Keywords:
Pseudotumor cerebri - headache - rheumatic diseases - childhood
Palavras-chave:
Pseudotumor cerebral - cefaleia - doenças reumáticas - infância
Pseudotumor cerebri, or benign intracranial hypertension, is a syndrome that presents
with clinical features of elevated intracranial pressure without radiological evidence
of an intracranial mass, infection, vascular abnormality, hydrocephalus or changes
in the level of consciousness[1],[2],[3],[4],[5].
The incidence of pseudotumor cerebri in general population is 1:100,000. It is rare
in childhood. The incidence increases between the ages of 12 and 15 years, and 60%
of the children who develop the syndrome are over 10 years of age[2],[6],[7],[8].
The pathogenesis of pseudotumor cerebri is still unknown; some hypotheses include
decreased absorption of cerebrospinal fluid (CSF) associated with vascular resistance
in the sinus[2],[7],[9],[10],[11].
Several conditions are associated with pseudotumor cerebri (secondary pseudotumor),
such as systemic diseases and drug exposure. The term idiopathic intracranial hypertension
is used when the cause of this condition is not found[12],[13],[14].
There are few studies in the literature, most of which are case reports, describing
secondary pseudotumor syndrome in Pediatrics. Our objective was to report all cases
of children and adolescents diagnosed with pseudotumor cerebri, with or without rheumatic
disease, who were followed by the pediatric rheumatologists and neurologists of our
hospital.
METHODS
This was a retrospective cohort study evaluating 29 patients, up to 18 years of age,
with the diagnosis of pseudotumor cerebri according to the criteria of Dandy et al.[15],[16] modified by Rangwala and Liu[17]. Patients were selected from the Pediatric Rheumatology and Neurology outpatient
clinics of the Federal University of São Paulo, in Brazil, until December 2016. The
following data were analyzed: demographics, pseudotumor etiology, clinical features,
treatment and outcome. All patients underwent diagnostic spinal manometry with opening
pressure equivalent to or greater than 25 mm of water[17].
RESULTS
Of the 29 patients, 51.7% (15 patients) were girls. The mean age of symptom onset
was 12.3 ± 4.3 years. The mean age at first evaluation was 15.4 ± 4.4 years.
Regarding the etiology of the pseudotumor cerebri, 11 (37.9%) patients were diagnosed
with idiopathic pseudotumor and 18 patients (62.1%) had secondary pseudotumors. In
four of these latter patients (13.8%) a rheumatic disease was identified. Among these,
two had juvenile dermatomyositis undergoing oral glucocorticoid withdrawal. One patient
had Henoch-Schönlein purpura, and was also receiving glucocorticoids. The fourth patient
presented with antiphospholipid antibody syndrome. Other causes were obesity/overweight
(three patients), use of drugs such as tacrolimus and growth hormone (two), renal
transplantation (two), cavernous sinus thrombosis (two), hypervitaminosis A (one),
Bardet-Biedl syndrome (one), cranial trauma (one), immune thrombocytopenic purpura
(one), and cavernous angioma (one). [Table 1] shows the demographic characteristics and etiology of the pseudotumor cerebri patients.
Table 1
Demographic characteristics and etiology of cerebral pseudotumor in 29 patients.
|
Patient
|
Sex
|
Age diagnosis (years)
|
Etiology
|
|
1
|
Male
|
14
|
Renal transplantation
|
|
2
|
Male
|
9
|
Idiopathic
|
|
3
|
Male
|
18
|
Hypervitaminosis A
|
|
4
|
Female
|
14
|
Cavernous sinus thrombosis
|
|
5
|
Male
|
6
|
Idiopathic
|
|
6
|
Male
|
17
|
Renal transplantation
|
|
7
|
Female
|
12
|
Cavernous angioma
|
|
8
|
Male
|
6
|
Cranial trauma
|
|
9
|
Female
|
18
|
Idiopathic
|
|
10
|
Male
|
10
|
Idiopathic
|
|
11
|
Male
|
10
|
Idiopathic
|
|
12
|
Female
|
12
|
Obesity
|
|
13
|
Female
|
16
|
Overweight
|
|
14
|
Female
|
10
|
Growth hormone use
|
|
15
|
Female
|
17
|
Idiopathic
|
|
16
|
Male
|
11
|
Idiopathic
|
|
17
|
Female
|
19
|
Bardet-Biedl syndrome
|
|
18
|
Female
|
8
|
Idiopathic
|
|
19
|
Female
|
18
|
Idiopathic
|
|
20
|
Female
|
9
|
Antiphospholipid syndrome
|
|
21
|
Female
|
5
|
Juvenile dermatomyositis
|
|
22
|
Female
|
18
|
Idiopathic
|
|
23
|
Male
|
15
|
Idiopathic
|
|
24
|
Female
|
13
|
Tacrolimus use
|
|
25
|
Female
|
14
|
Obesity
|
|
26
|
Male
|
6
|
Henoch-Schönlein Purpura
|
|
27
|
Male
|
7
|
Immune thrombocytopenic purpura
|
|
28
|
Male
|
15
|
Cavernous sinus thrombosis
|
|
29
|
Male
|
12
|
Juvenile dermatomyositis
|
The most frequent symptoms and signs were: papilledema and headaches in 20 patients
(69.0%), decreased visual acuity in 16 (55.2%), and nausea and vomiting in seven (24.1%).
Headache occurred in 13 patients with secondary pseudotumor and in seven patients
with primary pseudotumor. The most frequent characteristics of the headaches were:
holocranial location with nuchal irradiation, continuous, worse at night and in the
mornings and in some cases associated with nausea and vomiting.
[Table 2] shows the signs and symptoms presented by each patient.
Table 2
Signs and symptoms presented by 29 patients with cerebral pseudotumor.
|
Patient
|
Headache
|
Nausea/vomiting
|
Visual loss
|
Papilledema
|
|
1
|
No
|
No
|
No
|
No
|
|
2
|
Yes
|
No
|
Yes
|
Yes
|
|
3
|
Yes
|
No
|
Yes
|
Yes
|
|
4
|
No
|
No
|
No
|
No
|
|
5
|
No
|
No
|
No
|
No
|
|
6
|
Yes
|
No
|
Yes
|
Yes
|
|
7
|
Yes
|
Yes
|
Yes
|
Yes
|
|
8
|
Yes
|
No
|
Yes
|
No
|
|
9
|
Yes
|
v
|
Yes
|
Yes
|
|
10
|
Yes
|
Yes
|
Yes
|
Yes
|
|
11
|
No
|
Yes
|
No
|
Yes
|
|
12
|
Yes
|
Yes
|
No
|
Yes
|
|
13
|
Yes
|
No
|
Yes
|
Yes
|
|
14
|
Yes
|
No
|
No
|
Yes
|
|
15
|
Yes
|
No
|
Yes
|
No
|
|
16
|
No
|
No
|
No
|
Yes
|
|
17
|
Yes
|
No
|
Yes
|
No
|
|
18
|
No
|
No
|
No
|
Yes
|
|
19
|
Yes
|
Yes
|
No
|
Yes
|
|
20
|
Yes
|
No
|
Yes
|
Yes
|
|
21
|
Yes
|
No
|
No
|
Yes
|
|
22
|
Yes
|
No
|
No
|
No
|
|
23
|
No
|
No
|
Yes
|
Yes
|
|
24
|
Yes
|
No
|
Yes
|
Yes
|
|
25
|
Yes
|
No
|
Yes
|
Yes
|
|
26
|
No
|
No
|
No
|
No
|
|
27
|
No
|
No
|
Yes
|
Yes
|
|
28
|
Yes
|
Yes
|
No
|
No
|
|
29
|
Yes
|
Yes
|
Yes
|
Yes
|
Imaging studies were performed on all patients. The findings included: empty sella,
prominent gyri and sulci, and optic nerve sheath edema.
The most commonly-used medication was acetazolamide as monotherapy in 20 (69.0%) patients
and in combination with topiramate in four (13.8%) patients. Nine (31.0%) patients
did not use any drug treatment. [Table 3] shows the treatment for each patient.
Table 3
Treatment of 29 patients with cerebral pseudotumor.
|
Patient
|
Medication
|
Lumbar puncture
|
Spinal shunt
|
|
1
|
No
|
No
|
No
|
|
2
|
Acetazolamide
|
No
|
No
|
|
3
|
Acetazolamide
|
Yes
|
No
|
|
4
|
No
|
No
|
No
|
|
5
|
No
|
No
|
No
|
|
6
|
Acetazolamide
|
Yes
|
No
|
|
7
|
Acetazolamide
|
Yes
|
No
|
|
8
|
Acetazolamide
|
Yes
|
Yes
|
|
9
|
No
|
No
|
No
|
|
10
|
Acetazolamide + Slow-K
|
No
|
No
|
|
11
|
Acetazolamide
|
No
|
No
|
|
12
|
Acetazolamide + Topiramate
|
No
|
Yes
|
|
13
|
No
|
Yes
|
Yes
|
|
14
|
Acetazolamide + Topiramate
|
Yes
|
Yes
|
|
15
|
Acetazolamide
|
No
|
No
|
|
16
|
Acetazolamide
|
No
|
No
|
|
17
|
No
|
Yes
|
Yes
|
|
18
|
Acetazolamide + Slow-K
|
No
|
No
|
|
19
|
Acetazolamide + Topiramate
|
No
|
Yes
|
|
20
|
Acetazolamide + Bicarbonate
|
No
|
Yes
|
|
21
|
Acetazolamide
|
No
|
Yes
|
|
22
|
Acetazolamide
|
No
|
No
|
|
23
|
Acetazolamide
|
No
|
No
|
|
24
|
Acetazolamide
|
No
|
No
|
|
25
|
Acetazolamide + Topiramate
|
No
|
No
|
|
26
|
No
|
No
|
No
|
|
27
|
No
|
Yes
|
No
|
|
28
|
No
|
Yes
|
No
|
|
29
|
Acetazolamide
|
No
|
No
|
Regarding the outcome, there was a resolution of the condition in 27 patients. Two
patients developed blindness (partial/total) due to pseudotumor cerebri and there
were no deaths. The median of time until clinical resolution was 120 days (ranging
from 14 to 1,800 days) and 10 patients are still being followed up as outpatients.
DISCUSSION
Pseudotumor cerebri is a rare condition in childhood and adolescence. Association
with other entities and prognosis differ from the adult presentation due to lower
rates of chronicity and recurrence[8],[18]. In our study, we observed a predominance of secondary disease with an association
with rheumatic diseases in about a quarter of the identifiable etiologies. We found
a positive outcome in most cases, with the exception of visual sequelae in two patients.
The mean age of onset of the pseudotumor cerebri was approximately 12 years and the
youngest patient was five years old. This finding is consistent with Babikian et al.,
who reported that approximately 60% of pediatric patients with pseudotumor cerebri
were 10 years of age or older[19]. Disease frequency increases with age and peaks in adolescence[3]. In our study, sex did not influence the frequency of the disease[8],[20].
Clinical criteria are well established. We used Dandy's[15] criteria, modified by Friedman and adapted for children by Rangwala and Liu[16]. The definition of normal spinal manometry is still controversial. Several authors
postulate that opening pressure is related to the age group and to the presence or
absence of papilledema[2],[17],[21]. Headache relief after lumbar puncture is an alert for the diagnosis of pseudotumor[22].
The most frequent signs and symptoms in our study were papilledema and headaches,
followed by visual loss. Most authors describe headache as the most common symptom
(61% to 94% of cases)[18]. In the study by Tibussek et al., headache was described as chronic, daily, or mimicking
acute migrane[23].
In our study, four patients were diagnosed with pseudotumor secondary to rheumatic
diseases; glucocorticoid was used in three of these patients (two in tapering doses);
and there was one case related to antiphospholipid syndrome. The study by Sussman
et al.[24] showed that prothrombotic events play an important role in the pathogenesis of pseudotumor.
The presence of antiphospholipid antibodies was observed in 32% of the patients[24]. Leker and Steiner's study[25] described the association of pseudotumor cerebri and the presence of anticardiolipin
in six of 14 patients (43%), suggesting anticardiolipin as a risk factor for a thrombotic
cause of pseudotumor cerebri. The presence of these antibodies was assessed only in
the patient with antiphospholipid syndrome.
The role of glucocorticoid tapering in triggering pseudotumor has been described.
Although the pathogenesis is unknown, patients with onset of headaches after glucocorticoid
discontinuation should be evaluated for intracranial hypertension with eye fundoscopy,
CSF examination and imaging[25]. However, glucocorticoids are not recommended for the treatment of children with
chronic pseudotumor cerebri because of their adverse effects, such as weight gain
and rebound of intracranial hypertension during periods of medication tapering[25],[26].
Conditions of hypercoagulability, such as in Behçet's disease and systemic lupus erythematosus,
may lead to dural sinus thrombosis and pseudotumor[22]. There are no descriptions in the literature of pseudotumor associated with juvenile
dermatomyositis or Henoch-Schönlein purpura in childhood. Therefore, we believe that
the true cause of pseudotumor in our patients may have been glucocorticoid tapering,
since all patients were receiving this medication in progressively smaller doses.
Case reports of patients with Cushing's syndrome have shown that treating hypercortisolism
with drugs such as ketoconazole could trigger pseudotumor cerebri[27].
One of the most frequent causes of pseudotumor in adult patients is obesity[9],[10]. However, only three patients in our group were obese.
Similar to the literature, the first-choice medication was acetazolamide (20 patients),
followed by topiramate. Both drugs reduce the production of CSF. Acetazolamide decreases
the severity of headaches, reduces the risk of papilledema and stabilizes visual function[19]. Current knowledge shows no benefit in multiple relief lumbar punctures due to uncertain
results, technical difficulties, need for sedation and rapid reestablishment of previous
CSF levels. Some authors recommend the use of glucocorticoids to control CSF production,
but their use is restricted to cases of severe headache, severe papilledema and very
high intracranial pressure[18],[25],[26]. A spinal shunt was performed in seven patients due to failure of clinical treatment.
Nine patients did not receive medication because their headaches improved after lumbar
puncture.
Papilledema in childhood usually disappears after three to six months of treatment,
although in some cases it may last longer and lead to atrophy of the optic nerve[18]. Visual loss at onset was reported in 6% to 20% of pediatric cases, although loss
of the visual field may occur in up to 91% of these patients[18]. We observed visual loss in two patients. Studies show that children have an increased
risk of permanent visual loss due to papilledema[12].
Among the positive points of our study, we emphasize the description of pseudotumor
cerebri associated with rare systemic conditions in pediatric patients, such as in
rheumatic diseases. This is a rare and entity that can lead to permanent damage. This
study was a pioneer in reporting cases of pseudotumor cerebri associated with juvenile
dermatomyositis and Henoch-Schönlein purpura, although the most-likely cause in these
patients was glucocorticoid withdrawal.
Since this was a retrospective study, it was impossible to detail the data, such as
doses and glucocorticoid reduction. In addition, there was a small number of patients
and, in some of them, the determination of antiphospholipid antibodies was not performed.
Although rare, pseudotumor cerebri is a clinically severe syndrome that can cause
permanent visual loss in children if not promptly diagnosed. Rheumatic disorders are
important causes of this syndrome.
