusion of small blood vessels in peripheral nerves causes
axonal degeneration, with secondary demyelination. This is likely to be the
case throughout the nervous system. It has also been suggested that
vasculitis can lead to non-specific primary demyelination (vasculomyelino-
pathy) (Reik, 1980). In some of the neurological complications of these
disorders, there is inflammatory cell infiltration of the parenchyma of the
nervous system and circulating antibodies specific for nervous system
antigens. These findings indicate a direct immune attack on the parenchyma
of the nervous system. Furthermore, as susceptibility to autoimmunity
appears to be inherited as an autosomal dominant trait (Bias et al., 1986),
patients with a connective tissue disease such as SLE may simultaneously
have another autoimmune disease such as my asthenia gravis, chronic
inflammatory demyelinating polyradiculoneuropathy or multiple sclerosis.

Systemic lupus erythematosus

Recent evidence from PET scanning (Stimmler et al., 1993) strongly
suggests that ischaemia and its metabolic consequences are important in
producing the CNS complications of SLE. This is likely to be due to
inflammation and obstruction of small blood vessels. There is also a
considerable body of evidence supporting a role for antineuronal antibodies
(see above), but the proof that these antibodies are pathogenic, namely
passive transfer of disease to experimental animals, is not available.

Animal models of SLE

In the animal models of SLE there is evidence of vasculitis and anti-brain
antibodies. In NZB/W F1 mice, there is immune complex deposition in the
brain capillaries and lymphoid cell infiltration of the subarachnoid regions
and around blood vessels (Rudick & Eskin, 1983). Studies of MRL/lpr mice
demonstrate infiltration of the CNS with CD4+

T cells (Vogelweid et al,

CONNECTIVE TISSUE DISEASES AND VASCULITIS

353

1991). Anti-brain antibodies are produced in the mice, which develop SLE-
like syndromes (Narendran & Hoffman, 1989).

Sjogren's syndrome

Some of the neurological manifestations of primary Sjogren's syndrome are
likely to be secondary to vasculitis. In sensory neuronopathy complicating
primary Sjogren's syndrome there is inflammation of dorsal root ganglia and
circulating anti-neuronal antibodies (including anti-Hu antibodies), indi-
cating a specific immune attack on neural antigens. Models of Sjogren's
syndrome have been developed in mice (Sato & Sullivan, 1994; Yeoman &
Franklin, 1994), but have not yet been used to study the nervous system.

Other conditions

In rheumatoid arthritis, primary angiitis of the CNS, non-systemic vasculitic
neuropathy and the other vasculitides discussed in this chapter there is
strong evidence that ischaemia due to vasculitis is the primary cause of the
neurological disturbance.

Therapy

Systemic lupus erythematosus

Since the report of Dubois et al. (1974), high doses of corticosteroids have
been the main form of treatment in CNS lupus. Intravenous cyclophospha-
mide therapy is also of benefit in patients with CNS manifestations of SLE
/., 1991).

Primary Sjogren's syndrome

Alexander (1992) has suggested that corticosteroids and other immunosup-
pressive agents may improve the neurological status of patients with CNS
disease due to primary Sjogren's syndrome. Primary Sjogren's syndrome
may produce a dementia that responds to corticosteroid treatment (Caselli
etal., 1991; Kawashima, Shindo & Kohno, 1993). Peripheral neuropathy or
sensory neuronopathy in association with primary Sjogren's syndrome may
stabilize or improve with immunosuppressive therapy (Caselli et al., 1991;
McCombe etal., 1992).

354

AUTOIMMUNE NEUROLOGICAL DISEASE

Rheumatoid arthritis

Patients with neuropsychiatric abnormalities attributed to RA have re-
sponded to treatment with corticosteroids (Skowronski & Gatter, 1974;
Gupta & Ehrlich, 1976).

Isolated angiitis of the nervous system

Patients with primary angiitis of the CNS were initially thought to have a
poor prognosis. However, in the series of Calabrese et al. (1992) more than
half of the patients who were diagnosed in life made a complete recovery,
often after treatment with corticosteroids or other immunosuppressants.
Moore (1989«) and Crane et al., (1991) also suggested that aggressive
treatment with corticosteroids and immunosuppressants was helpful. Dyck
et al. (1987) reported that prednisone appeared to arrest the course of
disease in some patients with non-systemic vasculitic neuropathy.

Other conditions

The systemic vasculitides are usually treated rather aggressively with immu-
nosuppressive agents, which may lead to improvement of the neurological
complications (Cohen etal., 1993).

Conclusions

Connective tissue diseases and vasculitides are often complicated by in-
volvement of the CNS and/or the PNS. Ischaemia associated with vasculitis
is likely to be a common cause of this complication, but further studies of the
exact mechanisms of ischaemia and its effects are required. There is also
evidence that some neurological complications are due to a specific immune
attack on antigens in the parenchyma of the nervous system, for example in
the subacute sensory neuronopathy of primary Sjogren's syndrome. Further
studies are required to determine the relative roles of anti-neuronal T cells
and antibodies in the pathogenesis of these conditions. Understanding of the
neurological complications of these diseases would be aided by the develop-
ment of further animal models which would permit experimental studies.
The most appropriate treatment of these conditions is not yet known and
further study is required, because the types of treatment that appear likely to
be helpful include potentially harmful immunosuppressive agents.

CONNECTIVE TISSUE DISEASES AND VASCULITIS

355

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