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idiopathic intracranial hypertension in children: An experience of a tertiary care hospital
Brain & Development xxx (2013) xxx–xxx www.elsevier.com/locate/braindev
Original article
Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital Aydan Deg˘erliyurt a,⇑, Serap Teber a, Gu¨lhan Karakaya b, Alev Gu¨ven a, Esra Dag˘ S ß eker c, Ebru Petek Arhan a, Tu¨lin Revide S ß ayli b a
Department of Pediatric Neurology, Ankara Pediatrics, Hematology–Oncology Training and Research Hospital, Ankara, Turkey b Department of Pediatrics, Ankara Pediatrics, Hematology–Oncology Training and Research Hospital, Ankara, Turkey c Department of Ophthalmology, Ankara Pediatrics, Hematology–Oncology Training and Research Hospital, Ankara, Turkey Received 6 July 2013; received in revised form 16 September 2013; accepted 20 September 2013
Abstract Objective: Pseudotumor cerebri (PTC) is diagnosed at increasing rates probably due to the increase in obesity prevalence all over the world and awareness about the disease. Our aim in this study was to evaluate the PTC clinical picture and etiological factors in children at the present time. Method: The records of 53 patients with 32 females, who were diagnosed with PTC in a child neurology department between the years of 2005 and 2012 were retrospectively analyzed. Results: The mean age at presentation was 10.9 years (3–17 years) and approximately half of patients were aged of 11 years or less. While more than half of prepubertal patients were male, girls rate reaches 74% at puberty. An etiological factor such as venous sinus thrombosis, infections, anemia, steroid discontinuation, drugs, slit ventricle syndrome and minor head injury causing the PTC was identified in 43% of the patients. The mean duration of treatment was 6.4 months (3–24 months) and the mean follow-up duration 16.5 months (3–52 months). Visual field constriction was moderate in only two pubertal and obese female patients and mild in four patients. Conclusions: PTC is seen in prepubertal children as often as in puberty. An etiological factor causing PTC is present in about half the patients in childhood. The main etiological factors of the disease currently consist of cranial venous thrombosis, infections, anemia and drugs. Malnutrition, renutrition and related vitamin deficiencies or excesses commonly seen previously have become less important in PTC etiology. PTC is a disease that requires long-term treatment and follow-up but the prognosis is good in patients who are diagnosed early, receive appropriate treatment and show good compliance with the treatment. Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Pseudotumor cerebri; Idiopathic intracranial hypertension; Headaches; Papilledema
1. Introduction Idiopathic intracranial hypertension (IIH) or pseudotumor cerebri is a clinical picture of intracranial pressure increase where no intracranial pathology can be determined with clinical, laboratory or imaging findings [1]. Making the diagnosis in a patient with signs and symptoms due to intracranial pressure increase ⇑ Corresponding author. Address: Bebek Sokak, 9/7 Aydınlıkevler, Ankara, Turkey. Tel.: +90 312 596 96 51. E-mail address: [email protected] (A. Deg˘erliyurt).
or with papilledema in addition to cerebrospinal fluid (CSF) pressure elevation shown with lumbar puncture requires normal CSF content, no venous sinus abnormality or structural lesion of the brain parenchyma, ventricles or meninx that may cause pressure increase or ventriculomegaly on neuroimaging, and the exclusion of other causes of pressure increase such as drugs. While “idiopathic intracranial hypertension” a term that should be used for patients who meet all these criteria, “pseudotumor cerebri” is the term that is suitable for the patients where an etiology is definitely shown or suspected [2].
0387-7604/$ - see front matter Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2013.09.007
Please cite this article in press as: Deg˘erliyurt A et al. Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital.. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.09.007
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A. Deg˘erliyurt et al. / Brain & Development xxx (2013) xxx–xxx
PTC is a preventable cause of vision loss and it is therefore important to diagnose it and begin prompt treatment. The disorder can occur in both genders and all age groups, although it is seen mainly in obese women of childbearing age. Unlike the case in adults, obesity and female predominance are not associated with in prepubertal children and a factor responsible for the etiology is frequently identified. PTC is diagnosed at increasing rates probably due to the increase in obesity prevalence all over the world and awareness about the disease [3]. The current clinical characteristics of PTC in pediatric patients were analyzed in this study.
Differences between idiopathic/symptomatic, prepubertal/pubertal, female/male and obese/nonobese groups were assessed with the v2 test. A p value of <0.05 was considered significant.
2. Methods
4. Results
The charts and computer records of 53 pediatric patients who had been diagnosed with PTC at the Ankara Pediatrics, Hematology–Oncology Training and Research Hospital between 2005 and 2012 were examined. The PTC diagnosis was based on Modified Dandy criteria (Table 1) [4]. Accordingly, patients with symptoms and signs of increased intracranial hypertension whose neurological examination was normal except for papilledema and/or 6th and 7th cranial nerve palsy, and CSF pressure of 200 mm H2O and over, with normal biochemical and microbiological examination, and no hydrocephalus, mass, structural, or vascular lesion which would lead to increased intracranial hypertension on neuroimaging were included in the study. Patients over the age of 11 years were classified as pubertal and patients at or under the age of 11 as prepubertal. Patients with a body mass index at or over 95% according to age were grouped as obese. Patients in whom the increased intracranial pressure had occurred for any reason were classified as secondary (symptomatic) PTC and patients who did not have any etiological factor were classified as idiopathic intracranial hypertension. The general, neurological, and fundus examination of the patients was performed, and an eye examination including Snellen visual acuity and Goldman visual field perimetry was also performed in cooperating patients. All patients underwent tests for complete blood count, serum ferritin, serum iron and iron binding capacity, routine blood chemistry, thyroid function tests, parathyroid hormone, ACTH, cortisol, sedimentation rate, ANA, Anti-ds DNA, anticardiolipin antibodies, vita-
A total of 53 patients consisting of 32 females (60.4%) and 21 males (39.6%) diagnosed with PTC were analyzed. The mean age of the patients at admission was 10.9 years and ranged from 3 years to 17 years. There were 30 idiopathic, and 23 symptomatic cases. The etiological factor for PTC could be demonstrated in 43% of the patients. The distribution of idiopathic and symptomatic patients by gender, puberty status and obesity are presented in Table 2. Although using secondary sexual characteristics is recommended to separate pubertal and prepubertal children, this classification is rarely adopted in the pediatric PTC literature. Usually a certain age is chosen to separate older and younger children [4]. For this reason we accepted the patients under 12 years old, as prepubertal. Of the patients 51% (n = 27) were 12 years and older, and 49% (n = 26) were 11 years and younger. The pubertal and prepubertal patient percentages were almost equal. The male percentage was 54% (n = 14) for prepubertal patients while the female percentage was 74% (n = 20) for pubertal patients. The percentage of female patients in the pubertal period was significantly higher (p = 0,038). The relationship between gender and obesity at pubertal status is presented in Table 3. Obese patients made up 40% (n = 12) of idiopathic patients and 30% (n = 7) of symptomatic patients. The obesity rate was 41% (n = 11) for pubertal patients and 31% (n = 8) for prepubertal patients. We found no significant relationship between obesity and the etiology or puberty. The most common symptom was headache at 88% (n = 47). This was followed by nausea and/or vomiting in 30% (n = 16), diplopi and/or blurred vision in 28% (n = 15) and dizziness in 9% (n = 5). A patient with epilepsy and a patient with acute lymphoblastic leukemia (ALL) who was being prepared for a bone marrow transplant were found to have papilledema and diagnosed during routine examination although no symptoms were present (patients 23 and 52). Papilledema was found in all patients on neurological examination.
Table 1 Modified criteria of Dandy. 1. Signs of increased intracranial pressure. 2. No localizing neurologic signs otherwise, with the single exception of unilateral or bilateral paresis in nerve VI. 3. Cerebrospinal fluid can exhibit increased pressure, but no cytologic or chemical abnormalities otherwise. 4. Normal to small symmetric ventricles must be demonstrated.
mins A, D and, when necessary, infectious agents regarding the etiology of secondary pseudotumor cerebri. All patients except for one with a cochlear implant due to Usher syndrome underwent brain magnetic resonance imaging (MRI) and 47 patients underwent brain magnetic resonance venography (MRV). 3. Statistical analyses
Please cite this article in press as: Deg˘erliyurt A et al. Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital.. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.09.007
A. Deg˘erliyurt et al. / Brain & Development xxx (2013) xxx–xxx Table 2 The distribution of idiopathic and symptomatic patients by gender, puberty status and obesity.
Female Male Prepubertal Pubertal Obese Nonobese
Idiopathic n(%)
Symptomatic n(%)
p
19 11 14 16 12 18
13 (56.5) 10 (43.5) 12 (52.2) 11 (47.8) 7 (30.4) 16 (69.6)
0.615
(63.3) (36.7) (46.7) (53.3) (40.0) (60.0)
0.691 0.472
Table 3 The relationship between gender and obesity at pubertal status.
Female Male Obese Nonobese
Pubertal n(%)
Prepubertal n(%)
20 (74.1) 7 (25.9) 11 (40.7) 16 (59.3)
12 (46.2) 14 (53.8) 8 (30.8) 18 (69.2)
p 0.038* 0.449
Abducens nerve (patients 11,33,36,39,45) or facial nerve (patient 1) paresis was found in 6 patients (11.3%).The clinical characteristics of the patients are presented in Tables 4a and 4b. Cerebral venous sinus thrombosis was found in 6 patients, upper respiratory tract infections in 4 patients, anemia in 4 patients (iron deficiency anemia in three patients, aplastic anemia in one patient), steroid withdrawal in 3 drug resistant epilepsy patients, PTC probably related to all-trans retinoic acid (ATRA), risperidone, cyclosporine usage in 3 patients and PTC due to Brucella, post-traumatic, and slit ventricle syndrome in one patient each in the etiology of the secondary PTC group. The most common comorbid diseases in the idiopathic group were seemed to be related to obesity (Hypertension in 5 patients, deteriorated glucose tolerance, insulin resistance and diabetes in 5 patients, vitamin D deficiency in 4 patients, and polycystic ovarian syndrome (PCOS), renal agenesis/atrophy, and epilepsy in 2 patients each). The most common comorbid diseases seen in the symptomatic group were epilepsy in 4 patients, hematologic malignancy in 3 patients, and vitamin D deficiency in 2 patients. Brain imaging revealed unilateral transverse sinus narrowing in 7 patients (14.8%), cerebral venous sinus thrombosis in 6 patients (12.7%), and neurofibromatosis-related hamartoma in the optic nerve, posterior fossa arachnoid cysts, cystoperitoneal shunt in the patient with slit ventricle syndrome, encephalomalasia and chronic infarct sequelae in one patient each. All patients were started treatment with acetazolamide after the diagnosis except three idiopathic obese patients who were started topiramate. The papilledema recovered with only acetazolamide in 36 patients (72%). Topiramate was added to the treatment of six
3
patients who did not respond to acetazolamide treatment alone. Treatment was successful in three of these six patients. The three patients who did not benefit from acetazolamide plus topiramate therapy and 7 patients who had only received acetazolamide with no decrease in CSF pressure or papilledema after drug therapy for 3–9-months underwent a lumboperitoneal shunt procedure for a total of 10 (19%) patients. Improvement was seen in the papilledema in all patients after the lumboperitoneal shunt. None of the patients received steroid therapy or a ventriculoperitoneal shunt. Drug treatment duration ranged from 3 months to 24 months, with a mean duration of 6.4 months. Mean follow-up time was 9.5 months in idiopathic patients, 24.7 months in symptomatic patients, and 16.5 months (3–52 months) for all patients. Visual field assessment showed mild or moderate visual field defects in a total of 6 patients (11.3%). Visual field constriction was moderate in two pubertal and obese female patients (3.8%), one with venous thrombosis and the other idiopathic (patients 10,49). Recurrence developed in 3 (5.6%) prepubertal and symptomatic patients after a mean duration of 14 months. 5. Discussion 5.1. Clinical features Pseudotumor cerebri is a longtime recognized serious disorder that can cause some vision loss in most patients and lead to blindness in 10% although it has initially been thought to be a benign disease [5]. The incidence in the pediatric age group is unknown but it is considered to be rare, especially in prepubertal children [4]. However, 49% of our patient group was under 12 years of age. The percentages of pubertal and prepubertal patients were almost equal in our study group. Likewise the percentages of patients under the age of 12 or prepubertal varies between 45% and 60% in the literature [6– 9]. A few decades ago, a study from Canada reported that 50% of the cases were under the age of 6 in a series consisting of 38 patients [10]. These studies each had a significantly higher number of children than the general PTC literature, revealing that PTC is actually seen in younger children as frequently as in pubertal patients. However, the difficulty the children have in expressing their symptoms could have caused the PTC diagnosis to be missed or milder cases may not have been directed to pediatric neurology departments [4]. Although the female gender in adults is a risk for PTC, this relationship may not have been demonstrated in children because PTC in children may have due to other pathogenetic factors. While the male and female ratios in PTC are equal before puberty, the female patient ratio increases with age, and the adult gender
Please cite this article in press as: Deg˘erliyurt A et al. Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital.. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.09.007
4
No
Age (years)
Sex
Signs/symptoms
Neuroimaging (MRI–MRV)
Treatment/ duration
1
8
F
Facial paresis, headache
2 3 4
14 9 15
F M F
Headache, nausea Headache Headache, diplopi,
Left transverse, sigmoid sinuses and jugular vein narrow Normal Optic nerve hamartoma Normal
5 6
16 9
M M
Headache Headache
7
6
M
8 9
15 17
F F
10
14
F
Headache, nausea, vomiting Headache, blurred vision Headache, nausea, blurred vision Headache, dizziness
Vision prognosis
Comorbidity
Follow up period (months)
A – 3 months
Normal
–
3
Normal Normal Mild visual field constriction
Vit-D deficiency NF-type I –
19 18 15
Normal Normal
A – 3 months A – 3 months A–6 monthsL-P Shunt A – 5 months A – 9 months
– –
5 9
Retrocerebellar arachnoid cyst
A – 3 months
Normal Mild visual field constriction Normal
–
3
Normal Normal
A – 3 months TPM – 3 months A – 2 years L-P Shunt A – 3 months
Normal Normal
– Insu¨lin resistance
18 15
Moderate visual field constriction Normal
–
24
11
6
M
–
3
12
11
F
Normal
Vit-D deficiency
19
13 14 15 16 17
11 11 13 4 10
Normal Normal Normal Normal Mild visual field constriction
– – Vit-D deficiency – Usher syndrome + epilepsy + Cochlear implant
6 5 14 16 30
18
+
Normal
11
+
Mild visual field constriction
Hypertension + Renal atrophy, PCOS Hypertension
+
Normal
Hypertension,+ impaired glucose tolerance –
5
Normal MRV: Ø
Headache, diplopi, abducens paresis Headache, nausea, vomiting
Normal MRV: Ø
F M F F F
Headache, blurred vision Headache, diplopi Headache, diplopi Headache Headache
Normal MRV: Ø Normal Normal Normal CT: Normal MRV: Ø
17
F
Headache, blurred vision
Normal
19
8
M
Headache
Normal right transverse sinus narrow
20
15
M
21
16
F
22
12
F
Normal left transverse, sigmoid sinuses and jugular vein narrow Normal left transverse and sigmoid sinuses narrow Normal
23 24
7 15
M F
Headache, nausea, vomiting Headache, nausea, vomiting Headache, nausea, vomiting, blurred vision – Headache, vomiting, blurred vision
Normal
Normal Chronic infarct sequelae
A – 10 months TPM – 8 months A – 6 months A – 5 months A – 6 months A – 3 months A – 8 months TPM – 12 months L-P Shunt A – 3 months A – 12 months TPM – 4 months L-P Shunt A – 5 months
Obesity
+
+ +
+
A – 4 months
Normal
A – 3 months
+
Normal
A – 4 months TPM – 6 months
+ +
Normal Normal
Hypertension, PCOS + insu¨lin resistance Epilepsy Hypertension, stroke sequele, renal agenesis
12
8 5 7 6
A. Deg˘erliyurt et al. / Brain & Development xxx (2013) xxx–xxx
Please cite this article in press as: Deg˘erliyurt A et al. Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital.. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.09.007
Table 4a Clinical features of idiopathic PTC patients.
Impaired glucose tolerance, Vit-D deficiency
13 17
14
28 29
30
M F
8 13 11 25 26 27
F F M
A – 7 months A – 8 months A – 6 months TPM – 6 months A – 6 months A – 9 months TPM – 1 months TPM – 15 months
+
Normal
– Diabetes mellitus
+
Normal Normal
ANA + – – Normal Normal Normal
15 Normal left transverse sinus narrow Headache F
5.2. Etiology
6 10 Normal Normal Headache, nausea Headache
profile is reached after puberty [11]. Similarly, the male percentage was somewhat higher in our prepubertal patients while the female percentage was significantly higher after puberty (p = 0,038). These results confirm the notion of IIH in pubertal patients having the characteristics of adults and not childhood. IIH is found approximately 10 times more commonly in the obese population than the non-obese population (21/100,000 and 2.2/100,000) in adults [12]. Furthermore, obesity is seen more frequently in pubertal patients than prepubertal patients in PTC. The obesity rate was reported between 43% and 68% in pubertal patients and around 25% in prepubertal patients in relevant publications [8,9,13]. The obesity rate in our older children was also higher than in our prepubertal patients (41% and 31%). The most frequently reported symptoms in PTC are symptoms due to intracranial pressure increase such as headache, nausea and vomiting. Cranial nerve paresis can also be found on examination in addition to papilledema. Sixth nerve paresis has been reported in 9– 48% of cases. Cranial nerve paresis should improve on reduction of intracranial pressure in order to be able to say they are due to IIH [14]. Cranial nerve paresis that disappeared after treatment was observed in 9.4% of our patients. A cranial nerve paresis is reported to be more common in children under the age of 11 [9]. The majority (5 of 6 patients) of our patients with cranial nerve paresis were under the age of 11, supporting cranial nerve paresis is more frequent in younger children. Papilledema is usually considered to be a very significant neurological sign for PTC but the presence of PTC without papilledema has been demonstrated especially in patients with chronic headache and vomiting symptoms [7,15]. Papilledema was found in the neurological examination in all of our patients. In contrast to the cases without papilledema, asymptomatic PTC cases diagnosed by the identification of papilledema during routine ophthalmic examination are increasingly reported, especially at young ages [7,16,17]. Papilledema was identified and PTC was diagnosed during routine neurological examination of two patients who had no symptom or sign other than papilledema. Therefore, performing a careful fundus examination, is important not to miss the diagnosis.
12 9 6 Normal Normal Normal
5
Headache Headache Dizziness, nausea
A. Deg˘erliyurt et al. / Brain & Development xxx (2013) xxx–xxx
The absence of obesity and female gender dominance in young children with PTC suggests different mechanisms causing the pseudotumor cerebri in these patients. Therefore, a secondary cause, disease, or drug history that may cause PTC in an atypical patient such as prepubertal and/or non-obese adolescent should be investigated [7,18].
Please cite this article in press as: Deg˘erliyurt A et al. Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital.. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.09.007
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A. Deg˘erliyurt et al. / Brain & Development xxx (2013) xxx–xxx
A factor causing the PTC has been shown in 23 of our patients. The most frequent etiological factor in our patients was cerebral venous thrombosis that was present in 6 (11%) out of 53 patients. As about one third of cerebral venous thrombosis cases show clinical symptoms similar to idiopathic intracranial hypertension and the condition should be ruled out with imaging methods [19]. Cerebral venous thrombosis has been reported in 9–14% of PTC patients [9,20,21]. Unless computed tomographic venography (CTV) or MRV that formally show cerebral vascular formations is performed, CT or MRI may be insufficient in demonstrating cerebral venous thrombosis [5]. Therefore, venography for sinus thrombosis should be performed in all patients who present with a clinical picture of idiopathic intracranial hypertension. The relationship between infections and PTC has been known. PTC is commonly seen in children in seasons when pediatric viral–bacterial infections are frequently seen [22]. Upper respiratory tract infections were present in the etiology of four of our patients. PTC due to Brucella was diagnosed in one of our patients while being investigated for maculopapular rash and blurred vision. Brucella can present only with isolated intracranial hypertension without causing any other symptoms and must be considered in the PTC etiology especially in endemic regions [23]. Anemia was found in the PTC etiology of 4 of our patients. The patient with Fanconi aplastic anemia was using anabolic steroids. The good response to the PTC treatment and the absence of increased intracranial pressure despite continuation of anabolic steroids at the 27month follow-up suggest the anemia was responsible for the etiology. Tissue hypoxia developing due to anemia probably leads to changes in cerebral hemodynamics, causing capillary permeability increase and ultimately a rise in intracranial pressure [24]. Three patients with refractory epilepsy developed severe headaches after steroid therapy was decreased, and PTC was found. PTC related to steroids usually occurs following steroid termination. Headaches that occur during steroid discontinuation should therefore point towards intracranial hypertension. PTC due to steroid use has rarely been reported and is usually seen after long-term use [25]. Although PTC cases due to the use of steroids reported in the literature may be met with skepticism, 11b-hydroxysteroid dehydrogenase type 1, glucocorticoid dysregulation, and the presence of a multifactorial pathogenesis with inflammation in the center prevents ignoring the role of steroids [12,14]. Drugs and especially the vitamin A derivative ATRA have often been blamed in PTC etiology. We found that PTC had developed due to the use of ATRA, cyclosporine, and risperidone in 3 of our patients with hematologic malignancies. Our 4-year-old patient who had been started ATRA treatment developed PTC after
10 days, showing once again that the use of this drug in children under the age of 8 is hazardous in terms of PTC [26]. The patient taking risperidone for psychiatric disorders had stopped receiving multidrug chemotherapy a month ago and risperidone was therefore considered to be the probable etiologic agent. The third patient with hematological malignancy had been receiving cyclosporine when PTC emerged. The use of cyclosporine has rarely been reported in the etiology [27]. Slit ventricle syndrome can also cause secondary PTC. Patients who had previously been installed a ventriculoperitoneal (v-p) shunt, develop PTC later with the typical symptoms of increased intracranial pressure, and the ventricles are narrower unlike in shunt dysfunction. This clinical picture is not usually known and patients are examined in emergency services for hydrocephalus or shunt failure. Long-term headaches, worsening neurological status and sometimes vision loss develop due to delays in diagnosis. CSF pressure measurement must be performed for the diagnosis if no shunt dysfunction is present. Collapse of the ventricles around the catheter as a result of over drainage in these patients causes intermittent shunt dysfunction and symptoms of severe intracranial hypertension emerging intermittently [28]. Our patient who had been installed a v-p shunt about 10 years ago for a large arachnoid cyst had often presented at the emergency department recently because of severe headaches (patient 40) and had papilledema but no shunt dysfunction or ventricular dilatation. After a lumboperitoneal shunt was placed in the patient with a CSF pressure over 300 mm H2O, his symptoms decreased rapidly, the papilledema recovered, and the symptoms had disappeared completely on follow-up at 6 months. Intracranial hypertension due to slit ventricle syndrome must therefore be kept in mind in patients with shunts who have intermittent headaches, symptoms of increased intracranial pressure and no shunt dysfunction. Vitamin D deficiency was found in six (11.3%) of our patients. Vitamin D deficiency has been reported with PTC in previous publications. These patients have generalized malnutrition suggesting that PTC developed due to hypocalcemia or malnutrition, not lack of vitamin D [25]. However, Vitamin D has not been reported in the PTC etiology in Pubmed publications in English in the last 20 years. Vitamin D deficiency is a common health problem all over the world due to the habit of modern living today. Vitamin D deficiency and insufficiency in children were found at a rate of 40% in Ankara in a recent study [29]. Because of the lack of a clinical picture of hypocalcemia, malnutrition, or renutrition in our patients, the vitamin D deficiency was considered to be coincidental and not an etiological factor. The dural venous pressure increase due to venous sinus stenosis in idiopathic intracranial hypertension pathogenesis has attracted interest in recent years [30].
Please cite this article in press as: Deg˘erliyurt A et al. Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital.. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.09.007
No
Age (years)
Sex
Symptoms/signs
Etiology
Neuroimaging (MRI–MRV)
Treatment/duration
31
16
M
Headache
Sinus thrombosis
32
4
M
ATRA treatment
33
9
M
34
12
M
Headache, nausea, vomiting Headache, nausea, vomiting, diplopi, abducens paresis Headache
Right transverse sinus thrombosis Normal
35
6
F
Headache
36
9
F
37
5
F
Diplopi, abducens paresis Headache
38
5
F
39
16
F
40
16
M
41 42
9 17
M F
43
7
M
44
12
F
45
3
M
46
13
F
47
14
F
48
5
F
Headache, vomiting, dizziness
49
13
F
Headache
Sinus thrombosis
Fanconi aplastic anemia Thrombosis
Obesity
Vision prognosis
Comorbidity
Follow up period (months)
A – 6 months
Normal
–
19
A – 8 months
Normal
AML – M3
27
Superior sagittalis, confluence and left transverse sinuses thrombosis Normal
A – 6 months L-P Shunt
Normal
Nephrotic syndrome
23
A – 6 months
Normal
–
33
Vena jugularis interna thrombosis
Normal
–
26 Recurrence after a year
Normal
FMF
25
Congenital diseritropoetic anemia, refractory epilepsy AML + Bone marrow transplantation –
20
Sinusitis
Normal
A – 7 months again after recurrence A – 7 months) A – 8 months
Steroid discontinuation
Encephalomalasia
A – 6 months
Normal
Headache
Risperidone
Normal
Normal
Spotty vision, diplopi, abducens paresis Headache
Sinus thrombosis
Left transverse and sigmoid sinuses thrombosis Cystoperitoneal shunt MRV: Ø Normal Normal
A – 5 months L-P Shunt A – 4 months A– L-P A– A–
3 months Shunt 6 months 3 months
Normal
Headache Headache, nausea, dizziness Headache, nausea, vomiting Headache, blurred vision Headache, abducens paresis Skin rash, blurred vision Headache
Slit ventricle syn drome Post-traumatic Iron deficiency anemia Iron deficiency anemia Sinusitis
+
Normal
12
Normal Normal
Epilepsy, Cystoperitoneal shunt – Vit-D deficiency
12 3
A – 6 months
Normal
–
30
Normal
A – 9 months
Normal
–
32
Otitis
Normal
A – 6 months
Normal
–
19
Brucellosis
NormalMRV: Ø
A – 3 months
+
Normal
-
52
Iron deficiency anemia Otitis + rhinosinusitis
Normal
A – 3 months
+
Normal
Vit-D deficiency
36
Normal
A – 6 months TPM–2 months L-P Shunt A – 1 years L-P Shunt
+
Normal
–
32Recurrence after 2 years
+
Moderate visual field constriction
–
36
Sinus thrombosis
Left transverse and sigmoid sinuses thrombosis
Normal
24
6
A. Deg˘erliyurt et al. / Brain & Development xxx (2013) xxx–xxx
(continued on next page) 7
Please cite this article in press as: Deg˘erliyurt A et al. Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital.. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.09.007
Table 4b Clinical features of symptomatic PTC patients.
18Recurrence after 6 months
7
Normal
ALL + Bone marrow transplantation Refractory epilepsy Headache 7 53
M
15 52
M
Steroid discontinuation
A – 6 months
Left transverse, sigmoid sinuses and vena jugularis narrow Normal Cyclosporine
A – 12 months 13 51
F
Headache, vomiting, dizziness –
Thrombosis
Confluence sinu¨s thrombosis
A – 6 months again after recurrence A – 6 months)
+
Normal
12 – Normal
Follow up period (months) Comorbidity Vision prognosis Obesity Treatment/duration Neuroimaging (MRI–MRV) Etiology Symptoms/signs Sex Age (years) No
Table 4b Clinical features of symptomatic PTC patients.
A: Acetazolamide, AML: acute myeloid leukemia, ANA: anti nuclear antibody, ATRA: all-trans retinoic acid, CT: computerized tomography, F: female, FMF: familial mediterranean fever, L-P: lumboperitoneal, M: male, MRI: magnetic resonance imaging, MRV: magnetic resonance venography, PCOS: polycystic ovary syndrome, TPM: topiramate.
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If narrowing is present in the venous sinus, the highpressure gradient it creates will prevent reabsorption of CSF. In contrast, if the intracranial pressure is high, this will lead to vascular compression and ultimately venous collapse. The stenosis appearance in MRV was reported to recover with the intracranial pressure becoming normal with methods such as lumbar puncture, lumboperitoneal shunt, and endovascular stent in some studies. However, some studies report the appearance of the stenosis does not change and persists although the pressure has decreased. These different results suggest that some narrowed areas are fixed and thus play a role in the etiology of PTC, while some develop secondary to the increased intracranial pressure [31]. Transverse sinus stenosis, debated in the pathogenesis, was observed in 7 (13%) of our patients. Our patients did not have follow-up MRI/MRV so we do not know their post-treatment conditions and whether this finding in our patients was a constant finding or secondary to the PTC. The topic of venous sinus stenosis has not been examined sufficiently in other publications including large case groups of children related to PTC where modern imaging methods have been used. Although this may be related to the consideration of transverse sinus narrowing as a normal variation, follow-up brain MRI and MRV performed in studies including large case groups will clarify the vascular stenosis/collapse puzzle for which a role in pathogenesis is controversial. 5.3. Treatment The drug of choice in the treatment of PTC is the carbonic anhydrase inhibitor acetazolamide. Acetazolamide probably reduces intracranial pressure by decreasing CSF production. Topiramate is being preferred in the treatment of intracranial hypertension in recent years due to its characteristics of being a carbonic anhydrase inhibitor, as well as leading to analgesia and weight loss. A study demonstrated its efficacy as comparable to acetazolamide to treat PTC [32]. Acetazolamide alone provided improvement in papilledema in 72% of our patients. The rate of shunt treatment in idiopathic intracranial hypertension is reported to be around 20% [4]. Despite 3–9 months of drug treatment, no decrease was seen in the papilledema or CSF pressure in 19% (n = 10) of our patients and a lumboperitoneal shunt was therefore placed. The papilledema resolved and the headaches disappeared in all patients after shunt treatment. Steroid treatment and v-p shunting were not used in any of our patients. Although the presence of inflammatory cytokines in the pathogenesis of PTC suggests that steroid therapy is appropriate, steroids are not recommended in chronic idiopathic intracranial hypertension
Please cite this article in press as: Deg˘erliyurt A et al. Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital.. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.09.007
A. Deg˘erliyurt et al. / Brain & Development xxx (2013) xxx–xxx
treatment in children because of their side effects such as weight gain and rebound intracranial hypertension in reduction periods [14]. Steroids reduce intracranial pressure quickly and are therefore recommended for intravenous use or short-term oral therapy only in severe headache, severe papilledema and very high intracranial pressure [4,2]. 5.4. Prognosis Permanent visual field constriction in PTC has been reported 17% of the patients [9]. Mild or moderate visual field constriction was found in 11.3% of our patients in visual assessment on follow-up. The visual field constriction was moderate only in 2 pubertal and obese patients (3.7%), supporting the argument that puberty increases the vision loss risk [33]. The prognosis can be said to be very good in our patients except the patients who were moderately affected due to treatment compliance. PTC is a chronic disease and its treatment lasts for months. Patient compliance is crucial as treatment and follow-up take a long time. In conclusion, PTC is not uncommon in children and is seen as frequently as in adolescence. The pubertal PTC patients differ from prepubertal patients with characteristics such as female dominance and higher rate of obesity. An etiological factor causing PTC is present in about half the patients in childhood. Currently the main etiological factors of the disease in children consists of cranial venous thrombosis, infections, anemia and drugs. Vitamin D deficiency is not currently an important factor in the etiology when it is not together with other factors such as malnutrition and hypocalcemia. The reduction of steroids seems to be more important than the use of steroids in the development of PTC. Studies conducted in large case group including pretreatment and post-treatment MRVs are needed to clarify the controversial place of cerebral venous sinus stenosis in the pathogenesis. PTC is a disease that requires long-term treatment and follow-up but the prognosis is good in patients who are diagnosed early, receive appropriate treatment and show good compliance with the treatment. References [1] Skau M, Brennum J, Gjerris F, Jensen R. What is new about idiopathic intracranial hypertension? An updated review of mechanism and treatment. Cephalalgia 2006;26:384–99. [2] Spennato P, Ruggiero C, Parlato RS, Buonocore MC, Varone A, Cianciulli E, et al. Pseudotumor cerebri. Childs Nerv Syst 2011;27:215–35. [3] Dhungana S, Sharrack B, Woodroofe N. Idiopathic intracranial hypertension. Acta Neurol Scand 2010;121:71–82. [4] Standridge SM. Idiopathic intracranial hypertension in children: a review and algorithm. Pediatr Neurol 2010;43:377–90. [5] Ball AK, Clarke CE. Idiopathic intracranial hypertension. Lancet Neurol 2006;5:433–42.
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[6] Per H, Canpolat M, Gu¨mu¨ßs H, Poyrazog˘lu HG, Yıkılmaz A, Karaku¨ßcu¨k S, et al. Clinical spectrum of the pseudotumor cerebri in children: etiological, clinical features, treatment and prognosis. Brain Dev 2013;35:561–8. [7] Tibussek D, Schneider DT, Vandemeulebroecke N, Turowski B, Messing-Juenger M, Willems PH, et al. Clinical spectrum of the pseudotumor cerebri complex in children. Childs Nerv Syst 2010;26:313–21. [8] Kesler A, Fattal-Valevski A. Idiopathic intracranial hypertension in the pediatric population. J Child Neurol 2002;17:745–8. [9] Phillips PH, Repka MX, Lambert SR. Pseudotumor cerebri in children. J AAPOS 1998;2:33–8. [10] Couch R, Camfield PR, Tibbles JA. The changing picture of pseudotumor cerebri in children. Can J Neurol Sci 1985;12:48–50. [11] Balcer LJ, Liu GT, Forman S, Pun K, Volpe NJ, Galetta SL, et al. Idiopathic intracranial hypertension: relation of age and obesity in children. Neurology 1999;52:870–2. [12] Sinclair AJ, Ball AK, Burdon MA, Clarke CE, Stewart PM, Curnow SJ, et al. Exploring the pathogenesis of IIH: an inflammatory perspective. J Neuroimmunol 2008;201– 202:212–20. [13] Brara SM, Koebnick C, Porter AH, Langer-Gould A. Pediatric idiopathic intracranial hypertension and extreme childhood obesity. J Pediatr 2012;161:602–7. [14] Rangwala LM, Liu GT. Pediatric idiopathic intracranial hypertension. Surv Ophthalmol 2007;52:597–617. [15] Wraige E, Chandler C, Pohl KR. Idiopathic intracranial hypertension: is papiledema inevitable? Arch Dis Child 2002;87:223–4. [16] Distelmaier F, Sengler U, Messing-Juenger M, Assmann B, Mayatepek E, Rosenbaum T. Pseudotumor cerebri as an important differential diagnosis of papiledema in children. Brain Dev 2006;28:190–5. [17] Bassan H, Berkner L, Stolovitch C, Kesler A. Asymptomatic idiopathic intracranial hypertension in children. Acta Neurol Scand 2008;118:251–5. [18] Randhawa S, Van Stavern GP. Idiopathic intracranial hypertension (pseudotumor cerebri). Curr Opin Ophthalmol 2008;19:445–53. [19] De Simone Roberto, Ranieri A, Bonavita V. Advancement in idiopathic intracranial hypertension pathogenesis: focus on sinu¨s venous stenosis. Neurol Sci 2010;31(Suppl. 1) S33-9. [20] Lin A, Foroozan R, Danesh-Mayer HV, De Salvo G, Savino PJ, Sergott RC. Occurence of cerebral venous sinu¨s thrombosis in patients with presumed idiopathic intracranial hypertension. Ophthalmology 2006;113:2281–4. [21] Standridge SM, O’Brien SH. Idiopathic intracranial hypertension in a pediatric population: a retrospective analysis of the initial imaging evaluation. J Child Neurol 2008;23:1308–11. [22] Distelmaier F, Tibussek D, Schneider DT, Mayatepek E. Seasonal variation and atypical presentation of idiopathic intracranial hypertension in prepubertal children. Cephalalgia 2007;27:1261–4. [23] Yılmaz S, Serdarog˘lu G, Go¨kben S, Tekgu¨l H. A case of neurobrucellosis presenting with isolated intracranial hypertension. J Child Neurol 2011;26:1316–8. [24] Henry M, Driscoll MC, Miller M, Chang T, Minniti CP. Pseudotumor cerebri in children with sickle cell disease: a case series. Pediatrics 2004;113:e265–9. [25] Lessell S. Pediatric pseudotumor cerebri (idiopathic intracranial hypertension). Surv Ophthalmol 1992;37:155–66. [26] Mahmoud HH, Hurwitz CA, Roberts WM, Santana VM, Ribeiro RC, Krance RA. Tretinoin toxicity in children with acute promyelocytic leukaemia. Lancet 1993;342:1394–5. [27] Cruz OA, Fogg SG, Roper-Hall G. Pseudotumor cerebri associated with cyclosporine use. Am J Ophthalmol 1996;122:436–7. [28] Rekate HL. Shunt related headaches: the slit ventricle syndromes. Childs Nerv Syst 2008;24:423–30.
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[29] Andıran N, C ¸ elik N, Akcßa H, Dog˘an G. Vitamin D deficiency in children and adolescents. J Clin Res Pediatr Endocrinol 2012;4:25–9. [30] Dyknuizen MJ, Hall J. Cerebral venous sinus system and stenting in pseudotumor cerebri. Curr Opin Ophthalmol 2011;22:458–62. [31] Stienen A, Weinzierl M, Ludolph A, Tibussek D, Hausler M. Obstruction of cerebral venous sinus secondary to idiopathic intracranial hypertension. Eur J Neurol 2008;15:1416–8.
[32] C ¸ elebisoy N, Go¨kcßay F, S ß irin H, Akyu¨rekli O. Treatment of idiopathic intracranial hypertension: topiramate vs acetazolamide, an open-label study. Acta Neurol Scand 2007;116:322–7. [33] Stiebel-Kalish H, Kalish Y, Lusky M, Gaton DD, Ehrlich R, Shuper A. Puberty as a risk factor for less favorable visual outcome in idiopathic intracranial hypertension. Am J Ophthalmol 2006;142:279–83.
Please cite this article in press as: Deg˘erliyurt A et al. Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital.. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.09.007
Original article
Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital Aydan Deg˘erliyurt a,⇑, Serap Teber a, Gu¨lhan Karakaya b, Alev Gu¨ven a, Esra Dag˘ S ß eker c, Ebru Petek Arhan a, Tu¨lin Revide S ß ayli b a
Department of Pediatric Neurology, Ankara Pediatrics, Hematology–Oncology Training and Research Hospital, Ankara, Turkey b Department of Pediatrics, Ankara Pediatrics, Hematology–Oncology Training and Research Hospital, Ankara, Turkey c Department of Ophthalmology, Ankara Pediatrics, Hematology–Oncology Training and Research Hospital, Ankara, Turkey Received 6 July 2013; received in revised form 16 September 2013; accepted 20 September 2013
Abstract Objective: Pseudotumor cerebri (PTC) is diagnosed at increasing rates probably due to the increase in obesity prevalence all over the world and awareness about the disease. Our aim in this study was to evaluate the PTC clinical picture and etiological factors in children at the present time. Method: The records of 53 patients with 32 females, who were diagnosed with PTC in a child neurology department between the years of 2005 and 2012 were retrospectively analyzed. Results: The mean age at presentation was 10.9 years (3–17 years) and approximately half of patients were aged of 11 years or less. While more than half of prepubertal patients were male, girls rate reaches 74% at puberty. An etiological factor such as venous sinus thrombosis, infections, anemia, steroid discontinuation, drugs, slit ventricle syndrome and minor head injury causing the PTC was identified in 43% of the patients. The mean duration of treatment was 6.4 months (3–24 months) and the mean follow-up duration 16.5 months (3–52 months). Visual field constriction was moderate in only two pubertal and obese female patients and mild in four patients. Conclusions: PTC is seen in prepubertal children as often as in puberty. An etiological factor causing PTC is present in about half the patients in childhood. The main etiological factors of the disease currently consist of cranial venous thrombosis, infections, anemia and drugs. Malnutrition, renutrition and related vitamin deficiencies or excesses commonly seen previously have become less important in PTC etiology. PTC is a disease that requires long-term treatment and follow-up but the prognosis is good in patients who are diagnosed early, receive appropriate treatment and show good compliance with the treatment. Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Pseudotumor cerebri; Idiopathic intracranial hypertension; Headaches; Papilledema
1. Introduction Idiopathic intracranial hypertension (IIH) or pseudotumor cerebri is a clinical picture of intracranial pressure increase where no intracranial pathology can be determined with clinical, laboratory or imaging findings [1]. Making the diagnosis in a patient with signs and symptoms due to intracranial pressure increase ⇑ Corresponding author. Address: Bebek Sokak, 9/7 Aydınlıkevler, Ankara, Turkey. Tel.: +90 312 596 96 51. E-mail address: [email protected] (A. Deg˘erliyurt).
or with papilledema in addition to cerebrospinal fluid (CSF) pressure elevation shown with lumbar puncture requires normal CSF content, no venous sinus abnormality or structural lesion of the brain parenchyma, ventricles or meninx that may cause pressure increase or ventriculomegaly on neuroimaging, and the exclusion of other causes of pressure increase such as drugs. While “idiopathic intracranial hypertension” a term that should be used for patients who meet all these criteria, “pseudotumor cerebri” is the term that is suitable for the patients where an etiology is definitely shown or suspected [2].
0387-7604/$ - see front matter Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2013.09.007
Please cite this article in press as: Deg˘erliyurt A et al. Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital.. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.09.007
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PTC is a preventable cause of vision loss and it is therefore important to diagnose it and begin prompt treatment. The disorder can occur in both genders and all age groups, although it is seen mainly in obese women of childbearing age. Unlike the case in adults, obesity and female predominance are not associated with in prepubertal children and a factor responsible for the etiology is frequently identified. PTC is diagnosed at increasing rates probably due to the increase in obesity prevalence all over the world and awareness about the disease [3]. The current clinical characteristics of PTC in pediatric patients were analyzed in this study.
Differences between idiopathic/symptomatic, prepubertal/pubertal, female/male and obese/nonobese groups were assessed with the v2 test. A p value of <0.05 was considered significant.
2. Methods
4. Results
The charts and computer records of 53 pediatric patients who had been diagnosed with PTC at the Ankara Pediatrics, Hematology–Oncology Training and Research Hospital between 2005 and 2012 were examined. The PTC diagnosis was based on Modified Dandy criteria (Table 1) [4]. Accordingly, patients with symptoms and signs of increased intracranial hypertension whose neurological examination was normal except for papilledema and/or 6th and 7th cranial nerve palsy, and CSF pressure of 200 mm H2O and over, with normal biochemical and microbiological examination, and no hydrocephalus, mass, structural, or vascular lesion which would lead to increased intracranial hypertension on neuroimaging were included in the study. Patients over the age of 11 years were classified as pubertal and patients at or under the age of 11 as prepubertal. Patients with a body mass index at or over 95% according to age were grouped as obese. Patients in whom the increased intracranial pressure had occurred for any reason were classified as secondary (symptomatic) PTC and patients who did not have any etiological factor were classified as idiopathic intracranial hypertension. The general, neurological, and fundus examination of the patients was performed, and an eye examination including Snellen visual acuity and Goldman visual field perimetry was also performed in cooperating patients. All patients underwent tests for complete blood count, serum ferritin, serum iron and iron binding capacity, routine blood chemistry, thyroid function tests, parathyroid hormone, ACTH, cortisol, sedimentation rate, ANA, Anti-ds DNA, anticardiolipin antibodies, vita-
A total of 53 patients consisting of 32 females (60.4%) and 21 males (39.6%) diagnosed with PTC were analyzed. The mean age of the patients at admission was 10.9 years and ranged from 3 years to 17 years. There were 30 idiopathic, and 23 symptomatic cases. The etiological factor for PTC could be demonstrated in 43% of the patients. The distribution of idiopathic and symptomatic patients by gender, puberty status and obesity are presented in Table 2. Although using secondary sexual characteristics is recommended to separate pubertal and prepubertal children, this classification is rarely adopted in the pediatric PTC literature. Usually a certain age is chosen to separate older and younger children [4]. For this reason we accepted the patients under 12 years old, as prepubertal. Of the patients 51% (n = 27) were 12 years and older, and 49% (n = 26) were 11 years and younger. The pubertal and prepubertal patient percentages were almost equal. The male percentage was 54% (n = 14) for prepubertal patients while the female percentage was 74% (n = 20) for pubertal patients. The percentage of female patients in the pubertal period was significantly higher (p = 0,038). The relationship between gender and obesity at pubertal status is presented in Table 3. Obese patients made up 40% (n = 12) of idiopathic patients and 30% (n = 7) of symptomatic patients. The obesity rate was 41% (n = 11) for pubertal patients and 31% (n = 8) for prepubertal patients. We found no significant relationship between obesity and the etiology or puberty. The most common symptom was headache at 88% (n = 47). This was followed by nausea and/or vomiting in 30% (n = 16), diplopi and/or blurred vision in 28% (n = 15) and dizziness in 9% (n = 5). A patient with epilepsy and a patient with acute lymphoblastic leukemia (ALL) who was being prepared for a bone marrow transplant were found to have papilledema and diagnosed during routine examination although no symptoms were present (patients 23 and 52). Papilledema was found in all patients on neurological examination.
Table 1 Modified criteria of Dandy. 1. Signs of increased intracranial pressure. 2. No localizing neurologic signs otherwise, with the single exception of unilateral or bilateral paresis in nerve VI. 3. Cerebrospinal fluid can exhibit increased pressure, but no cytologic or chemical abnormalities otherwise. 4. Normal to small symmetric ventricles must be demonstrated.
mins A, D and, when necessary, infectious agents regarding the etiology of secondary pseudotumor cerebri. All patients except for one with a cochlear implant due to Usher syndrome underwent brain magnetic resonance imaging (MRI) and 47 patients underwent brain magnetic resonance venography (MRV). 3. Statistical analyses
Please cite this article in press as: Deg˘erliyurt A et al. Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital.. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.09.007
A. Deg˘erliyurt et al. / Brain & Development xxx (2013) xxx–xxx Table 2 The distribution of idiopathic and symptomatic patients by gender, puberty status and obesity.
Female Male Prepubertal Pubertal Obese Nonobese
Idiopathic n(%)
Symptomatic n(%)
p
19 11 14 16 12 18
13 (56.5) 10 (43.5) 12 (52.2) 11 (47.8) 7 (30.4) 16 (69.6)
0.615
(63.3) (36.7) (46.7) (53.3) (40.0) (60.0)
0.691 0.472
Table 3 The relationship between gender and obesity at pubertal status.
Female Male Obese Nonobese
Pubertal n(%)
Prepubertal n(%)
20 (74.1) 7 (25.9) 11 (40.7) 16 (59.3)
12 (46.2) 14 (53.8) 8 (30.8) 18 (69.2)
p 0.038* 0.449
Abducens nerve (patients 11,33,36,39,45) or facial nerve (patient 1) paresis was found in 6 patients (11.3%).The clinical characteristics of the patients are presented in Tables 4a and 4b. Cerebral venous sinus thrombosis was found in 6 patients, upper respiratory tract infections in 4 patients, anemia in 4 patients (iron deficiency anemia in three patients, aplastic anemia in one patient), steroid withdrawal in 3 drug resistant epilepsy patients, PTC probably related to all-trans retinoic acid (ATRA), risperidone, cyclosporine usage in 3 patients and PTC due to Brucella, post-traumatic, and slit ventricle syndrome in one patient each in the etiology of the secondary PTC group. The most common comorbid diseases in the idiopathic group were seemed to be related to obesity (Hypertension in 5 patients, deteriorated glucose tolerance, insulin resistance and diabetes in 5 patients, vitamin D deficiency in 4 patients, and polycystic ovarian syndrome (PCOS), renal agenesis/atrophy, and epilepsy in 2 patients each). The most common comorbid diseases seen in the symptomatic group were epilepsy in 4 patients, hematologic malignancy in 3 patients, and vitamin D deficiency in 2 patients. Brain imaging revealed unilateral transverse sinus narrowing in 7 patients (14.8%), cerebral venous sinus thrombosis in 6 patients (12.7%), and neurofibromatosis-related hamartoma in the optic nerve, posterior fossa arachnoid cysts, cystoperitoneal shunt in the patient with slit ventricle syndrome, encephalomalasia and chronic infarct sequelae in one patient each. All patients were started treatment with acetazolamide after the diagnosis except three idiopathic obese patients who were started topiramate. The papilledema recovered with only acetazolamide in 36 patients (72%). Topiramate was added to the treatment of six
3
patients who did not respond to acetazolamide treatment alone. Treatment was successful in three of these six patients. The three patients who did not benefit from acetazolamide plus topiramate therapy and 7 patients who had only received acetazolamide with no decrease in CSF pressure or papilledema after drug therapy for 3–9-months underwent a lumboperitoneal shunt procedure for a total of 10 (19%) patients. Improvement was seen in the papilledema in all patients after the lumboperitoneal shunt. None of the patients received steroid therapy or a ventriculoperitoneal shunt. Drug treatment duration ranged from 3 months to 24 months, with a mean duration of 6.4 months. Mean follow-up time was 9.5 months in idiopathic patients, 24.7 months in symptomatic patients, and 16.5 months (3–52 months) for all patients. Visual field assessment showed mild or moderate visual field defects in a total of 6 patients (11.3%). Visual field constriction was moderate in two pubertal and obese female patients (3.8%), one with venous thrombosis and the other idiopathic (patients 10,49). Recurrence developed in 3 (5.6%) prepubertal and symptomatic patients after a mean duration of 14 months. 5. Discussion 5.1. Clinical features Pseudotumor cerebri is a longtime recognized serious disorder that can cause some vision loss in most patients and lead to blindness in 10% although it has initially been thought to be a benign disease [5]. The incidence in the pediatric age group is unknown but it is considered to be rare, especially in prepubertal children [4]. However, 49% of our patient group was under 12 years of age. The percentages of pubertal and prepubertal patients were almost equal in our study group. Likewise the percentages of patients under the age of 12 or prepubertal varies between 45% and 60% in the literature [6– 9]. A few decades ago, a study from Canada reported that 50% of the cases were under the age of 6 in a series consisting of 38 patients [10]. These studies each had a significantly higher number of children than the general PTC literature, revealing that PTC is actually seen in younger children as frequently as in pubertal patients. However, the difficulty the children have in expressing their symptoms could have caused the PTC diagnosis to be missed or milder cases may not have been directed to pediatric neurology departments [4]. Although the female gender in adults is a risk for PTC, this relationship may not have been demonstrated in children because PTC in children may have due to other pathogenetic factors. While the male and female ratios in PTC are equal before puberty, the female patient ratio increases with age, and the adult gender
Please cite this article in press as: Deg˘erliyurt A et al. Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital.. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.09.007
4
No
Age (years)
Sex
Signs/symptoms
Neuroimaging (MRI–MRV)
Treatment/ duration
1
8
F
Facial paresis, headache
2 3 4
14 9 15
F M F
Headache, nausea Headache Headache, diplopi,
Left transverse, sigmoid sinuses and jugular vein narrow Normal Optic nerve hamartoma Normal
5 6
16 9
M M
Headache Headache
7
6
M
8 9
15 17
F F
10
14
F
Headache, nausea, vomiting Headache, blurred vision Headache, nausea, blurred vision Headache, dizziness
Vision prognosis
Comorbidity
Follow up period (months)
A – 3 months
Normal
–
3
Normal Normal Mild visual field constriction
Vit-D deficiency NF-type I –
19 18 15
Normal Normal
A – 3 months A – 3 months A–6 monthsL-P Shunt A – 5 months A – 9 months
– –
5 9
Retrocerebellar arachnoid cyst
A – 3 months
Normal Mild visual field constriction Normal
–
3
Normal Normal
A – 3 months TPM – 3 months A – 2 years L-P Shunt A – 3 months
Normal Normal
– Insu¨lin resistance
18 15
Moderate visual field constriction Normal
–
24
11
6
M
–
3
12
11
F
Normal
Vit-D deficiency
19
13 14 15 16 17
11 11 13 4 10
Normal Normal Normal Normal Mild visual field constriction
– – Vit-D deficiency – Usher syndrome + epilepsy + Cochlear implant
6 5 14 16 30
18
+
Normal
11
+
Mild visual field constriction
Hypertension + Renal atrophy, PCOS Hypertension
+
Normal
Hypertension,+ impaired glucose tolerance –
5
Normal MRV: Ø
Headache, diplopi, abducens paresis Headache, nausea, vomiting
Normal MRV: Ø
F M F F F
Headache, blurred vision Headache, diplopi Headache, diplopi Headache Headache
Normal MRV: Ø Normal Normal Normal CT: Normal MRV: Ø
17
F
Headache, blurred vision
Normal
19
8
M
Headache
Normal right transverse sinus narrow
20
15
M
21
16
F
22
12
F
Normal left transverse, sigmoid sinuses and jugular vein narrow Normal left transverse and sigmoid sinuses narrow Normal
23 24
7 15
M F
Headache, nausea, vomiting Headache, nausea, vomiting Headache, nausea, vomiting, blurred vision – Headache, vomiting, blurred vision
Normal
Normal Chronic infarct sequelae
A – 10 months TPM – 8 months A – 6 months A – 5 months A – 6 months A – 3 months A – 8 months TPM – 12 months L-P Shunt A – 3 months A – 12 months TPM – 4 months L-P Shunt A – 5 months
Obesity
+
+ +
+
A – 4 months
Normal
A – 3 months
+
Normal
A – 4 months TPM – 6 months
+ +
Normal Normal
Hypertension, PCOS + insu¨lin resistance Epilepsy Hypertension, stroke sequele, renal agenesis
12
8 5 7 6
A. Deg˘erliyurt et al. / Brain & Development xxx (2013) xxx–xxx
Please cite this article in press as: Deg˘erliyurt A et al. Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital.. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.09.007
Table 4a Clinical features of idiopathic PTC patients.
Impaired glucose tolerance, Vit-D deficiency
13 17
14
28 29
30
M F
8 13 11 25 26 27
F F M
A – 7 months A – 8 months A – 6 months TPM – 6 months A – 6 months A – 9 months TPM – 1 months TPM – 15 months
+
Normal
– Diabetes mellitus
+
Normal Normal
ANA + – – Normal Normal Normal
15 Normal left transverse sinus narrow Headache F
5.2. Etiology
6 10 Normal Normal Headache, nausea Headache
profile is reached after puberty [11]. Similarly, the male percentage was somewhat higher in our prepubertal patients while the female percentage was significantly higher after puberty (p = 0,038). These results confirm the notion of IIH in pubertal patients having the characteristics of adults and not childhood. IIH is found approximately 10 times more commonly in the obese population than the non-obese population (21/100,000 and 2.2/100,000) in adults [12]. Furthermore, obesity is seen more frequently in pubertal patients than prepubertal patients in PTC. The obesity rate was reported between 43% and 68% in pubertal patients and around 25% in prepubertal patients in relevant publications [8,9,13]. The obesity rate in our older children was also higher than in our prepubertal patients (41% and 31%). The most frequently reported symptoms in PTC are symptoms due to intracranial pressure increase such as headache, nausea and vomiting. Cranial nerve paresis can also be found on examination in addition to papilledema. Sixth nerve paresis has been reported in 9– 48% of cases. Cranial nerve paresis should improve on reduction of intracranial pressure in order to be able to say they are due to IIH [14]. Cranial nerve paresis that disappeared after treatment was observed in 9.4% of our patients. A cranial nerve paresis is reported to be more common in children under the age of 11 [9]. The majority (5 of 6 patients) of our patients with cranial nerve paresis were under the age of 11, supporting cranial nerve paresis is more frequent in younger children. Papilledema is usually considered to be a very significant neurological sign for PTC but the presence of PTC without papilledema has been demonstrated especially in patients with chronic headache and vomiting symptoms [7,15]. Papilledema was found in the neurological examination in all of our patients. In contrast to the cases without papilledema, asymptomatic PTC cases diagnosed by the identification of papilledema during routine ophthalmic examination are increasingly reported, especially at young ages [7,16,17]. Papilledema was identified and PTC was diagnosed during routine neurological examination of two patients who had no symptom or sign other than papilledema. Therefore, performing a careful fundus examination, is important not to miss the diagnosis.
12 9 6 Normal Normal Normal
5
Headache Headache Dizziness, nausea
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The absence of obesity and female gender dominance in young children with PTC suggests different mechanisms causing the pseudotumor cerebri in these patients. Therefore, a secondary cause, disease, or drug history that may cause PTC in an atypical patient such as prepubertal and/or non-obese adolescent should be investigated [7,18].
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A factor causing the PTC has been shown in 23 of our patients. The most frequent etiological factor in our patients was cerebral venous thrombosis that was present in 6 (11%) out of 53 patients. As about one third of cerebral venous thrombosis cases show clinical symptoms similar to idiopathic intracranial hypertension and the condition should be ruled out with imaging methods [19]. Cerebral venous thrombosis has been reported in 9–14% of PTC patients [9,20,21]. Unless computed tomographic venography (CTV) or MRV that formally show cerebral vascular formations is performed, CT or MRI may be insufficient in demonstrating cerebral venous thrombosis [5]. Therefore, venography for sinus thrombosis should be performed in all patients who present with a clinical picture of idiopathic intracranial hypertension. The relationship between infections and PTC has been known. PTC is commonly seen in children in seasons when pediatric viral–bacterial infections are frequently seen [22]. Upper respiratory tract infections were present in the etiology of four of our patients. PTC due to Brucella was diagnosed in one of our patients while being investigated for maculopapular rash and blurred vision. Brucella can present only with isolated intracranial hypertension without causing any other symptoms and must be considered in the PTC etiology especially in endemic regions [23]. Anemia was found in the PTC etiology of 4 of our patients. The patient with Fanconi aplastic anemia was using anabolic steroids. The good response to the PTC treatment and the absence of increased intracranial pressure despite continuation of anabolic steroids at the 27month follow-up suggest the anemia was responsible for the etiology. Tissue hypoxia developing due to anemia probably leads to changes in cerebral hemodynamics, causing capillary permeability increase and ultimately a rise in intracranial pressure [24]. Three patients with refractory epilepsy developed severe headaches after steroid therapy was decreased, and PTC was found. PTC related to steroids usually occurs following steroid termination. Headaches that occur during steroid discontinuation should therefore point towards intracranial hypertension. PTC due to steroid use has rarely been reported and is usually seen after long-term use [25]. Although PTC cases due to the use of steroids reported in the literature may be met with skepticism, 11b-hydroxysteroid dehydrogenase type 1, glucocorticoid dysregulation, and the presence of a multifactorial pathogenesis with inflammation in the center prevents ignoring the role of steroids [12,14]. Drugs and especially the vitamin A derivative ATRA have often been blamed in PTC etiology. We found that PTC had developed due to the use of ATRA, cyclosporine, and risperidone in 3 of our patients with hematologic malignancies. Our 4-year-old patient who had been started ATRA treatment developed PTC after
10 days, showing once again that the use of this drug in children under the age of 8 is hazardous in terms of PTC [26]. The patient taking risperidone for psychiatric disorders had stopped receiving multidrug chemotherapy a month ago and risperidone was therefore considered to be the probable etiologic agent. The third patient with hematological malignancy had been receiving cyclosporine when PTC emerged. The use of cyclosporine has rarely been reported in the etiology [27]. Slit ventricle syndrome can also cause secondary PTC. Patients who had previously been installed a ventriculoperitoneal (v-p) shunt, develop PTC later with the typical symptoms of increased intracranial pressure, and the ventricles are narrower unlike in shunt dysfunction. This clinical picture is not usually known and patients are examined in emergency services for hydrocephalus or shunt failure. Long-term headaches, worsening neurological status and sometimes vision loss develop due to delays in diagnosis. CSF pressure measurement must be performed for the diagnosis if no shunt dysfunction is present. Collapse of the ventricles around the catheter as a result of over drainage in these patients causes intermittent shunt dysfunction and symptoms of severe intracranial hypertension emerging intermittently [28]. Our patient who had been installed a v-p shunt about 10 years ago for a large arachnoid cyst had often presented at the emergency department recently because of severe headaches (patient 40) and had papilledema but no shunt dysfunction or ventricular dilatation. After a lumboperitoneal shunt was placed in the patient with a CSF pressure over 300 mm H2O, his symptoms decreased rapidly, the papilledema recovered, and the symptoms had disappeared completely on follow-up at 6 months. Intracranial hypertension due to slit ventricle syndrome must therefore be kept in mind in patients with shunts who have intermittent headaches, symptoms of increased intracranial pressure and no shunt dysfunction. Vitamin D deficiency was found in six (11.3%) of our patients. Vitamin D deficiency has been reported with PTC in previous publications. These patients have generalized malnutrition suggesting that PTC developed due to hypocalcemia or malnutrition, not lack of vitamin D [25]. However, Vitamin D has not been reported in the PTC etiology in Pubmed publications in English in the last 20 years. Vitamin D deficiency is a common health problem all over the world due to the habit of modern living today. Vitamin D deficiency and insufficiency in children were found at a rate of 40% in Ankara in a recent study [29]. Because of the lack of a clinical picture of hypocalcemia, malnutrition, or renutrition in our patients, the vitamin D deficiency was considered to be coincidental and not an etiological factor. The dural venous pressure increase due to venous sinus stenosis in idiopathic intracranial hypertension pathogenesis has attracted interest in recent years [30].
Please cite this article in press as: Deg˘erliyurt A et al. Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital.. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.09.007
No
Age (years)
Sex
Symptoms/signs
Etiology
Neuroimaging (MRI–MRV)
Treatment/duration
31
16
M
Headache
Sinus thrombosis
32
4
M
ATRA treatment
33
9
M
34
12
M
Headache, nausea, vomiting Headache, nausea, vomiting, diplopi, abducens paresis Headache
Right transverse sinus thrombosis Normal
35
6
F
Headache
36
9
F
37
5
F
Diplopi, abducens paresis Headache
38
5
F
39
16
F
40
16
M
41 42
9 17
M F
43
7
M
44
12
F
45
3
M
46
13
F
47
14
F
48
5
F
Headache, vomiting, dizziness
49
13
F
Headache
Sinus thrombosis
Fanconi aplastic anemia Thrombosis
Obesity
Vision prognosis
Comorbidity
Follow up period (months)
A – 6 months
Normal
–
19
A – 8 months
Normal
AML – M3
27
Superior sagittalis, confluence and left transverse sinuses thrombosis Normal
A – 6 months L-P Shunt
Normal
Nephrotic syndrome
23
A – 6 months
Normal
–
33
Vena jugularis interna thrombosis
Normal
–
26 Recurrence after a year
Normal
FMF
25
Congenital diseritropoetic anemia, refractory epilepsy AML + Bone marrow transplantation –
20
Sinusitis
Normal
A – 7 months again after recurrence A – 7 months) A – 8 months
Steroid discontinuation
Encephalomalasia
A – 6 months
Normal
Headache
Risperidone
Normal
Normal
Spotty vision, diplopi, abducens paresis Headache
Sinus thrombosis
Left transverse and sigmoid sinuses thrombosis Cystoperitoneal shunt MRV: Ø Normal Normal
A – 5 months L-P Shunt A – 4 months A– L-P A– A–
3 months Shunt 6 months 3 months
Normal
Headache Headache, nausea, dizziness Headache, nausea, vomiting Headache, blurred vision Headache, abducens paresis Skin rash, blurred vision Headache
Slit ventricle syn drome Post-traumatic Iron deficiency anemia Iron deficiency anemia Sinusitis
+
Normal
12
Normal Normal
Epilepsy, Cystoperitoneal shunt – Vit-D deficiency
12 3
A – 6 months
Normal
–
30
Normal
A – 9 months
Normal
–
32
Otitis
Normal
A – 6 months
Normal
–
19
Brucellosis
NormalMRV: Ø
A – 3 months
+
Normal
-
52
Iron deficiency anemia Otitis + rhinosinusitis
Normal
A – 3 months
+
Normal
Vit-D deficiency
36
Normal
A – 6 months TPM–2 months L-P Shunt A – 1 years L-P Shunt
+
Normal
–
32Recurrence after 2 years
+
Moderate visual field constriction
–
36
Sinus thrombosis
Left transverse and sigmoid sinuses thrombosis
Normal
24
6
A. Deg˘erliyurt et al. / Brain & Development xxx (2013) xxx–xxx
(continued on next page) 7
Please cite this article in press as: Deg˘erliyurt A et al. Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital.. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.09.007
Table 4b Clinical features of symptomatic PTC patients.
18Recurrence after 6 months
7
Normal
ALL + Bone marrow transplantation Refractory epilepsy Headache 7 53
M
15 52
M
Steroid discontinuation
A – 6 months
Left transverse, sigmoid sinuses and vena jugularis narrow Normal Cyclosporine
A – 12 months 13 51
F
Headache, vomiting, dizziness –
Thrombosis
Confluence sinu¨s thrombosis
A – 6 months again after recurrence A – 6 months)
+
Normal
12 – Normal
Follow up period (months) Comorbidity Vision prognosis Obesity Treatment/duration Neuroimaging (MRI–MRV) Etiology Symptoms/signs Sex Age (years) No
Table 4b Clinical features of symptomatic PTC patients.
A: Acetazolamide, AML: acute myeloid leukemia, ANA: anti nuclear antibody, ATRA: all-trans retinoic acid, CT: computerized tomography, F: female, FMF: familial mediterranean fever, L-P: lumboperitoneal, M: male, MRI: magnetic resonance imaging, MRV: magnetic resonance venography, PCOS: polycystic ovary syndrome, TPM: topiramate.
A. Deg˘erliyurt et al. / Brain & Development xxx (2013) xxx–xxx
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If narrowing is present in the venous sinus, the highpressure gradient it creates will prevent reabsorption of CSF. In contrast, if the intracranial pressure is high, this will lead to vascular compression and ultimately venous collapse. The stenosis appearance in MRV was reported to recover with the intracranial pressure becoming normal with methods such as lumbar puncture, lumboperitoneal shunt, and endovascular stent in some studies. However, some studies report the appearance of the stenosis does not change and persists although the pressure has decreased. These different results suggest that some narrowed areas are fixed and thus play a role in the etiology of PTC, while some develop secondary to the increased intracranial pressure [31]. Transverse sinus stenosis, debated in the pathogenesis, was observed in 7 (13%) of our patients. Our patients did not have follow-up MRI/MRV so we do not know their post-treatment conditions and whether this finding in our patients was a constant finding or secondary to the PTC. The topic of venous sinus stenosis has not been examined sufficiently in other publications including large case groups of children related to PTC where modern imaging methods have been used. Although this may be related to the consideration of transverse sinus narrowing as a normal variation, follow-up brain MRI and MRV performed in studies including large case groups will clarify the vascular stenosis/collapse puzzle for which a role in pathogenesis is controversial. 5.3. Treatment The drug of choice in the treatment of PTC is the carbonic anhydrase inhibitor acetazolamide. Acetazolamide probably reduces intracranial pressure by decreasing CSF production. Topiramate is being preferred in the treatment of intracranial hypertension in recent years due to its characteristics of being a carbonic anhydrase inhibitor, as well as leading to analgesia and weight loss. A study demonstrated its efficacy as comparable to acetazolamide to treat PTC [32]. Acetazolamide alone provided improvement in papilledema in 72% of our patients. The rate of shunt treatment in idiopathic intracranial hypertension is reported to be around 20% [4]. Despite 3–9 months of drug treatment, no decrease was seen in the papilledema or CSF pressure in 19% (n = 10) of our patients and a lumboperitoneal shunt was therefore placed. The papilledema resolved and the headaches disappeared in all patients after shunt treatment. Steroid treatment and v-p shunting were not used in any of our patients. Although the presence of inflammatory cytokines in the pathogenesis of PTC suggests that steroid therapy is appropriate, steroids are not recommended in chronic idiopathic intracranial hypertension
Please cite this article in press as: Deg˘erliyurt A et al. Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital.. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.09.007
A. Deg˘erliyurt et al. / Brain & Development xxx (2013) xxx–xxx
treatment in children because of their side effects such as weight gain and rebound intracranial hypertension in reduction periods [14]. Steroids reduce intracranial pressure quickly and are therefore recommended for intravenous use or short-term oral therapy only in severe headache, severe papilledema and very high intracranial pressure [4,2]. 5.4. Prognosis Permanent visual field constriction in PTC has been reported 17% of the patients [9]. Mild or moderate visual field constriction was found in 11.3% of our patients in visual assessment on follow-up. The visual field constriction was moderate only in 2 pubertal and obese patients (3.7%), supporting the argument that puberty increases the vision loss risk [33]. The prognosis can be said to be very good in our patients except the patients who were moderately affected due to treatment compliance. PTC is a chronic disease and its treatment lasts for months. Patient compliance is crucial as treatment and follow-up take a long time. In conclusion, PTC is not uncommon in children and is seen as frequently as in adolescence. The pubertal PTC patients differ from prepubertal patients with characteristics such as female dominance and higher rate of obesity. An etiological factor causing PTC is present in about half the patients in childhood. Currently the main etiological factors of the disease in children consists of cranial venous thrombosis, infections, anemia and drugs. Vitamin D deficiency is not currently an important factor in the etiology when it is not together with other factors such as malnutrition and hypocalcemia. The reduction of steroids seems to be more important than the use of steroids in the development of PTC. Studies conducted in large case group including pretreatment and post-treatment MRVs are needed to clarify the controversial place of cerebral venous sinus stenosis in the pathogenesis. PTC is a disease that requires long-term treatment and follow-up but the prognosis is good in patients who are diagnosed early, receive appropriate treatment and show good compliance with the treatment. References [1] Skau M, Brennum J, Gjerris F, Jensen R. What is new about idiopathic intracranial hypertension? An updated review of mechanism and treatment. Cephalalgia 2006;26:384–99. [2] Spennato P, Ruggiero C, Parlato RS, Buonocore MC, Varone A, Cianciulli E, et al. Pseudotumor cerebri. Childs Nerv Syst 2011;27:215–35. [3] Dhungana S, Sharrack B, Woodroofe N. Idiopathic intracranial hypertension. Acta Neurol Scand 2010;121:71–82. [4] Standridge SM. Idiopathic intracranial hypertension in children: a review and algorithm. Pediatr Neurol 2010;43:377–90. [5] Ball AK, Clarke CE. Idiopathic intracranial hypertension. Lancet Neurol 2006;5:433–42.
9
[6] Per H, Canpolat M, Gu¨mu¨ßs H, Poyrazog˘lu HG, Yıkılmaz A, Karaku¨ßcu¨k S, et al. Clinical spectrum of the pseudotumor cerebri in children: etiological, clinical features, treatment and prognosis. Brain Dev 2013;35:561–8. [7] Tibussek D, Schneider DT, Vandemeulebroecke N, Turowski B, Messing-Juenger M, Willems PH, et al. Clinical spectrum of the pseudotumor cerebri complex in children. Childs Nerv Syst 2010;26:313–21. [8] Kesler A, Fattal-Valevski A. Idiopathic intracranial hypertension in the pediatric population. J Child Neurol 2002;17:745–8. [9] Phillips PH, Repka MX, Lambert SR. Pseudotumor cerebri in children. J AAPOS 1998;2:33–8. [10] Couch R, Camfield PR, Tibbles JA. The changing picture of pseudotumor cerebri in children. Can J Neurol Sci 1985;12:48–50. [11] Balcer LJ, Liu GT, Forman S, Pun K, Volpe NJ, Galetta SL, et al. Idiopathic intracranial hypertension: relation of age and obesity in children. Neurology 1999;52:870–2. [12] Sinclair AJ, Ball AK, Burdon MA, Clarke CE, Stewart PM, Curnow SJ, et al. Exploring the pathogenesis of IIH: an inflammatory perspective. J Neuroimmunol 2008;201– 202:212–20. [13] Brara SM, Koebnick C, Porter AH, Langer-Gould A. Pediatric idiopathic intracranial hypertension and extreme childhood obesity. J Pediatr 2012;161:602–7. [14] Rangwala LM, Liu GT. Pediatric idiopathic intracranial hypertension. Surv Ophthalmol 2007;52:597–617. [15] Wraige E, Chandler C, Pohl KR. Idiopathic intracranial hypertension: is papiledema inevitable? Arch Dis Child 2002;87:223–4. [16] Distelmaier F, Sengler U, Messing-Juenger M, Assmann B, Mayatepek E, Rosenbaum T. Pseudotumor cerebri as an important differential diagnosis of papiledema in children. Brain Dev 2006;28:190–5. [17] Bassan H, Berkner L, Stolovitch C, Kesler A. Asymptomatic idiopathic intracranial hypertension in children. Acta Neurol Scand 2008;118:251–5. [18] Randhawa S, Van Stavern GP. Idiopathic intracranial hypertension (pseudotumor cerebri). Curr Opin Ophthalmol 2008;19:445–53. [19] De Simone Roberto, Ranieri A, Bonavita V. Advancement in idiopathic intracranial hypertension pathogenesis: focus on sinu¨s venous stenosis. Neurol Sci 2010;31(Suppl. 1) S33-9. [20] Lin A, Foroozan R, Danesh-Mayer HV, De Salvo G, Savino PJ, Sergott RC. Occurence of cerebral venous sinu¨s thrombosis in patients with presumed idiopathic intracranial hypertension. Ophthalmology 2006;113:2281–4. [21] Standridge SM, O’Brien SH. Idiopathic intracranial hypertension in a pediatric population: a retrospective analysis of the initial imaging evaluation. J Child Neurol 2008;23:1308–11. [22] Distelmaier F, Tibussek D, Schneider DT, Mayatepek E. Seasonal variation and atypical presentation of idiopathic intracranial hypertension in prepubertal children. Cephalalgia 2007;27:1261–4. [23] Yılmaz S, Serdarog˘lu G, Go¨kben S, Tekgu¨l H. A case of neurobrucellosis presenting with isolated intracranial hypertension. J Child Neurol 2011;26:1316–8. [24] Henry M, Driscoll MC, Miller M, Chang T, Minniti CP. Pseudotumor cerebri in children with sickle cell disease: a case series. Pediatrics 2004;113:e265–9. [25] Lessell S. Pediatric pseudotumor cerebri (idiopathic intracranial hypertension). Surv Ophthalmol 1992;37:155–66. [26] Mahmoud HH, Hurwitz CA, Roberts WM, Santana VM, Ribeiro RC, Krance RA. Tretinoin toxicity in children with acute promyelocytic leukaemia. Lancet 1993;342:1394–5. [27] Cruz OA, Fogg SG, Roper-Hall G. Pseudotumor cerebri associated with cyclosporine use. Am J Ophthalmol 1996;122:436–7. [28] Rekate HL. Shunt related headaches: the slit ventricle syndromes. Childs Nerv Syst 2008;24:423–30.
Please cite this article in press as: Deg˘erliyurt A et al. Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital.. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.09.007
10
A. Deg˘erliyurt et al. / Brain & Development xxx (2013) xxx–xxx
[29] Andıran N, C ¸ elik N, Akcßa H, Dog˘an G. Vitamin D deficiency in children and adolescents. J Clin Res Pediatr Endocrinol 2012;4:25–9. [30] Dyknuizen MJ, Hall J. Cerebral venous sinus system and stenting in pseudotumor cerebri. Curr Opin Ophthalmol 2011;22:458–62. [31] Stienen A, Weinzierl M, Ludolph A, Tibussek D, Hausler M. Obstruction of cerebral venous sinus secondary to idiopathic intracranial hypertension. Eur J Neurol 2008;15:1416–8.
[32] C ¸ elebisoy N, Go¨kcßay F, S ß irin H, Akyu¨rekli O. Treatment of idiopathic intracranial hypertension: topiramate vs acetazolamide, an open-label study. Acta Neurol Scand 2007;116:322–7. [33] Stiebel-Kalish H, Kalish Y, Lusky M, Gaton DD, Ehrlich R, Shuper A. Puberty as a risk factor for less favorable visual outcome in idiopathic intracranial hypertension. Am J Ophthalmol 2006;142:279–83.
Please cite this article in press as: Deg˘erliyurt A et al. Pseudotumor cerebri/idiopathic intracranial hypertension in children: An experience of a tertiary care hospital.. Brain Dev (2013), http://dx.doi.org/10.1016/j.braindev.2013.09.007