CNS lupus
A study of 41 patients

Fady G. Joseph,
MRCP, MD
G. Alistair Lammie,
FRCPath
Neil J. Scolding,
FRCP, PhD

ABSTRACT

CME

(CNS-SLE) was performed largely in the southwest of England and South Wales, covering the
period 1990 to 2002.

Address correspondence and
reprint requests to Dr. N.J.
Scolding, Institute of Clinical
Neurosciences, Frenchay
Hospital, Bristol, UK BS16 1LE
n.j.scolding@bristol.ac.uk

Background: CNS lupus is a serious but potentially treatable illness, which, though long recognized, may still present very difficult diagnostic challenges. We believed that further detailed
study of patients with neuropsychiatric lupus would yield clinical information of practical value in
improving both recognition and management of this difficult illness.

Methods: A retrospective case analysis of 41 patients with CNS systemic lupus erythematosus

Results: We found that primary neurologic presentation of SLE was not rare (10/41 patients),
and there was an unexpected emergence of movement disorders (particularly parkinsonism
and myoclonus) early in the disease course (4/10 patients). These showed a good response to
immunosuppressants, but not to standard dopaminergic therapy. Typically, the erythrocyte
sedimentation rate (ESR) or plasma viscosity was elevated during neurologic episodes while
C-reactive protein levels were normal, and lupus-related serum antibody tests usually supportive. But, significantly, neither a normal ESR nor negative serology excluded CNS lupus.
MR brain imaging is more commonly abnormal in patients with focal neurologic deficits and
normal or shows wholly nonspecific change with more diffuse manifestations (cognitive decline, epilepsy). Abnormal CSF correlated significantly with poorer outcome. At the end of the
period of study, 54% had no more than minor functional disability, the remainder having a
severe or fatal outcome.

Conclusions: Our observations, particularly the emergence of non-choreic movement disorders,
the blood, serum, and imaging findings, and the prognostic importance of CSF abnormalities,
should help improve both the recognition of CNS systemic lupus erythematosus, perhaps particularly in elderly individuals, and its management. Neurology® 2007;69:644–654

Systemic lupus erythematosus (SLE) has a tendency for widespread organ involvement.
Its current prevalence is approximately 6 to 50 per 100,000, and its incidence has more
than tripled over the last 40 years, from 1.51 per 100,000 during 1950 through 1979 to 5.56
per 100,000 during 1980 through 1992 (adjusted figures), with a statistically significant
improvement in survival.1 Women (especially in the childbearing years) and those of
African Caribbean and Asian racial origin are five times more likely to be affected than
men or Caucasians.2 The diagnosis is now commonly based on the widely accepted revised (1997) diagnostic criteria3 (table 1).
Hebra and Kaposi in 1875 were the first to note CNS involvement in lupus,4 and
writing on the “erythema group of skin diseases” in 1895, Osler discussed cerebral
changes in SLE and reported on a young doctor with SLE and hemiplegia and another
patient who “imagines all sorts of things.”5 CNS disease is generally associated with a
poor prognosis that is only second in severity to renal involvement. Although studies
vary, the consensus of opinion suggests that about 50% of SLE patients will have neuropsychiatric phenomena at some time during their illness.6-10 However, presentation with
From the Institute of Clinical Neurosciences (F.G.J., N.J.S.), Frenchay Hospital, Bristol, and Department of Pathology (G.A.L.), University of
Wales College of Medicine, Cardiff, UK.
Fady Joseph was supported by the Neurological Research Fund established by Dr. M.J. Campbell.
Disclosure: The authors report no conflicts of interest.
644

Copyright © 2007 by AAN Enterprises, Inc.

Table 1

Diagnosis of systemic lupus
erythematosus based on American
College of Rheumatology criteria3

Table 2

Neuropsychiatric manifestations of
systemic lupus erythematosus11

Central nervous system
Malar rash
Discoid rash
Photosensitivity
Oral ulcers

Aseptic meningitis
Cerebrovascular disease
Demyelinating syndrome

Arthritis

Headache (including migraine and idiopathic intracranial
hypertension)

Serositis (pleurisy or pericarditis)

Movement disorder (chorea)

Renal disorder (proteinuria above 0.5 g/24 h or cellular
casts)

Myelopathy

Neurologic disorder
Hematologic disorder (hemolytic anemia, leukopenia, or
lymphopenia on two or more occasions) or
Immunologic disorder (thrombocytopenia)
Antinuclear antibody

Seizure disorder
Acute confusional state
Anxiety disorder
Cognitive dysfunction
Mood disorder
Psychosis

Four of 11 features are required.

neurologic features at the onset of the disease is regarded as rare, occurring only in
approximately 3%. A 1999 consensus document defined the neurologic and psychiatric manifestations of SLE.11 The authors
proposed that 19 syndromes (table 2) be
grouped under the common definition of
neuropsychiatric SLE.
The wholly nonspecific nature of these
features helps explain why the clinical
identification of CNS lupus remains in
practice a serious diagnostic challenge,
which is complicated by the lack of specific
laboratory tests, nonspecific neuroimaging
findings, and inaccessible brain parenchyma for histologic confirmation. The
possibility of opportunistic infection in individuals who may well have received significant previous immune suppression also
contributes to the extraordinarily difficult
diagnostic problems lupus patients with
neurologic disease may present.12
We hypothesized that further detailed
study of patients with neuropsychiatric lupus would yield clinical information of
practical value in improving the recognition and management of this difficult and
serious illness. We therefore identified and
have retrospectively studied a large local
cohort of patients with CNS-SLE to gain
clearer insight to the neurologic features,
course, behavior, outlook, and management of neuropsychiatric SLE.

Peripheral nervous system
Acute inflammatory demyelinating polyradiculopathy
(Guillain–Barré syndrome)
Autonomic disorder
Mononeuropathy, single or multiplex
Myasthenia gravis
Cranial neuropathy
Plexopathy
Polyneuropathy

METHODS The case records of patients with CNS-SLE
were identified from the hospital records of nine major centers in southwestern England and south Wales, with additional cases from two centers in Edinburgh and Oxford, over
a 12-year period. Cases were identified from three main
sources: Specific requests were made individually to all neurology and rheumatology specialist consultants (32 patients
with CNS lupus were identified through this mechanism).
Information analysts at each hospital (using International
Classification of Diseases 9th and 10th ed. codes) were consulted: These would have included the diagnosis of CNS lupus from all specialties and departments (seven further
patients with CNS lupus were identified through this mechanism). Pathology department records in each hospital were
also searched (two additional patients with CNS lupus patients were identified through this route).
Approximately 300 records concerning individuals who
had at some stage been suspected of having CNS-SLE were
obtained and scrutinized for the certainty of this possibility,
using the American College of Rheumatology (ACR) criteria
for SLE and CNS involvement (tables 1 and 2). Patients with
CNS symptoms attributable to intracranial infections, uremia, or any other suspected secondary causes were excluded
from the study. Those patients deemed to have CNS-SLE
were then studied for basic demographic details, length of
follow-up, CNS features (particularly initial neurologic presentation or “early CNS involvement” compared with “later
neurologic involvement” occurring at any time subsequently
in the course of the follow up period), systemic (nonneuropsychiatric) features (either prior or subsequent to CNS features), further investigation findings, therapeutic measures,
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645

Figure 1

Frequency of various systemic manifestations occurring prior to
neurologic systemic lupus erythematosus

clinical progression, and final outcome. The “outcome” for
each admission was recorded as “asymptomatic,” “minor
disability” (e.g., mild weakness or sensory disturbance not
causing significant functional impairment, or deficit in visual
acuity better than 6/12), “moderate disability” (e.g., monoparesis, paraparesis, optic neuropathy reducing visual acuity
to 6/12 vision or less, with significant functional impairment), “severe disability” (requiring wheelchair and dependent on others for activities of daily living), or “death.”

Illustrative cases. Case 1. A 38-year old Caucasian
woman initially presented with attacks of myoclonus and
memory impairment and diverse systemic features of SLE
such as Raynaud, arthralgia, dyspnea, chest pain, photosensitivity, alopecia, and proteinuria. Renal biopsy confirmed
lupus nephritis, supported by neutropenia, lymphopenia,
positive antinuclear antibodies (ANA) (1/320), persistently
elevated anti-DNA titers, and low complement level. She
later had visual difficulties and hallucinations, headaches,
fatigue, with evidence of a hemiparesis, dysarthria, ataxia,
paranoid delusions, and disinhibition. MRI of brain and
spine were normal. EEG and CSF analysis was unremarkable, and CSF oligoclonal bands were absent. She received
various immunosuppressant drugs including pulsed methylprednisolone, oral prednisolone, hydroxychloroquine, and
azathioprine with relatively little response. A beneficial response was only eventually seen with mycophenolate treatment, which appeared to improve renal function and
systemic disease more than CNS features. She had moderate
disability over 3 years later with occasional myoclonus (at no
stage was there evidence of renal failure sufficient to cause
myoclonus).
Case 2. A 74-year old Caucasian woman presented with
a 1-month history of left facial weakness and a 1-week history of a painful red left eye with diplopia, ptosis, limb
tremor, and bradykinesia. When seen, the ocular pain had
settled, but not the diplopia and ptosis. Examination re646

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vealed an alert, normotensive individual, with a resolving
left lower motor neuron facial weakness and a partial left
third nerve palsy. She had a classic parkinsonian rest tremor
of the right hand with cogwheel rigidity at the right wrist
with impaired arm swing on walking. Brain CT was normal.
Routine blood tests were normal. Erythrocyte sedimentation
rate (ESR) was raised at 64 mm/h and C-reactive protein
(CRP) level was ⬍6 g/L. Rheumatoid factor was negative,
but ANA was high at 1 in 5,120, anti-DNA antibodies elevated at 371 (normal ⬍75), with low serum complement levels: C3 0.53 g/L (0.75 to 1.65), C4 0.13 g/L (0.14 to 0.54).
Three weeks later her partial third nerve lesion had completely resolved spontaneously, but her rest tremor persisted.
She had “slightly sore” metacarpophalangeal joints, but
there were no other clinical systemic features. Her parkinsonism deteriorated significantly with progressive hypokinesia; both bromocriptine and later levodopa proved
ineffectual and were discontinued. Over the next 3 months,
she developed a papular urticarial rash over the abdomen
and upper legs, with progressive cognitive decline and
marked episodic confusion (in the absence of any psychotropic medication), and was admitted for further investigation. The skin lesions were considered compatible with
vasculitis. Brain MRI showed nonspecific changes and a few
probably ischemic lesions in the brainstem. In view of her
dementing illness (abbreviated Mini-Mental Test [MMT]
3/10) and evidence of active lupus, she was started on prednisolone 40 mg and hydroxychloroquine 200 mg b.d. At discharge 1 month later her abbreviated MMT was 8/10, and
her parkinsonism was strikingly improved. A further month
on, she had only a slight left hand tremor and mild cogwheel
rigidity. She experienced an extensive left leg deep vein
thrombosis a few days after discharge and was anticoagulated with warfarin as lifelong therapy. Hydroxychloroquine
was discontinued uneventfully at 18 months. At 3 years’
follow-up on alternate-day 10 mg of oral prednisolone, with
warfarin and dothiepin, she was independent with good cognitive function and little if no evidence of parkinsonism.
Case 3. A 13-year-old girl was diagnosed as having definite SLE on clinical and serologic grounds, with fever,
lymphadenopathy, photosensitivity, a malar rash, and proteinuria. She had neutropenia, and serologically was ANF
positive and anti-DNA positive; antiphospholipid antibody
(APA) titer was within normal limits, and lupus anticoagulant assay was negative/normal; complement levels also were
normal. After 6 years of systemic disease, she experienced a
generalized seizure; subsequently she developed an abrupt
onset of left hemiparesis, accompanied by headaches and
progressive impairment of consciousness. Brain CT showed
a right hemisphere infarct; her CSF was not examined. Despite treatment with high-dose steroids, her deterioration
continued and she died. At postmortem examination, she
was found to have SLE-associated cerebral vasculitis
(figure 1).
RESULTS Forty-one patients satisfied the criteria
for CNS-SLE: 38 women and 3 men. The remaining records were not included as they either had
no genuine evidence of CNS-SLE or were perceived to be consequences of secondary factors associated with systemic lupus or its treatment. All
were Caucasian apart from one African Caribbean woman. Patients’ case notes included details

Figure 2

Comparison of neurologic features occurring early in the course of the disease with frequency at any
time in the course of the illness

over a total of 4,534 months, with a mean of 111
months (9.2 years) per patient (range 2 to 474
months). Mean age at first neuropsychiatric presentation was 41 years (range 13 to 74 years) and
the mean latency of CNS-SLE from initial systemic involvement was 5.75 years (range 0 to 37).

Major non-CNS features. The most commonly re-

ported systemic features were skin and mucosal
involvement (malar, vasculitic, discoid or nonspecific rash, photosensitivity, livedo reticularis, alopecia, and oral ulceration) seen in 87% of
patients, joint involvement with arthralgia and
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647

Figure 3

Systemic lupus erythematosus–
associated vasculitis

Leptomeningeal vessel of a 13-year-old child with a CNS autopsy diagnosis of florid vasculitis associated with systemic
lupus erythematosus, leading to a temporoparietal infarction. Widespread evidence of vasculitis was present in the
brain in the absence of vasculitis elsewhere, confirming isolated cerebral vasculitis. Acute inflammatory infiltrate is
present in the leptomeninges associated with cocci, which
were isolated from blood culture. The lesions in the vessel
walls appear to vary from older lesions in which the vessel
wall is virtually necrotic to more recent lesions in which the
acute inflammatory infiltrate is just present. (Photograph
courtesy of Dr. G. Alistair Lammie, Consultant Neuropathologist, University Hospital of Wales, Cardiff, UK).

arthropathy (56%), pulmonary involvement
(24%), renal disease (20%), hypertension (20%),
deep vein thrombosis (17%), Raynaud phenomena (15%), fever (15%), chest pain (12%), anorexia (10%), lymphadenopathy (10%), and
myalgia (7%). Less frequently noted were night
sweats (5%), pre-eclamptic toxemia (2%), pulmonary embolism (2%), avascular necrosis of the
hip (2%), retinal vasculitis (2%), central scotoma
(2%), and scleritis (2%).
Skin, joint, and renal involvement were most
frequently observed features that preceded CNS
complications (figure 2). Their frequency did not
differ substantively from their overall frequency
during the course of the disease.
Major clinical neurologic, ocular, and psychiatric
features. A plethora of CNS manifestations were

recorded, but the most commonly reported features were headaches (54%), seizures (42%), visual failure (32%), fatigue (27%), hemiparesis
(24%), memory impairment (24%), confusion
(24%), personality change (20%), and depression
(18%).
A similar pattern of frequency was seen for
first neurologic event; a comparison of initial and
all CNS features encountered is illustrated in figure 3. However, one exception to this was visual
failure, which was significantly more common as
648

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August 14, 2007

a later rather than early feature of the disease (77
vs 23%) and more likely to be bilateral in late
disease (80 vs 20%). Optic neuritis occurred in 3
of 41 cases (7.3%), retinopathy with cotton wool
exudates and hemorrhages was observed in 1 of
41 (2.4%), unexplained vitreous hemorrhage was
seen in 1 of 41 (2.4%), and scleritis during a flare
of SLE in 1 of 41 (2.4%). Uveitis was not reported
in our series.
Arterial strokes featured in 17% (seven patients), with a mean age at onset of 36.7 years
(range 26 to 50 years). The majority presented
with persistent hemimotor and sensory phenomena, dysphasia, or dysarthria, with good clinical–
radiologic correlation. Cerebral hemorrhage was
noted in two patients and a subarachnoid hemorrhage in another. No case of venous sinus thrombosis was identified (though MR venography was
not performed on all patients). There were no
other relevant risk factors (hypertension, diabetes
mellitus, hypercholesterolemia, or smoking history) in any but one patient who had a preexisting treated hypertension. Four of seven had
transthoracic echocardiography: None showed
any source of emboli. IgG APA was elevated in
two of seven (29%), and one of these was diagnosed as having a secondary antiphospholipid
syndrome.
Two patients had spinal cord involvement in
this study with MRI spinal changes. Prior systemic features preceded both cases of myelopathy
in this current series.
CNS manifestations as presenting feature of SLE.

CNS manifestations as the initial presenting feature of SLE occurred in 10 patients (24%). The
ACR criteria for SLE require that at least four
characteristic features occur at any time during
the disease course, not necessarily simultaneously. Although these criteria were not fulfilled
at this early stage, the later emergence of more
typical features of the disease confirmed the diagnosis in each case. Various manifestations were
observed, but movement disorders (four cases),
seizures (four cases), or meningism (two cases)
featured. Of the four with movement disorders,
one had hemichorea, one had myoclonus, and
two had parkinsonism (e.g., see Cases 1 and 2).
There was very strong evidence for parkinsonism
and cognitive impairment being directly related to
SLE in one case with supportive typical clinical
and investigation findings and a dramatic improvement in the movement disorder and mental
state of this patient with immunosuppression
(Case 2).

Investigation findings. Blood tests and serology. One

patient was pancytopenic, four thrombocytopenic, 3 neutropenic, and 5 lymphopenic. The ESR
or plasma viscosity was elevated in 17 of 34 patients (50%). The CRP was elevated in 3 of 34
(9%). ANA level results were available in 34 patients at the time of a neuropsychiatric episode,
and 29 (85%) were significantly elevated. AntiDNA antibody results were documented in 29
cases at the time of illness, and 21 (72%) were
positive. There was no association between the
above blood test results and clinical outcome.
Serum complement results were available in 26
patients, and 11 (42%) showed abnormally low
C3 and/or C4 levels, but 17 (66%) of complement
levels were normal during a typical neurologic
disease flare-up. Of patients with a relatively
good outcome (asymptomatic or minor disability), 4 of 12 (33%) of subjects tested had low serum complement levels, whereas in those with
adverse outcomes, 7 of 14 (50%) showed hypocomplementemia (p value 0.22 by Fisher exact
test).
Thirteen of 29 (45%) were APA positive; just
one of these patients was thought to have secondary APA syndrome, with lupus anticoagulant activity. Thirty-three percent of patients with
asymptomatic or minor final outcomes were APA
positive compared with 55% in the other outcome groups (p value 0.18 by Fisher exact test).
Of nine stroke patients, two had elevated IgG
APA. Five of 29 (17%) were lupus anticoagulant
positive, with only 1 patient being lupus anticoagulant positive and APA negative.
Spinal fluid examination. CSF analysis was performed in 23 cases with abnormal results in 39%.
There was an elevation in CSF protein in five
(22%) with a range of 0.67 to 2.43 g/L. A lymphocytic pleocytosis was seen in five (22%) patients
(range of 8 to 95 lymphocytes/mm3) and was associated with a raised CSF protein in three cases.
Oligoclonal bands were present in 4 of 18 (22%)
and were associated with other CSF abnormalities in 2 of these.
Of patients with normal CSF, 77% had eventual minor disability, and 23% with moderate, severe disability or death. The converse was true of
abnormal CSF (p ⫽ 0.01, Fisher exact test).
Radiology. CT brain scans results were available for 25 patients. Sixteen were normal,
whereas nine (36%) showed abnormalities: Three
had patchy low attenuation areas, two had intracranial hemorrhage, and four demonstrated infarcts (two within the basal ganglia and two
cortical).

MRI brain scans were performed on 31 patients. Eleven (36%) were normal. Of the remainder, 10 showed nonspecific white matter lesions, 3
had periventricular white matter changes, 2
showed subcortical lesions, 2 had evidence of intracranial hemorrhage, 1 had infarcts in the basal
ganglia and parietal cortex, 1 showed leptomeningeal enhancement, and 1 MRI supported clinical evidence of optic neuritis. Of the patients with
normal scans, 64% (7/11) had diffuse CNS features such as headaches, meningism, memory impairment, confusion, and seizures, and the
remaining 36% had focal events such as monoparesis, hemiparesis, and hemisensory symptoms in
the absence of MRI brain lesions. Of those with
abnormal MR scans, 14 of 20 (70%) had focal
clinical features and 6 of 20 (30%) diffuse phenomena (p ⫽ 0.06, Fisher exact test).
Four patients had spinal MRI: Two were normal, and the others showed areas of increased signal in the cervical spine (both C5 to C6)
suggesting cervical inflammation.
One patient had normal digital subtraction angiography (and a normal CT and brain MRI).
One other patient, with evidence of unilateral infarcts in the basal ganglia and the parietal cortex,
had “spasm of the circle of Willis” reported from
MR angiography of the brain.
EEG. EEG was abnormal in 11 of 14 (79%) patients tested, showing nonspecific generalized
slowing. A “liability to seizures” was also reported in three of these.
Treatment and outcome. The final outcome at the
end of the follow-up study period was recorded.
Five patients (12%) were asymptomatic, 17 (42%)
had minor disability, 12 (32%) moderate disability, 2 (5%) severe disability, and 5 (12%) had
died. Nine (22%) of patients only had one neuropsychiatric attack, 14 (34%) had a further episode, 11 (27%) had three separate episodes, 6
(15%) had four separate attacks, and 1 patient
had seven episodes of neuropsychiatric manifestations. There was no apparent relationship between the number of clinical neuropsychiatric
relapses and the final outcome.
Thirty-six received steroid therapy either as
methylprednisolone pulses and oral prednisolone.
Of these, four were given steroids alone, but the
remainder were given combination therapy with
antiplatelet agents or warfarin only (2 patients) or
with more potent immunosuppressants (35 patients). Cyclophosphamide was used in nine patients, all of whom had been severely affected:
Following treatment, four had eventual minor
disability and four were left severely disabled.
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649

One of these died. Ten patients received azathioprine; two of these emerged asymptomatic, five
were deemed to have minor disability, two had
moderate disability, and one died. Cyclophosphamide and azathioprine were used in succession in
four cases. Hydroxychloroquine was used in 12
patients: One was left asymptomatic, seven had
only minor disability, three moderate disability,
and one had died. Plasmapheresis was used in two
patients, one of whom had moderate disability
outcome and one eventual death. Hydroxychloroquine was given in conjunction with azathioprine in five patients and with cyclophosphamide
in two patients. IV immunoglobulin therapy was
given to two patients. Other treatments tried were
cyclosporin in one patient and mycophenolate in
another.
One patient received no treatment at all and
made a full recovery after a monophasic illness
with headache, an episode of transient loss of
consciousness, and a probable partial seizure. Six
patients in this series were anticoagulated with
warfarin, and this was the sole treatment in one
patient following a stroke. Two patients were
given symptomatic treatment with antiepileptic
drugs only (one had an asymptomatic outcome
and the other died as a result of an intracerebral
hemorrhage). One was given a combination of antiplatelet and antiepileptic drugs and had severe neurologic disability following her severe illness with
marked headaches, visual failure, ataxia, paraparesis, and seizures. Two patients were given antiparkinsonian medication in conjunction with steroids
and various immunosuppressants.
Histopathology. Of five deaths, two were autopsied. One 23-year-old woman had extensive bilateral hemorrhagic infarction involving the caudate
nucleus and putamen, along with typical microscopic features of the disease. The second autopsy
was that of a 13-year-old girl with definite clinical
and serologic evidence of SLE. After careful examination by two experienced neuropathologists,
she received a postmortem diagnosis of “cerebral
vasculitis associated with SLE.” Although true
CNS vasculitis in SLE is regarded as being rare,
she was found to have widespread vasculitis of
the brain and leptomeninges (in the absence of
vasculitis elsewhere), with a clinically eloquent
infarction in the right cerebral hemisphere probably caused by occlusion from necrosis and acute
inflammatory infiltrate of small vessels associated
with the vasculitic process (figure 1).
DISCUSSION In summary, we have identified

features that may aid the recognition and diagno650

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sis of this difficult illness. Primary neurologic presentation of SLE was commoner than anticipated
(10/41 patients) and included both seizures (4
cases) and an unexpected emergence of movement disorders such as parkinsonism and myoclonus (4 cases).
Seizures are already known to occur in 14 to
25% of lupus patients compared with 0.5 to 1%
in the general population.13 They are usually primary generalized, but partial episodes also occur.
Our study suggested a higher overall frequency:
42% (usually with other CNS and systemic features). They were an early manifestation in 27%,
and in 10% were the first SLE symptom. Seizures
as an early CNS manifestation are also well described (often erroneously diagnosed as isolated
epilepsy14), with reported frequencies of 8 to
27%,8,15-18 more frequent in children (9.4 to 51%,
mean ⫽ 35%).19-26
The higher figures in our study must be viewed
cautiously: it is not community based and clearly
prone to neurologic case-ascertainment bias. But,
arguably, other surveys set in rheumatology departments might easily have missed some neurologic cases. The real frequency of the various
neurologic features we found to be commoner
than other studies, if exaggerated in our study,
might nonetheless be higher than currently
considered.
Movement disorders were not included in the
ACR criteria. Chorea has been regarded as a
“hallmark feature” of SLE, though, in fact, is uncommon, seen in under 4% of patients.8,15,27,28 We
noted only one case (2.4%), as the presenting
manifestation of SLE, responding to corticosteroids. There are few reports of myoclonus in SLE,
none as a presenting feature.29-31
Parkinsonism (Case 2) is very rare in SLE, not
even mentioned in the major series.8,9,15,16,20 We
found 26 cases reported in 16 publications from
1930.32-47 Rest tremor is reported as a first manifestation of SLE,48,49 but SLE presenting with
overt parkinsonism has only been documented
once before, in a 24-year-old man who also had a
hemiplegia and thrombocytopenia, with T2 MRI
hyperintensities in the brainstem, occipital and
parietal lobes, thalamus, and internal capsule; he
showed almost complete recovery after steroids.39
Other reported cases followed SLE diagnosis by
months or years. Presentation at the age of 74
(our Case 2) is most unusual. Other cases were 9
to 57 years (mean 23 years), parkinsonism thus
having been considered a juvenile SLE manifestation, often associated with severe multisystem
CNS involvement. A previous case series of CNS-

SLE in the elderly50 revealed subacute confusional
state, dementia, and depression associated with
the disease and, as with our study, suggested that
SLE is more common in this group than originally
thought and is treatment responsive.
Our Case 2 was elderly, but her very clear
parksinonian features failed to respond to dopaminergic agents. Although only CNS histology
could prove whether this was coincidence of idiopathic Parkinson disease (or multisystem atrophy,
etc.) and CNS lupus, the dramatic sustained
improvement in both cognitive function and
parkinsonism following prednisolone and hydroxychloroquine strongly suggested that CNS
lupus was indeed responsible and that one neurologic condition, not two, was present. Partial or
complete recovery was seen in nearly all other reported cases, commonly after immune therapy.
The mechanisms underlying parkinsonism in SLE
are unknown; both direct immune-mediated effects and indirect consequences such as vasculopathy and coagulopathy are the likely principal
mechanisms of CNS lupus, and immunologically
both B- and T-cell-related mechanisms are
implicated.51-53 A strong case for antibodies crossreacting with neuronal antigens has emerged.41,52
Of other features, 54% of our patients had
headaches and 27% migraine. Only 7 of 14 (50%)
of our APA-positive individuals had significant
headache, consistent with the reported absence of
any direct link between migraines and APA.54 Arterial strokes featured in 17% of patients, similar
to other studies.8,16,20,55 The important and wellvalidated observation that cognitive dysfunction
in SLE is commonly reversible56 is also supported:
All our cases improved either before or following
steroid treatment (also supporting reports that
true “lupus psychosis” exists and is not simply a
steroid-induced phenomenon).57 Two patients
(5%) had an aseptic meningitis, confirming its
documented relative rarity,17,55 but in both, isolated meningism was the presenting feature of
SLE.
Myelopathy, seen in just two of our cases, is an
infrequent though serious manifestation.8,16,17,20,58
Cranial nerve involvement is also relatively uncommon and usually transient.59,60
Visual disturbance, the third commonest
symptom in our study, is known to be frequent in
SLE and to involve any ocular structure.61,62 Visual difficulties were significantly more likely to
be bilateral (80%) and to occur late in the disease
course (77%). Migraine may account for reversible visual phenomena (probably five cases).
There was clinical evidence of optic neuritis in 3

of 41 of our cases (7.3%), comparable with other
studies.63 Retinopathy has been more frequently
observed with cotton wool exudates (indicative of
local retinal ischemia) and hemorrhages (one
patient).
The classic finding of a low CRP but elevated
ESR or plasma viscosity was seen in 44% of patients. Importantly (as other studies have shown),
anti-DNA antibody testing is positive in only
about 70% of CNS episodes. There was one positive anti-P result in a patient with depression,
confusion, and headaches, but this test was not
routinely offered by most units in our study. APA
were present in 45% of those tested, consistent
with the 16 to 60% reported.64-66 Two of nine
stroke patients in this study had elevated APA,
both IgG.
CSF abnormalities were seen in 39% of our patients, comparable with other studies. The frequency of CSF oligoclonal bands has varied
between reports,7,67,68 our results supporting a
lower figure of 22%.
Thirty-six percent of CT brain scans were abnormal, and 65% of MR scans, but CT remains
valuable in identifying hemorrhages and larger infarcts. Perisulcal cortical atrophy is reported as a
frequent finding on CT,69 but was not seen in our
study. MRI features were often nonspecific,
though often differed with the clinical pattern of
CNS disease: Abnormal scans were associated
with focal neurologic deficits, normal scans with
more diffuse phenomena such as headaches, meningism, memory impairment, confusion, and generalized seizures. Clinical–radiologic correlates
are not always obvious; MRI lesions may resolve
completely within days in keeping with clinical
improvement or persist despite clear remission.
Seventy-nine percent had a diffusely abnormal
EEG. The reported selective left temporolimbic
region changes70 were not observed in our study.
EEG may be useful in confirming the organic nature of the illness and in distinguishing steroidinduced from primary lupus psychosis.
We have avoided the term “lupoid sclerosis,”71
which may imply mechanistic similarities between SLE and multiple sclerosis. Although
neuro-SLE may mimic multiple sclerosis clinically, pathologic studies clearly show them to be
very distinct disorders.72,73 We found no cases
where there had been any such diagnostic
ambiguity.
Two previous studies suggested that articular
disease may be “protective” and associated with a
reduced chance of CNS involvement,74,75 but our
study demonstrated the opposite—37% of indiNeurology 69

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651

viduals with CNS lupus had prior joint involvement—as have others.35 Although ANA and
anti-DNA results did not appear to have any
bearing on disease outcome or CNS relapse rate,
an abnormal CSF was associated with a poor
prognosis.
ACKNOWLEDGMENT
The authors are grateful for the enthusiastic support and cooperation
of their colleagues in neurology and rheumatology departments
throughout the southwest of England and south Wales and in Oxford
and Edinburgh.

14.

15.

16.

17.

Received January 1, 2007. Accepted in final form March 12,
2007.
18.
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