Pseudotumor cerebri syndrome (PTCS) is a rare condition described for the first time in 1893 [9], with elevated intracranial pressure, normal CSF analysis, and without intracranial lesions on neuroimaging. PTCS can be primary (also known as IIH), if no cause is identified, or secondary, if a specific cause is recognized (i.e. drugs administration, abnormalities of the cerebral venous system, or predisposing systemic diseases).
Though PTCS can affect both children and adults, there are significant differences regarding the clinical spectrum, risk factors and epidemiology. In children, the incidence is 0.6–0.9/100,000/year [10], and it is very rare in infancy. To our knowledge, only 26 infants have been described so far; among them only 6 met all the diagnostic criteria [1,2,3,4,5]. In order to find literature on already described cases of infantile PTCS, we searched Pubmed from inception to February 2021; age limit was 0–23 months and we used the following terms combined with boolean operators AND and OR: idiopathic intracranial hypertension, infantile idiopathic intracranial hypertension, pseudotumor cerebri, infants. Out of 354 articles, 143 were case reports, reviews and systematic reviews; finally, 17 papers describing 26 infants were included in our brief review.
IIH is the most common kind of PTCS both in children and adults [11]. Though female gender, obesity, and polycystic ovary represent risk factors for IIH in pubertal children, this is not shown in younger ones, particularly in infants [12]. Among the 26 infants with IIH described in literature, a couple of twins were affected by cystic fibrosis and Vitamin A deficiency, one had isolated Vitamin A deficiency, four had Vitamin D deficiency, two had positive serum human herpesvirus-6 testing, two had hypophosphatasia, and four had a history of topical hydrocortisone treatment some days before the onset of symptoms. In our case, elevated serum Vitamin A level was found.
The clinical manifestations of IIH vary with age. Headache is a key symptom, described as progressive frontal pain worsening with Valsalva maneuver and postural changes, but it is reported only by 36.6% of pediatric patients [13]. Other symptoms include nausea, vomiting, neck pain, tinnitus, visual impairment and diplopia secondary to VI cranial nerve palsy [14].
Younger children may show nonspecific symptoms like irritability, hyporeactivity, anorexia, sleep disruption, head tilting, and less often papilledema. Infants may present a bulging fontanel and irritability as the most commonly reported initial symptoms, as well as vomiting [1,2,3,4,5]. Another unequivocal sign of intracranial hypertension is papilloedema, however it was reported only in 9 of the 26 infants described in literature.
Diagnostic criteria were firstly formulated by Dandy in 1937 [15], then Smith re-proposed them in 1985 [16], as follows: 1) signs and symptoms of intracranial hypertension, 2) localized neurological signs (except paralysis of the VI pair of cranial nerves), 3) CSF opening pressure > 25 cmH20, with normal examination, 4) negative head CT scan.
A new revision was published in 2013 (Table 1): the new criteria are more restrictive and differentiate the diagnosis into confirmed IIH (papilloedema and increased CSF pressure), probable IIH (papilloedema and normal CSF pressure), and IIH without papilloedema (only increased pressure with VI cranial nerve palsy) [8]. Therefore, ophthalmological evaluation of fundus oculi, LP and neuroimaging are required to make a diagnosis. The ophthalmological evaluation aims to identify papilloedema and should be performed by a pediatric specialist. Typically, the optic disc is pale and oedematous, with surrounding tortuous and dilated retinal vessels [17].
MRI of the brain is necessary to exclude any lesion that could produce intracranial hypertension, and should include contrast medium infusion and angiographic study [8]. Moreover, characteristic radiological signs are: sella turcica with narrowed pituitary peduncle, as observed in our infant, and crushing of the posterior pole of the eye [8].
The LP, which is both a diagnostic and a therapeutic procedure itself, must be performed whenever intracranial hypertension is suspected, after excluding possible contraindications. Not only the opening pressure, but also CSF analysis is important for diagnostic purposes. In our infant, no abnormal CSF values were found, except for proteins slightly higher than normal.
Even if the measurement of CSF opening pressure could be an important additional diagnostic factor, actually it is not routinely performed [18]. In our case, the neurosurgeon described the opening pressure as increased on both occasions by counting the number of CSF drops flowing through the spinal needle in a specified period, as already described [6, 7], however we do not know the precise pressure measurement. In published studies on PTCS, CSF opening pressure was not documented for all the patients, because other factors documented indirectly elevated CSF pressure (symptoms, imaging data) [8, 19]. Our infant presented with papilloedema and bulging anterior fontanel, which represent indirect signs of high CSF pressure. Indeed, data about CSF opening pressure in childhood are scanty and come mainly from patients ageing 1–18 years [20, 21], but to our knowledge no clear threshold has been established in infants < 1 year, in which the open fontanel and sutures might influence the measure. Moreover, other factors may affect the opening pressure value: in particular sedation-related hypercapnia may raise it, as well as crying in not sedated children [8, 20]. For these reasons, a cut-off of 28 cmH2O could be useful more for research than for clinical purpose [20]. In his article, Ellis concluded that the normal range for CSF opening pressure measured in a flexed lateral decubitus position in children is 10 to 28 cm H2O [6]. However, Avery et al. presented a case to describe the inaccuracy of CSF opening pressure measures by LP: they concluded that a single CSF opening pressure value should not be considered as the only determinant of elevated intracranial pressure [20]. On the other hand, low opening pressure should not exclude the diagnosis of PTCS if typical symptoms and papilloedema are reported [8].
Principles of therapy in children are based on guidelines for adult, aiming mainly to prevent permanent loss of vision and relieve from symptoms (above all irritability in infants, and headache in older children). The therapeutic cornerstone is acetazolamide, a carbonic anhydrase inhibitor that reduces the production of CSF; in a recent study, acetazolamide was effective in 76% of children with IIH [21]. The recommended starting dose is 10–20 mg/kg/day, which can be progressively increased up to 100 mg/kg or 2 g per day. Side effects are mild metabolic acidosis, fatigue, dysgeusia and paraesthesia. In case of failure or contraindications to give acetazolamide, topiramate can be used, thanks to its weak inhibitory action on carbonic anhydrase [22].
I.v. corticosteroids could be prescribed in association with acetazolamide, in case of severe visual impairment at the onset. However, currently acetazolamide alone is preferred also in this case, due to fewer side effects [23]. In our case, the corticosteroid was administered for anti-oedema purposes in association with acetazolamide, in consideration of poor general conditions and marked irritability.
The optimal duration of therapy is not well defined, but it should be continued until complete resolution of the papilloedema. A recent review of pediatric cases shows that the course of the disease is highly variable, usually showing remission after more than 7 months [1]. In our case, the infant was treated for 2 months with acetazolamide, with complete resolution of papilloedema and of symptoms 3 months after discharge.
In case of rapid worsening of visual function despite adequate medical therapy, neurosurgical interventions may be needed, such as fenestration of the optic nerve, or lumboperitoneal or ventriculoperitoneal shunt [24].
The main complication of untreated IIH is permanent vision loss (up to 20% of children), so prompt therapy and strict pediatric and ophthalmological follow-up is required [25].
Negative prognostic factors are visual impairment and severe papilloedema already at the onset. Finally, the risk of recurrence is estimated at 18–20% and is more frequent in the first 18 months after diagnosis [26].
In conclusion, infantile IIH is an extremely rare disease, not yet well described in literature. Of course, affected infants cannot describe typical symptoms such as visual impairment, diplopia, tinnitus, headache and nausea, and this makes the diagnosis difficult and often late. Bulging anterior fontanel in otherwise healthy infants with normal neuroimaging should be always considered suggestive of IIH, but can be a late sign. In accordance with literature, our case shows how irritability and anorexia, especially if associated with vomiting [1], may represent an early sign of intracranial hypertension in infancy. In such cases, LP should be always done, hopefully with CSF opening pressure measurement, which is among coded diagnostic criteria, but whose threshold is controversial in infants. Early diagnosis, timely start of acetazolamide and strict pediatric and ophthalmological follow-up help in reducing the risk of relapse and safeguard the patient’s visual acuity.
