Original Article

Neurologic Symptoms in Children

With Systemic Lupus Erythematosus
Ana I. Quintero-Del-Rio, MD, Van Miller, MD

ABSTRACT

Neurologic complications of systemic lupus cerebritis are not as well known in children as in adults. Twenty-five children
with neurologic complications were identified after reviewing the hospital medical records of 86 children with systemic
lupus erythematosus. Seven children (28%) had neurologic symptoms at the time of initial diagnosis of systemic lupus ery-
thematosus ; median time between diagnosis of systemic lupus erythematosus and onset of neurologic complications was
1 month (range 0-5 years). Seizures were the most common neurologic symptoms overall, but headaches were the most
frequent neurologic manifestation in children without a previous diagnosis of systemic lupus erythematosus. Sixteen chil-
dren had seizures, and 12 children had seizures as the initial central nervous system involvement. Almost all children who
developed seizures had an established diagnosis of systemic lupus erythematosus; only one child had seizures that led to
the diagnosis of systemic lupus erythematosus. No patient had status epilepticus, and, in general, seizures were not diffi-
cult to control. In six children, headache was the initial symptom of central nervous system involvement. Five children
had lupus cerebritis, three children had stroke, and two had isolated cranial neuropathies. Chorea was seen in only two
cases, and three children had pseudotumor cerebri. Treatment with high-dose intravenous methylprednisolone led to a
good response in 18 children; cyclophosphamide was required in 6 patients and plasmapheresis in 1 child. Outcome was
generally good, although one child developed fulminant cerebritis with intracranial hypertension and died. (J Child Neurol
2000;15:803-807).

Systemic lupus erythematosus is an autoimmune disease of not as well known and may show clinically important dif-

unknown etiology characterized by multisystemic involve-
ment and the presence of autoantibodies. Central nervous
system complications occur in 9% to 45% of adult and pedi-
atric systemic lupus erythematosus patientsl-3 and include
seizures, cranial nerve palsies, psychosis, altered mental sta-
ferences. Therefore, we reviewed the incidence, course,
response to treatment, and prognosis of the neurologic
involvement of our pediatric patients with systemic lupus
erythematosus and briefly describe the atypical clinical
course of two children.

tus, coma, headaches, neuropathies, chorea, transient

ischemic attacks, sinus thrombosis, and encephalopathy. 2-8
The clinical spectrum of central nervous system pathology
in systemic lupus erythematosus has been described pri-
marily in adults; the incidence and severity of neurologic
sequelae of systemic lupus erythematosus in children is
Received Oct 28, 1999. Received revised Mar 24, 2000. Accepted for
cation Mar 27, 2000.
From the Departments of Pediatrics, Division of Rheumatology (Dr Quintero-
Del-Rio), and Neurology (Dr Miller), The University of Texas Southwestern
Medical Center at Dallas, Dallas, TX.
Address correspondence to Dr Ana I. Quintero-Del-Rio, Oklahoma Medical
Research Foundation, 825 N.E. 13 Street, M.S. #24, Oklahoma City, OK
73104. Tel: 405-271-7921; fax: 405-271-4110; e-mail: Ana-Quintero@ouhsc.edu.
METHODS
Twenty-five children with neurologic complications were identified
after reviewing the hospital medical records of 86 children admit-
ted to Children’s Medical Center of Dallas between December
1979 and December 1996 for evaluation and treatment of systemic
lupus erythematosus. All patients met at least four of the 1982 cri-
teria of the American Rheumatism Association for the classifica-
publi-
tion of systemic lupus erythematosus (Table 1).9 Summary
demographic features of the children are presented in Table 2. As
expected, there was a strong female predominance: only three
boys with systemic lupus erythematosus were identified. The mean
age of the patients at the time of systemic lupus erythematosus diag-
nosis was 12 years (range 5-16 years).

803

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804
Table 1: Summary of the Revised Criteria for
the Diagnosis of Systemic Lupus Erythematosus
The patient must have 4 of the 11 criteria, serially or simultaneously, to
diagnosed with systemic lupus erythematosus.
RESULTS
Neurologic Symptoms
Seven children (28%) had neurologic symptoms at the time
of initial diagnosis of systemic lupus erythematosus; the
median time between the diagnosis of systemic lupus ery-
thematosus and the onset of neurologic complications was
1 month (range 0-5 years). Seizures were the most common
neurologic symptom overall, but headaches were the most
common neurologic manifestation in children without a
previous diagnosis of systemic lupus erythematosus. Most
of our children had multiple neurologic complications (60%);
in one child, episodes were separated by as much as 6 years.
Table 2. Demographic Summary of Children With Systemic Lupus Erythematosus
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Sixteen of our children had seizures, and 12 of these chil-
dren had seizures as the initial central nervous system
involvement. No consistent pattern of neurologic symp-
toms was seen prior to seizure onset. In four children, com-
plaints of transient dizziness, muscle weakness, or Bell’s
palsy preceded seizures by several months, and in one child,
seizures were preceded by headaches of a few days’ dura-
tion. Almost all children who developed seizures had an
established diagnosis of systemic lupus erythematosus;
only one child had seizures that led to the diagnosis of sys-
temic lupus erythematosus. Most children had focal or gen-
be
eralized tonic-clonic seizures, although one child presented
with Jacksonian (progressive partial motor) seizures. No
patient had status epilepticus.
Electroencephalography (EEG) was performed in 18
children and was abnormal in 12 children. Diffuse slow-wave
activity was the most common abnormal pattern, although
focal abnormalities (epileptiform discharges and focal slow-
ing) were present in two children. Only 3 of the 14 children
with seizures had normal EEGs. Anticonvulsant therapy
was required in 11 children for seizures, and the medications
used were phenytoin, phenobarbital, clonazepam, valproic
acid, and ethosuximide. No anticonvulsant medication
appeared superior to the others, and, in general, seizures
were not difficult to control. The one patient whose seizures
were difficult to control was the only child in our series who
died from lupus cerebritis. Therefore, increasingly difficult

seizure control may suggest the presence of an aggressive
cerebritis, and such patients should be monitored carefully
for signs of increased intracranial pressure.
Headaches were the second most frequent neurologic
manifestation of systemic lupus erythematosus in our chil-
dren. In six children, headache was the initial symptom of
central nervous system involvement. Headaches were char-
acterized as migraine or migraine variants in most children,
but three children developed pseudotumor cerebri, as evi-
denced by papilledema and elevated lumbar cerebrospinal
fluid pressure. Interestingly, two patients had persistent
headaches for 3 (patient 20) and 7 months (patient 13) prior
to the onset of chorea. Patient 20 progressed to pseudotumor
cerebri and bilateral cerebral sinus thrombosis. Another
child (patient 12) developed a transient IIIrd cranial nerve
paralysis 3 months after headaches began; 6 years later,
she developed pseudotumor cerebri. One child (patient 21)
developed pseudotumor cerebri 3 months after headaches
began.
Lupus cerebritis was suspected in five children because
of acutely altered mental status. One child (patient 16) with
cerebritis progressed to coma secondary to increased
intracranial pressure over several days but responded to
high-dose intravenous steroid therapy. In two other children,
lupus cerebritis was heralded by new-onset seizures, and one
patient experienced acute transient psychosis as the pre-
senting symptom of lupus cerebritis. The fifth child presented
with auditory and visual hallucinations, confusion, and
decreased school performance that were attributed to lupus
cerebritis, although this was not confirmed by neuroimag-
ing. Surprisingly, two of the children with cerebritis did not
have a prior diagnosis of systemic lupus erythematosus.
Cerebral infarction occurred in three children, presumably
due to cerebral vasculitis. In two patients with stroke
(patients 8 and 9), cerebral infarctions were preceded by
seizures and in one child (patient 14) by headaches for sev-
eral days.
There was no apparent relationship between
logic complication and type or severity of involvement
other organ systems (see Table 1).
Laboratory and Studies
Serum antinuclear antibodies were increased in 24 of 25
(96%) patients and anti-double-stranded DNA levels were ele-
vated in 22 of 25 (88%) patients at the time of central ner-
vous system symptoms. Serum complement levels (C3, C4,
and CH50) were normal in 16 of 25 (64%) children. Lupus
anticoagulant was screened for in the serum of eight patients;
only two children were positive. Twenty children had a nor-
mal peripheral white blood cell count (5-10 cells/mm3) but
had increased erythrocyte sedimentation rate (above 20
MMmt) at the time of the central nervous system symptoms.
Eleven children had lumbar punctures for cerebrospinal
fluid analysis as part of their evaluation. Bacterial and viral
spinal fluid cultures were normal in all patients. Cere-
brospinal fluid protein levels were mildly increased in three
children. The cerebrospinal fluid leukocyte count was ele-
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805
vated (10-19 cells/mm3) in only two patients; both of these
patients had headaches as their initial central nervous sys-
tem symptom, which in one child were due to cerebral
sinus thrombosis. The cerebrospinal fluid leukocytosis was
unexplained in the second child, but this was one of only
two of our patients who eventually developed chorea.
Cranial imaging studies were obtained in 18 patients
with central nervous system symptoms. Cerebral computed
tomography (CT) imaging was abnormal in 6 of the 12
patients imaged with this modality. Five of these patients had
seizures as their initial or secondary central nervous system
manifestation, and the other patient had sinus thrombosis
as her central nervous system complication. Cranial mag-
netic resonance imaging (MRI) was performed in 15 patients,
and it was abnormal in 12 children. Radiographic findings
included diffuse cerebral atrophy, ventricular enlargement,
intracranial hemorrhage secondary to cerebral sinus throm-
bosis, diffuse cerebral edema secondary to cerebritis, and
both focal and multifocal ischemic changes.
Therapy and Course
In general, patients were managed in the hospital on the
our
general pediatric floor; five patients required intensive care
for a short period (range 1-8 days). Fifteen patients were
on oral corticosteroid therapy for systemic complications
of systemic lupus erythematosus at the onset of their neu-
rologic manifestations, and although this was clearly insuf-
ficient to prevent central nervous system involvement, there
was a suggestion that oral steroids were partially protective.
The 10 children not on corticosteroid treatment at the time
of central nervous system symptoms onset tended to pre-
sent with more severe central nervous system involvement,
including stroke in three children, seizures in three children,
psychosis in two children, and lupus cerebritis and parkin-
sonism in one patient each.
High-dose immunosuppressive pharmacotherapy was
administered to all of our children with systemic lupus
neuro- erythematosus with central nervous system involvement.
of Eighteen children received an intravenous methylpred-
nisolone pulse (30 mg/kg/dose) every 24 hours for 3 days
during the acute central nervous system episode. Twelve
of these children (75%) responded well to the steroid puls-
ing and had prompt resolution of the central nervous sys-
tem symptoms. The other six children required
cyclophosphamide therapy, in three cases because of an
incomplete response of the neurologic symptoms to the
intravenous steroid pulse and in three children because of
other organ involvement, most often renal insufficiency.
Only one child (patient 12) was treated with plasmapheresis,
which led to a rapid improvement.
CASES
Case 1
A 14-year-old African-American girl (patient 7) developed tonic-
clonic seizures as her first central nervous system manifestation
of systemic lupus erythematosus. Initially, her seizures responded
806
well to intravenous steroids and phenytoin, but 1 month later, she
developed visual and auditory hallucinations and difficulty walk-
ing. On neurologic evaluation, she was ataxic and confused, with
slurred speech. She could answer only simple questions, was
unable to do two-step commands, and could recall only one of three
objects after 5 minutes. Mild proximal muscle weakness was pres-
ent, and she had a subtle left hemiparesis. Her gait was broad-based
and she could not tandem walk. Cranial CT showed cerebral atro-
phy, and MRI revealed a recent infarction in the right temporal lobe.
Electroencephalography showed only generalized slowing in the
awake state without epileptiform discharges. Laboratory evalua-
tion revealed elevated serum antinuclear antibodies (ANAs) 1:2560,
erythrocyte sedimentation rate 121 mm/hr, and negative anti-dou-
ble-stranded DNA. Her first cerebrospinal fluid protein was sig-
nificantly elevated (200 mg/dL), the highest value seen in our
series.
She was treated withhigh-dose intravenous methylpred-
nisolone for 3 days, and oral prednisone was begun after the
methylprednisolone pulse. Her mental status improved to normal,
but 1 month later, the hallucinations and ataxia worsened, and she
developed bradykinesia and rigidity, consistent with parkinsonism.
Intravenous methylprednisolone pulses at this time were ineffec-
tive, but there was an immediate response to plasmapheresis
administered daily for 4 days. Her improvement continued over sev-
eral months after discontinuation of plasmapheresis.
Case 2
A 13-year-old Hispanic female (patient 22) was diagnosed with
systemic lupus erythematosus 2 years prior to the development of
myoclonic and complex partial seizures. Cranial MRI showed an
arachnoid cyst in the right middle fossa. The lumbar puncture
revealed normal cerebrospinal protein and cell counts. Elec-
troencephalography showed generalized slowing and frequent
multifocal spikes, greater in the left than in the right hemisphere,
suggesting diffuse cortical dysfunction consistent with lupus
cerebritis. Laboratory evaluation revealed a serum ANA 1:2560,
rheumatoid factor 1:40, and erythrocyte sedimentation rate
61 mm/hr. Her cerebrospinal fluid showed normal protein value and
cell counts.
Carbamazepine, clonazepam, and valproic acid were begun
sequentially for seizure control, and oral prednisone was alternated
with high-dose intravenous methylprednisolone pulses. However,
despite multiple anticonvulsant medications and maximal steroid
therapy, her seizures worsened, and 10 days after the seizures
began, she developed hallucinations and violent behavior. Later that
day, her mental status worsened, she lost corneal reflexes, and her
pupils became fixed and dilated, consistent with central herniation
secondary to severe cerebral edema. She developed cardiac
arrhythmia that progressed quickly to ventricular tachychardia
and full cardiac arrest; resuscitation efforts were unsuccessful.
Autopsy was refused.
DISCUSSION
Neurologic symptoms in children with systemic lupus ery-
thematosus appear to be common: 29% of our patients had
significant neurologic manifestations secondary to systemic
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lupus erythematosus. Less than one third of our patients had
central nervous system symptoms at the time of diagnosis
of their systemic lupus erythematosus. Other reports showed
a 32% to 70% of central nervous system involvement at the
time of systemic lupus erythematosus diagnosis. 1,10
Previous studies have found that seizures and psy-
chotic disorders are the most common manifestations of cen-
tral nervous system lUpUS.1O-14 In our series, seizures were
the most common initial central nervous system manifes-
tation, followed by headaches. Seizures may occur simul-
taneously with the diagnosis of systemic lupus
erythematosus or during an exacerbation of the disease. In
addition, seizures often occur as an isolated episode, but
recurrent seizures may develop. 15 The majority of our chil-
dren presented with generalized tonic-clonic seizures, but
Jacksonian, psychomotor, and absence seizures have been
reported. 3,15-17 Fortunately, the seizures in our children were
not difficult to manage, and we had no cases of status
epilepticus. The occurrence of seizures did not seem to
portend a poor prognosis.
Headaches were the single condition most commonly
associated with other central nervous system complica-
tions in our children, and it was the neurologic symptom
most likely to lead to the diagnosis of systemic lupus ery-
thematosus in children previously undiagnosed. Headaches
in patients with systemic lupus erythematosus tend to be of
vascular origin (migraine or migraine variant) or tension
type. 18 In most patients with systemic lupus erythematosus,
headaches are benign, but they occasionally occur sec-
ondary to renal disease, hypertension, or steroid therapy.is
The possibility of cerebritis or cerebral venous thrombosis
should also be considered in a child with systemic lupus ery-
thematosus and new-onset headaches.
Chorea developed after persistent headaches in two chil-
dren. These choreiform movements are more frequent
among girls and can begin before or after the diagnosis of
systemic lupus erythematosus.~ ~ This movement disor-
der tends to be bilateral and has been associated with
stroke,16 although none of our children had chorea due to
stroke. One child with chorea progressed to pseudotumor
cerebri and bilateral sinus thrombosis. Pseudotumor cere-
bri can occur as the initial manifestation of systemic lupus
erythematosus,2 with increased intracranial pressure and
papilledema without focal neurologic signs. Pseudotumor
cerebri may result from sinus thrombosis, as in one of our
patients.l7 Cranial neuropathy was not a common finding in
our series. Only two of our children had a cranial neuropa-
thy attributable to systemic lupus erythematosus; one patient
each had a HIrd nerve and VHth nerve palsy. As in myasthenia
gravis, extraocular muscles appear to be especially sensi-
tive to circulating serum antibodies in systemic lupus ery-
thematosus. Unlike myasthenia, pupillomotor abnormalities
occur with some frequency in patients with systemic lupus
erythematosus, 15 although isolated pupillary dysfunction
was not seen in our children.
Lupus cerebritis was suspected in five of our children,
and it was usually preceded by seizures or by a brief episode

of psychosis. Reported psychiatric disorders in systemic
lupus erythematosus include brief reactive or atypical psy-
chosis, schizophreniform disorder, hallucinations, anxiety
disorder, phobias, and depression. 15,17 Frank psychosis
occurs in only 5% to 15% of systemic lupus erythematosus
castes. 17 The onset of seizures or altered mental status should
prompt consideration of cerebritis in a child with systemic
lupus erythematosus.
Strokes occurred in three children in our series as a man-
ifestation of central nervous system lupus. The frequency
of cerebrovascular disease had been reported between 0%
and 28% in systemic lupus erythematosus. I The exact mech-
anism of strokes in systemic lupus erythematosus is
unknown but may be secondary to microvascular injury
and focal thrombus formation.m,2o
Serum ANA levels were increased in nearly all of our
children, and anti-double-stranded DNA values were elevated
in 88%. Conversely, serum complement levels (C3, C4, and
CH50) were normal in most children (64%) in our series at
the time of the central nervous system manifestations. This
was an unexpected finding, as some studies report that
serum complement levels are decreased and the anti-dou-
ble-stranded DNA values are increased in patients with sys-
temic lupus erythematosus. 1,17 Serum complement levels
do not appear to be a sensitive screening test for neurologic
complications in children with systemic lupus erythe-
matosus. Indeed, serum complement values were normal in
our patient with fulminant cerebritis. Thus, although it
would be desirable to predict from laboratory testing which
patients will have serious neurologic complications of sys-
temic lupus erythematosus, we were unable even retro-
spectively to identify these children.
Previous studies have found that EEG abnormalities in
patients with systemic lupus erythematosus are nonspe-
cific.13,15 Electroencephalography, although abnormal in
two thirds of our patients, was generally of limited value in
the management of these children, but it was more sensi-
tive for cerebral pathology than cranial MRI. In general,
MRI was more sensitive than CT. On the other hand, cranial
MRI was superior to EEG and cranial CT in revealing a spe-
cific etiology, such as cerebral infarction or venous throm-
bosis. Previous reports have shown that the clinical findings
in systemic lupus erythematosus correlate poorly with
neuroimaging.4,13,14
In summary, neurologic symptoms are common in chil-
dren with systemic lupus erythematosus. They may appear
anytime in the course of the disorder and may be the pre-
senting symptom in undiagnosed patients. Early and aggres-
sive treatment with high-dose immunosuppression seems
to improve neurologic outcome but may not prevent ful-
minant cerebritis and death. Laboratory tests do not reliably
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807
predict those children who will experience serious neuro-
logic complications.
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