Pediatric Intracranial Hypertension

Accepted Manuscript Pediatric Intracranial Hypertension: A Current Review Shawn C. Aylward, MD, Assistant Professor, Rachel E. Reem, MD, Assistant Professor PII:

S0887-8994(16)30285-5

DOI:

10.1016/j.pediatrneurol.2016.08.010

Reference:

PNU 8967

To appear in:

Pediatric Neurology

Received Date: 22 April 2016 Revised Date:

8 August 2016

Accepted Date: 10 August 2016

Please cite this article as: Aylward SC, Reem RE, Pediatric Intracranial Hypertension: A Current Review, Pediatric Neurology (2016), doi: 10.1016/j.pediatrneurol.2016.08.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Pediatric Intracranial Hypertension: A Current Review

Shawn C Aylwarda

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Rachel E Reemb

Correspondence: Shawn Aylward, M.D. Nationwide Children’s Hospital

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a. MD, Assistant Professor, Dept. of Neurology Nationwide Children’s Hospital. Columbus, OH. [email protected] b. MD, Assistant Professor, Dept. of Ophthalmology Nationwide Children’s Hospital. Columbus, OH. [email protected]

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Ohio State University College of Medicine Division of Child Neurology E526 700 Children’s Drive

Telephone:

614-722-4625

614-722-4633

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Telefax:

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Columbus, Ohio 43205

[email protected] Word Count: 5,862 Running Title: Pediatric IH Review

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Abstract Primary (idiopathic) intracranial hypertension has traditionally been considered a rare entity,

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with no good estimates of the pediatric incidence in the United States. There have been attempts to revise the criteria over the years and adapt the adult criteria for use in pediatrics. The clinical presentation varies with age, with symptoms tending to be less evident in younger individuals. In

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the pre-pubertal population, incidentally discovered optic disc edema is relatively common. By far the most consistent symptom is headache, with other symptoms including nausea, vomiting

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tinnitus and diplopia. Treatment mainstays include weight loss and acetazolamide. Furosemide can be considered and has shown synergistic benefit when used in conjunction with acetazolamide. Surgical interventions are relatively uncommon, but include optic nerve sheath fenestration and cerebrospinal fluid shunting. Pain and permanent vision loss are the two major complications of this disorder and thus warrant aggressive treatment. Once intracranial

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hypertension has resolved, up to 2/3 of patients develop a new or chronic headache type that is

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different from their initial presenting headache.

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Search terms: pseudotumor cerebri; intracranial hypertension; pediatric; headache

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History Primary intracranial hypertension (idiopathic intracranial hypertension, pseudotumor cerebri) has

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traditionally been considered a rare entity. Though the annual incidence in the United States adult population is estimated at 0.9 per 100,000, there are no good estimates in the pediatric population.1 In Germany the annual pediatric incidence is estimated at 0.47 per 100,000, and in Croatia, 1.2 per 100,000.2,3 In the provinces of Nova Scotia and Prince Edward Island, the annual

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incidence was 0.9 per 100,000 in children 2 to 15 years old between 1979 and 1994.4

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Surprisingly in the same population from 1997 to 2007, the annual incidence fell to 0.6 per 100,000 in children 2 to 16 years, despite increased rates of childhood obesity during this period.5

The original description by Quincke appeared in 1897. He described the clinical findings in a

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series of patients with increased intracranial pressure in the context of normal cerebral spinal fluid (CSF) and labeled this as “meningitis serosa”.6 In the 120 years following Quincke’s publication, it has gone by many different names including serous meningitis, otitic

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hydrocephalus, toxic hydrocephalus, and hypertensive meningeal hydrops. In 1904, “pseudotumor cerebri” was coined by Nonne reflecting the similarities in presentation to patients

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with an intracranial mass.7 In 1955, Foley suggested the condition be renamed “benign intracranial hypertension” to avoid the negative connotation associated with a “pseudo-cancer” diagnosis.8 In the 1980s, following a series of reports describing permanent visual defects, the syndrome was renamed idiopathic intracranial hypertension.9,10 Today, pseudotumor cerebri and idiopathic intracranial hypertension remain the two common terms amongst both practitioners and the lay public. There remains confusion with both of these terms and practitioners still often misdiagnose patients with pseudotumor cerebri despite a direct

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cause being found. There have been recent attempts to clarify the terminology surrounding the ambiguity in these terms. Some have attempted to use a broader designation of “pseudotumor cerebri syndrome” which still includes the designation of idiopathic when a cause is not found.11The authors prefer the use of the terms primary intracranial hypertension (PIH) and secondary

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intracranial hypertension (SIH).14 In cases where a clear precipitant of increased intracranial pressure is not found, individuals would be labeled as primary in place of idiopathic. Although

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they may have risk factors for increased intracranial pressure, such as female gender, post-

pubertal status, obesity or polycystic ovarian syndrome, these conditions do not directly result in

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increased pressure. The concept of SIH is reserved for cases where the intracranial hypertension is the direct result of another condition, such as cerebral sinus venous thrombosis, or minocycline use.

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Diagnostic Criteria

The diagnostic criteria for adult PIH stems from a series of 22 patients reported by Dandy in 1937.15 His report resulted in a set of initial criteria bearing his name, though he did not propose

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them in his series. The main limitation of this set of criteria is that imaging of the time was

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limited to pneumoencephalograms, in which evidence of an intracranial mass would only be noted by distortion or compression of the ventricles on plain film skull x-ray. This method would make it impossible to visualize non-mass causes such as a sinus venous thrombosis. In 1985, Smith proposed modernization of the criteria into what is now accepted as the modified Dandy criteria to include more current imaging criteria.16 These criteria include: 1) signs and symptoms of raised intracranial pressure (headache, nausea, vomiting, transient visual obscurations, or papilledema), 2) absence of localizing neurologic signs with the exception of unilateral or

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bilateral abducens nerve palsy, 3) CSF opening pressure of >25cm H20 with normal composition, 4) normal to small ventricles as demonstrated by Computed tomography (CT)

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study (today magnetic resonance imaging (MRI) is the modality of choice). Recently there have been further revisions to the criteria for PIH and the requirements increased, though the basic requirements remain.12 The major concern with these stricter criteria is that it

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will result in missed cases, and thus potential morbidity.17-20 There has been debate as to

application of the adult criteria to pediatric cases. One area that has seen recent change is the

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normative values for CSF opening pressure. Adult normative values are well established but due to ethical considerations there have not been many pediatric studies sampling normal patients. Adult studies have consistently shown that the pressure must be in excess of 25cm H20 to be considered abnormal.21-24 There has not been a correlation found to degree of obesity and opening pressure in normal patients.21-23 Studies have shown that flexed positioning and changes

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in arterial carbon dioxide (CO2) result in an increased opening pressure in pediatric patients.25-27 One study compared readings in both the flexed and extended position and found a statistically significant difference.25 Although the authors state that this change is likely of little clinical

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significance, there were some patients that had a change of 5cm H20 or more. Lim et al. found

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that an increase of 1kPa in end-tidal CO2 resulted in an increased in CSF pressure of 3.5-12 cmH20.27

Some practitioners use < 18 cm H20 for children under 8 years of age and < 25 cm H20 for children 8 years or above (mirrors adult normals) as cut-offs based on previously published works.28-30 There are three recent articles that have questioned the use of these values.31-33 Avery et al. performed an analysis of patients 1-18 years of age receiving lumbar punctures at The Children’s Hospital of Philadelphia.31 They observed a mean opening pressure of 19.8 cm H20

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and suggest an upper limit of normal (i.e. the 90th percentile) of 28 cm H20. Sub-analysis showed a small positive relationship between opening pressure and BMI and no influence of age on opening pressure. In a separate analysis of 33 patients with verified optic nerve edema, they

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found an average opening pressure of 41.4 cm H20 (range 22-56).32 Lee et al. reviewed 44

patients aged 1.1-16.8 years who had a sedated lumbar puncture and found a mean of 20.3 cm H20.33 Both study groups included patients with demyelinating and white matter disease in their

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normal patient sample (discussion in the online appendix provided by Avery et al.). Lee et al. did conduct a separate analysis of patients with demyelinating disease, and found a mean opening

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pressure of 21.5cm H20, which is higher than that of their total population (20.3 cm H20).33 The inclusion of patients with demyelinating disease as a normal patient does raise the concern for a falsely elevated average as other published studies have shown increased opening pressures in this population.34-36 Narula et al found that 28% of children with demyelinating disorders had an

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elevated opening pressure using the cut-off of 28cm H20 previously proposed by one of the coauthors.36 The percentage of cases with elevated opening pressures likely would have been

Demographics

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higher if examined with the older cut-offs.

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In pediatrics, PIH is typically divided into pre-pubertal or pubertal groups. Pubertal patients have the same risk factors as adults, whereas sex and weight are not prominent risk factors in prepubertal patients. The pediatric female-to-male ratio ranges from 1:1 to 13:6, and concurrent obesity ranges from 10-78%, largely depending on whether or not patients are divided by pubertal status (table 1).3-5,37-41 Balcer et al. found that obesity did correlate with an increased risk of PIH in older children but not in those <11 years old.42 Bursztyn found a similar

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correlation in those >12 years old.5 Aylward et al. examined pediatric cases enrolled in a large intracranial hypertension registry and found significantly higher BMI in post-pubertal PIH patients (30.7 versus 21.6).41 Rare reports of familial links with PIH can be found in the

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literature.41,43-45 Many of the case reports involve a parent and offspring relationship, though affected siblings have also been reported. Although this pattern suggests a dominant inheritance

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pattern, genetic links have not been found.

Signs and symptoms

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The clinical presentation of intracranial hypertension in pediatric patients can vary depending on age, with symptoms tending to be less evident in younger individuals. In the pre-pubertal population, incidentally discovered optic disc edema is relatively common and reported in up to 33% of cases.3,38-40,46,47 When compared to children with symptomatic PIH, asymptomatic cases

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are often younger, have a lower percentage of obesity, and a male predominance.47 Asymptomatic cases typically require shorter duration of treatment and result in complete resolution of papilledema.47 Up to 17.8% of cases lack papilledema, yet have other symptoms

39,41,48

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consistent with elevated intracranial pressure and documented elevated opening pressure.2,3,37One small study of 27 patients did find 48% lacked optic nerve edema.49 Typically optic

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nerve edema is bilateral, though unilateral presentation has been reported.41,50,51 The exact mechanism in which papilledema develops is poorly understood. Since not every individual with intracranial hypertension develops papilledema, there has to be some anatomic variant that offers a protective effect for those individuals without papilledema. The likely site of anatomic variation is the optic canal. In this area, there is a trabecular meshwork that reduces in size similar to capillaries, and there is wide variation in the size of these spaces.52 As the size of these

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spaces varies, so does the transmission of the intracranial pressure to the optic nerve sheath resulting in axoplasmic flow stasis leading to the development of papilledema over a period of

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days.52,53 By far the most consistent symptom is headache, reported in 30-96.5%.3,38-41,46,48 The headache is typically constant but can have variable severity throughout the day. Headaches tend to be most

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severe in the morning after prolonged horizontal positioning and may be exacerbated by certain maneuvers, such as Valsalva, bending over or coughing. Other symptoms include nausea and

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vomiting (12.7-52%) and diplopia (16-42.3%).3,38-41

Visual field abnormalities are present in 74-85% of patients at the time of presentation.3,40 Best corrected visual acuity is often not affected until late in the disease process. If diminished, this is more likely to be due to associated subfoveal fluid than to optic nerve swelling alone. An

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enlarged blind spot is the most common visual field defect, found in 42-46% of patients.3,11,38,40 Other visual field findings include peripheral constriction, paracentral scotoma, nasal field loss, and inferior arcuate defects.11,40 Transient visual obscurations (TVOs) are reported by patients as

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brief episodes (30 seconds or less) of binocular or monocular blurring of vision. Events can be precipitated by position changes, though may also be unprovoked, and occur multiple times per

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day. An afferent pupillary defect is rare in intracranial hypertension, though if found should raise concern for optic neuritis in the differential diagnosis.54 Motility exam is typically performed with careful attention to abduction deficits, signaling a cranial nerve VI palsy. Seen in 12-60% of cases, patients will complain of diplopia when looking in the direction of the nerve palsy. 38,40,41,55,56 They tend to present with esotropia greater with focusing at a distance than near, and measurements to this effect should be performed if esotropia is found.11,54

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Tinnitus is experienced in up to 44.3% of pediatric PIH, though it is often unreported until asked.3,41 Patients report a “whooshing” sound that coincides with their heartbeat, and is referred to as pulsatile tinnitus. The tinnitus is often unilateral and the practitioner may notice a bruit on

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the ipsilateral side on examination.57 Patients report resolution of the tinnitus with Valsalva maneuver, jugular compression on the affected side, or head turning to the opposite side.

Lowering the intracranial pressure, via lumbar puncture or medication also results in resolution.

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The tinnitus quickly returns following lumbar puncture as the pressure returns to the prepuncture level.

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Spontaneous CSF leaks (those without a clear cause) may be an initial sign of PIH, and there have been reports linking these two conditions. CSF rhinorrhea and otorrhea have both been reported.58,59 Patients may only have signs or symptoms related to the current CSF leak at the time of presentation. These include rhinorrhea, otorrhea, headache resulting from intracranial

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hypotension, and bacterial meningitis. It is not until after the leak is repaired or spontaneously resolves that typical symptoms of PIH present, often very soon after the leak stops. Recently there has been attention paid to olfactory dysfunction in adult PIH.60,61 In a study of 17

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adult PIH patients and 17 sex and age-matched controls, specific questioning uncovered 5 PIH and none of the controls complained of reduced sense of smell. Direct testing found hyposmia in

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41% (7/17) of PIH subjects and only 6% (1/17) of normals. Acute PIH cases showed the highest degree of olfactory dysfunction and decreased odor detection threshold.60 Bershad et al. examined 19 adult PIH and similar age, sex and weight matched controls and also found impaired olfactory detection and mild impaired smell identification in PIH patients.61 Some patients and/or parents report cognitive decline in PIH. A comparison of adult patients with PIH to healthy, headache-free patients found that PIH patients performed significantly

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lower in 4 of 6 cognitive domains and in 13 of 19 subtests. Marked deficits were noted in processing speed and reaction time. No overall deficits were found in working memory. Repeat examination at 3 months in 29 PIH patients found normalization of attention scores and

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visuospatial memory tests above that in healthy controls. Fourteen of 28 had achieved a normal opening pressure (1 refused repeat LP), though the overall mean pressure had dramatically

improved from a mean of 41cm H20 to 25.9cm H20 at the time of follow up. There was no

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difference in performance of those with normalized pressure compared to those with continued elevated pressure.62 Zur et al. found similar findings of multidomain mild cognitive impairment

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in a series of 30 adult patients. They found statistically significant differences in all test categories but memory. They excluded patients with any psychiatric diagnoses, or chronic headaches and participants had to be greater than 2 months out from diagnosis or relapse.63

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Unfortunately there have not been similar studies performed in the pediatric population.

Mimickers of Papilledema

A patient is diagnosed with papilledema in the presence of optic disc edema and verified

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increased intracranial pressure. Optic disc edema in absence of increased intracranial pressure is

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seen in optic neuritis, neuroretinitis, anterior ischemic optic neuropathy, and infiltration of the optic nerve head by tumor cells. There are also conditions that can have the appearance of optic nerve edema to those unfamiliar with the fundus exam (and even the experienced at times). These include anomalous optic nerves, nerve fiber layer myelination, and optic nerve drusen (at the nerve head or buried). These should always be considered in patients with unilateral or marked asymmetric edema. Secondary Intracranial Hypertension

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As technology advances we are finding more conditions which would result in classification of patients’ increased pressure as secondary (see table 2). Conditions such as traumatic brain injury, hydrocephalus, intracranial masses, subarachnoid hemorrhage and meningitis have a high

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propensity to develop intracranial hypertension. There have been previous reviews of these

conditions and treatment guidelines developed for some. For the purposes of this review, we

Cerebral Venous Sinus Thrombosis (CVST)

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have chosen to focus on those associated with lower morbidity and mortality.

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The incidence of CVST is estimated at 0.3-0.67 per 100,000 per year for children born at term to 18 years of age; of these, neonates make up 43%.64,65 Superior sagittal sinus and the transverse sinuses are most often the culprits (figure 1), though any of the larger venous outflows including those outside the cranium can result in increased pressure (figure 2). Prior to the widespread use

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of antibiotics to treat chronic otitis or mastoiditis, patients would develop thrombosis of the sigmoid sinus or jugular vein as a sequela of the infection, previously referred to as otitic hydrocephalus.66 As treatment with antibiotics has increased, the number of children with CVST

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due to these infections has decreased. Hypercoagulability can also result in CVST. Causes can include acute post-partum period, oral contraceptive use, cancer such as lymphoma/leukemia and

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various inherited coagulopathies. Post-Malnutrition Syndrome

A transient increase in intracranial pressure is seen in the acute period following initiation of feeding in cases of poor nutrition from starvation or malabsorption syndromes.67,68 It is estimated to occur in 10% of cystic fibrosis patients in the first week following pancreatic enzyme replacement.68 Infants are often asymptomatic aside from bulging of the anterior fontanel. Older

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children may develop irritability and cranial suture separation. In most cases, it is a transient process that self resolves within a few days, rarely several weeks.

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CSF flow abnormalities The typical symptoms associated with Chiari I malformation include headache, extremity

weakness, and paresthesias. If the tonsillar displacement is severe enough, hydrocephalus and

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rarely papilledema with increased intracranial pressure can develop. Fortunately the increased pressure and papilledema respond to decompression surgery.69 There are reports in the literature

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of acute intracranial hypertension following failure of a shunt draining an arachnoid cyst; patients often note rapid resolution of symptoms following shunt replacement or revision.70

Medications

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Numerous medications have been reported to lead to secondary intracranial hypertension (table 2). The tetracycline class of medications has long been reported to cause SIH, including tetracycline, minocycline and doxycycline.71-78 There have only been two case-control studies

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involving tetracycline, which failed to show intracranial hypertension resulting from its use.79,80 Cessation has been shown to cause return to normal pressure within one month, though some do

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have persistent symptoms.71,72,74 There are three presentation periods reported with minocycline; early onset (2 months), delayed (>2 months), and indeterminate (asymptomatic).75 Some case series report the ability to restart the offending medication without recurrence, though this is not common practice.72

Hypervitaminosis A can result from excessive intake of fish, liver, eggs, carrots, broccoli, and leafy greens. 73,81-84 The best indicator of vitamin A levels in patients with increased intracranial

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pressure is analysis of CSF vitamin levels.81,82 Theory postulates that retinol impairs CSF reabsorption at the arachnoid villi resulting in increased pressure.85 All-Trans Retinoic Acid, a vitamin A derivative used in conjunction with chemotherapy, and hypovitaminosis A have also

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been implicated.86-88

Withdrawal of chronic corticosteroids can be more problematic than side effects associated with

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their long term use. Increased pressure can be seen secondary to obesity as the result of steroid use, but also with acute withdrawal or rapid wean.89,90 Presenting symptoms can include

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irritability, vomiting, headache and optic nerve edema. In younger children with open sutures, optic edema may be absent. Resumption of the previous steroid dose and addition of acetazolamide often results in symptom resolution. Subsequent wean should be gradual with reduction in dosage by <50% at a time over the course of 4 weeks. The wean should be longer in

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any condition with associated cerebral edema.

Patients being treated with recombinant growth hormone can develop symptoms of intracranial hypertension including headache and optic nerve edema.91-95 The timing from initiation of

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growth hormone to presentation is often in the first 12 weeks of treatment, though it can occur years later.95 Growth hormone’s ability to cross the blood-brain barrier and increase IGF-1 has

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been well documented. IGF-I receptors have been found in rat choroid plexus.92 It is hypothesized this is the same in humans resulting in increased intracranial pressure. Treatment includes cessation of the growth hormone and often acetazolamide until symptom resolution. Once symptoms resolve, patients can be restarted on a lower dose of growth hormone with gradual titration without recurrence of symptoms.

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Other medications repeatedly linked to SIH in the literature include lithium and nalidixic acid.96100

Oral contraceptives are reported to be associated with SIH, though the association is likely

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due to CVST from the use of contraceptives.101,102

Diagnosis

The ophthalmic exam is a critical component in the diagnosis and subsequent management of

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intracranial hypertension. Key components include visual acuity, pupillary and motility

assessments, color vision evaluation, and detailed funduscopic examination with special attention

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paid to the optic nerve. Humphrey or Goldmann visual field testing, optical coherence tomography (OCT) of the retinal nerve fiber layer, and fundus autofluorescence are all helpful testing modalities for initial evaluation as well as monitoring.11,103-105 Funduscopic exam of the optic nerve should be performed to assess for the presence of edema,

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which is graded using the Frisén scale (figure 3).106 Spontaneous venous pulsations (SVPs) at the optic nerve have been evaluated as a marker for increased intracranial pressure. They are present in 87-90% of the normal population, and even those with documented elevated intracranial

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pressure.107-109 Thus decisions regarding further evaluation and treatment should not hinge upon

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the presence or absence of SVPs.

Humphrey or Goldmann visual fields are acceptable modalities for use in the initial evaluation and subsequent monitoring of patients with intracranial hypertension; some younger children unable to cooperate with Humphrey visual field testing tend to do slightly better with Goldmann testing. Humphrey visual field testing is preferred as it is automated and thus has reliable consistency across tests. OCT is a noninvasive test modality which evaluates the thickness of the retinal nerve fiber layer (RNFL) surrounding the optic nerve.54,110-112 Historically, b-scan

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ultrasound has been used to detect calcified optic nerve head drusen, and thus differentiate true papilledema from pseudo-papilledema. However, in younger patients whose drusen do not yet contain calcifications detectable by b-scan, fundus autofluorescence photography can be a

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valuable substitute.104,113,114 B-scan can also be used to evaluate the diameter of the optic nerve sheath. Although it is not meant to replace the lumbar puncture, a recent small pediatric study did find that optic nerve sheath diameters in excess of 4.5 mm correlated with elevated opening

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pressure (using a cutoff of 20cm H20).115

Neuroimaging should include MRI and MRV to rule out secondary causes. Subtle findings seen

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by the astute practitioner can include empty or partially empty sella turcica (figure 4), flattening of the posterior globe (figure 5), anterior protrusion of the optic nerve head, vertical tortuosity of the optic nerve, dilation of the optic nerve sheath (figure 5), distal transverse sinus stenosis, enhancement of the optic nerve head, and slit-like ventricles.116-118 Presence of one or more of

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these radiographic findings greatly increases the probability of having intracranial hypertension. Yet, lack of these findings does not decrease the likelihood of having intracranial hypertension.116,118 Caution should be exercised in patients with bilateral stenosis as there are

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reports of resolution of bilateral transverse venous stenosis or narrowing following treatment of the intracranial hypertension, suggesting it is a result and not cause of the intracranial

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hypertension.119,120

The final diagnostic component is the lumbar puncture (LP). Proper positioning includes lateral decubitus with the legs and head extended at the time of measurement. Popular convention dictates withdrawal of large CSF volumes to return the pressure to normal and help protect the vision. Johnston and colleagues achieved a normal pressure in a series of adult PIH patients through removal of 15-25 ml of CSF. Using continuous pressure monitoring, they followed the

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time to return of their initial pressure, which averaged 82 minutes.121 Thus there is questionable benefit to achieving a normal pressure in intracranial hypertension patients. The authors’ experience has found attempts to normalize higher pressures increases the likelihood of

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developing a post-LP headache, while reduction of <10cm H20 in pressure still affords the patient transient headache relief.

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There remains a persistent question as to the influence of sedation on the opening pressure.

Propofol has been found to lower the intracranial pressure compared to inhaled anesthetic agents

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in adult patients.122 Another study in children found that propofol administration results in elevated pressures when monitored as the patient woke from sedation.123 Initial studies suggested ketamine increases the intracranial pressure in children, however a more recent study has shown that it actually results in a lower pressure following administration.124,125 Avery et al. observed those under moderate to deep sedation did have a slightly higher opening pressure (28 vs 25 cm

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H20), though they did not specify the anesthetic agents used.31 As suggested by the work of Lim et al., the respiratory status as measured by CO2 levels has the greatest influence on the

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Treatment

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intracranial pressure which is closely linked with the level of sedation.27

A multidisciplinary team is optimal to address the needs of a patient with intracranial hypertension. At a minimum, that team should consist of a neurologist and ophthalmologist. If the situation dictates, a neurosurgeon, dietitian, physical therapist, psychologist, hematologist and/or endocrinologist should be included. Often adult patients report a recent weight gain over the 12 months preceding diagnosis.79,126 There are no pediatric studies, but numerous adult studies have shown improvements in

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symptoms and intracranial pressure through weight loss.127-131 The oldest study showing this relationship was published in 1974.127 Patients were treated with a low calorie and sodium rice diet with fluids limited to 750-1250 mL per day. None of the patients were treated with

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medications for intracranial hypertension. Through weight loss ranging from 11-56 Kg, all had resolution of their papilledema and the 2 symptomatic patients had full symptom resolution. Sinclair et al. followed a series of women with PIH over successive 3 month periods of no

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intervention, strict diet and follow up.128 The diet consisted of a nutritionally complete, low energy, liquid diet providing 425 kcal/day with an additional 2 liters of fluid a day. Patients

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already on acetazolamide (44%) were maintained on the same dose through the study and none underwent CSF diversion or optic nerve sheath fenestration. During the diet portion, mean weight fell by 15.7kg, mean intracranial pressure by 8 cm H20; headaches and papilledema also improved. Adult studies have shown that a loss of 6% of total body weight can result in

Medications

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resolution of optic nerve edema.131

Acetazolamide is considered the first line treatment for intracranial hypertension. The primary

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method of action is carbonic anhydrase inhibition, decreasing CSF production.132 In children doses of 25-100mg/kg/day (maximum 2 gm/day) divided BID can be tolerated.39 Typical

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adolescent dosing is 1 - 2g divided BID. Doses above this show questionable benefit at the risk of more side effects. Patients may complain of food having a metallic taste to it, especially when drinking carbonated beverages. This often leads to transient anorexia (in turn, aiding in weight loss).

Furosemide is also a weak carbonic anhydrase inhibitor, but this is not felt to be the main mechanism of action.132 It is felt to be due to diuresis and thus reduced sodium transport into the

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brain.133 The usual dose is 1-2mg/kg/day divided BID/TID.39 Due to its diuretic effect, serum electrolytes must be monitored and potassium supplementation given as needed. This is the main

synergistic effect when used in conjunction with acetazolamide.134

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reason this medication is second line in pediatric intracranial hypertension. Studies do suggest a

There is a theoretical risk for cross reactivity to acetazolamide and furosemide in patients with reported allergy to sulfonamides. Thus pharmacologic literature provided with both medications

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suggests patients with a sulfa allergy should refrain from taking these medications. Lee et al. reviewed the charts of patients with intracranial hypertension and self-reported sulfa allergy that

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were given regimens of acetazolamide, furosemide or a combination of acetazolamide and furosemide.135 They did not find any evidence of cross reactivity in their patients and suggest use in these patients can be done safely.

Topiramate has weak carbonic anhydrase inhibition properties, making its mode of action similar

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to that of acetazolamide. Celebisoy et al. alternately assigned 40 adult patients to open label treatment with either acetazolamide or topiramate. Topiramate dosing was 100 to 150 mg per day, whereas acetazolamide was 1000 to 1500 mg. Using visual field grades to assess for

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improvement, they found a statistically significant improvement amongst both groups.136 Methazolamide is another carbonic anhydrase inhibitor and is sometimes used in intracranial

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hypertension.

Although chronic corticosteroids can cause SIH, they used to be a mainstay of treatment for PIH. Use has waned with the discovery of improved benefits and fewer side effects with other medications such as acetazolamide. In cases with severe visual compromise at the time of presentation, use of steroids in addition to acetazolamide has been shown to improve the outcome. 137,138 Dose recommendations are largely anecdotal and mirror those used for optic

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neuritis and other inflammatory neurologic disorders. A typical course involves intravenous methylprednisolone 20mg/kg (maximum 1 gram) daily for 5 days followed by an oral taper.

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Gastrointestinal prophylaxis should also be given during the treatment period. Octreotide is used subcutaneously in adults with intracranial hypertension. Typical dosing is 100 micrograms TID increased by 100 micrograms every three days until symptoms resolve or until

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total dosage is 1000 micrograms/day. This dose is continued for 6 months, and then slowly

weaned over 2 months. There are concerns with the use of this medication in children, as it is a

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known strong inhibitor of growth hormone and insulin-like growth factor-1 (IGF-1). 139 Surgery

In the pediatric population, surgical intervention in the context of papilledema is rarely necessary. Surgical intervention is reserved for patients in whom intracranial pressure remains elevated with associated papilledema or pain in spite of maximum medical care, medical therapy

permanent vision loss.103

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cannot be tolerated, or optic nerves are severely swollen at presentation with concern for

In general, optic nerve sheath fenestration (ONSF) is utilized to preserve optic nerve function by

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redirecting pressure away from the optic nerve head, but does not effectively lower ICP by

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itself.54,103 Risks include ischemic optic neuropathy, transient blindness, pupillary mydriasis and retrobulbar hemorrhage. Interestingly it has been demonstrated that unilateral fenestration can offer protection with resolution of edema noted in the un-fenestrated eye.140,141 Caution should be used with ONSF in the acute presentation of intracranial hypertension, particularly in the presence of signs of ischemia, as the severe swelling and ischemia increase the risks of postoperative ischemic optic neuropathy.

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CSF diversion is sometimes required and is more effective in those with pain as the primary symptom, though it can be used to protect a patient’s vision in the acute stages. There remains some debate even amongst neurosurgeons about whether lumbar or ventricular diversion is

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superior. Abubaker et al. compared outcomes for 25 patients shunted for management of their intracranial hypertension. They defined shunt failure as continuation or return of initial

symptoms with radiographically verified shunt placement and normal opening pressure. The

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need for revision was determined by radiographic evidence of shunt disturbance, blockage or increased opening pressure. They found a failure rate of 11% and 14% and revision rate of 60%

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and 30% for LP and VP shunts respectively.142 Liu et al. examined the effectiveness of shunt studies in adult PIH patients presenting to the ED with issues related to their PIH. They found that shunt series detected issues with the shunt 3.9% of the time. When they looked at CT scans, only 4% of scans revealed new pathology, most commonly signs of overdrainage. Furthermore,

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individual changes in management were the same regardless of whether a shunt series or CT scan was obtained. This suggests shunt series and CT scans may not be useful screening tools to diagnose shunt malfunctions in PIH.143,144

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Stenting of sinus venous stenosis has been tried in adults with varying degrees of success.145-148 Improvement or resolution in headaches is reported at 58.4- 84.6%, and papilledema resolution

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at 62.5 -100%. The most common side effect is transient headache, or partial hearing loss on the treated side. Rare side effects include temporary unsteadiness, venous guidewire perforation, subdural, subarachnoid, and intracerebral hemorrhage. Development of new stenosis at the ends of the stents has been seen. Presentation is typically recurrence of papilledema with worsening headaches and new stenosis proximal to the stent.147

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An Australian study compared the costs of transverse sinus stenting for PIH in 86 adult patients to 110 pediatric patients who received CSF shunting for hydrocephalus.149 Cost calculations included consultations, imaging, medications, materials, surgical, anesthetics and hospital stays.

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The average cost per procedure was similar between the two. Increased costs were associated with problems and complications leading to a high revision rate. Shunts were far more likely to require revisions compared to stents, with >90% of stent patients only requiring one procedure.

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The additional costs associated with shunts were due to infections, which were not seen with stents. Unfortunately when seen in shunts they necessitate admission, device removal,

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antibiotics, and eventual replacement resulting in prolonged hospitalization and thus added costs.

OUTCOME

Pain and permanent vision loss are the two major complications of intracranial hypertension,

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both of which can have a major impact on quality of life.150,151 Headache is typically the first symptom to resolve within the first few weeks, with papilledema averaging 4.2-5 months until resolution.3,40,152 Post-pubertal status has been found to result in a worse visual outcome in one

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study.153 Another study found grade 3 or higher papilledema was the more predictive marker of

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permanent vision deficits, with 50% of those eyes having some degree of permanent visual loss. In this study, pubertal patients were 100% female, compared to only 37% of pre-pubertal patients.154

Recurrence is estimated around 18-20% for all patients.37,152 Ko et al. followed a series of adult patients for recurrence, defined as return of optic nerve edema, after resolution of their PIH.129 All patients lost weight over the course of treatment. At the time of recurrence, patients’ BMI was an average of 5.5% higher than at initial diagnosis. Those without recurrence showed an

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average of 17.9% weight loss from diagnosis through the follow-up period. Interestingly, the average BMI in those without recurrence was greater than those with recurrence throughout the follow-up period.

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Once intracranial hypertension has resolved, 43-68% of patients report developing a new or chronic headache type that is different from their intracranial hypertension headache.155 The most frequent diagnosis is episodic tension type headache or migraine without aura. Fortunately

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these headache types respond to the typical migraine prophylactic medications.

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Acknowledgements

A special thank you to Dr. E. Steve Roach for allowing us to use the stage 5 fundus photograph. References

4. 5.

6. 7. 8. 9.

10. 11.

TE D

3.

EP

2.

Schexnayder LK, Chapman K. Presentation, investigation and management of idiopathic intracranial hypertension in children. Current Paediatrics. 2006;16(5):336-341. Tibussek D, Distelmaier F, von Kries R, Mayatepek E. Pseudotumor cerebri in childhood and adolescence -- results of a Germany-wide ESPED-survey. Klinische Padiatrie. 2013;225(2):81-85. Dessardo NS, Dessardo S, Sasso A, Sarunic AV, Dezulovic MS. Pediatric idiopathic intracranial hypertension: clinical and demographic features. Collegium antropologicum. 2010;34 Suppl 2:217-221. Gordon K. Pediatric pseudotumor cerebri: descriptive epidemiology. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques. 1997;24(3):219-221. Bursztyn LL, Sharan S, Walsh L, LaRoche GR, Robitaille J, De Becker I. Has rising pediatric obesity increased the incidence of idiopathic intracranial hypertension in children? Canadian journal of ophthalmology. Journal canadien d'ophtalmologie. 2014;49(1):87-91. Quincke H. Uber Meningitis serosa and verwandte Zustande. Dtsch Z Nervenheilkd. 1897;9:149168. Nonne M. Ueber Falle vom Symptomkomplex "tumor cerebri" mit Ausgang in Heilung. Dtsch Z Nervenheilkd. 1904;27:169-216. Foley J. Benign forms of intracranial hypertension; toxic and otitic hydrocephalus. Brain. 1955;78(1):1-41. Corbett JJ, Savino PJ, Thompson HS, et al. Visual loss in pseudotumor cerebri. Follow-up of 57 patients from five to 41 years and a profile of 14 patients with permanent severe visual loss. Arch Neurol. 1982;39(8):461-474. Wall M, Hart WM, Jr., Burde RM. Visual field defects in idiopathic intracranial hypertension (pseudotumor cerebri). Am J Ophthalmol. 1983;96(5):654-669. Friedman DI. The pseudotumor cerebri syndrome. Neurologic clinics. 2014;32(2):363-396.

AC C

1.

ACCEPTED MANUSCRIPT

19. 20. 21. 22. 23. 24. 25. 26. 27.

28.

29. 30. 31. 32. 33. 34.

RI PT

18.

SC

16. 17.

M AN U

15.

TE D

14.

EP

13.

Friedman DI, Liu GT, Digre KB. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2013;81(13):1159-1165. Johnston I, Hawke S, Halmagyi M, Teo C. The pseudotumor syndrome. Disorders of cerebrospinal fluid circulation causing intracranial hypertension without ventriculomegaly. Arch Neurol. 1991;48(7):740-747. Aylward SC. Pediatric idiopathic intracranial hypertension: a need for clarification. Pediatr Neurol. 2013;49(5):303-304. Dandy WE. Intracranial Pressure without Brain Tumor: Diagnosis and Treatment. Ann Surg. 1937;106(4):492-513. Smith JL. Whence pseudotumor cerebri? J Clin Neuroophthalmol. 1985;5(1):55-56. Friedman DI, Jacobson DM. Diagnostic criteria for idiopathic intracranial hypertension. Neurology. 2002;59(10):1492-1495. Liguori C, Romigi A, Albanese M, et al. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2014;82(19):1752-1753. De Simone R, Ranieri A, Montella S, Friedman DI, Liu GT, Digre KB. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2014;82(11):1011-1012. Wall M, Corbett JJ. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2014;83(2):198-199. Corbett JJ, Mehta MP. Cerebrospinal fluid pressure in normal obese subjects and patients with pseudotumor cerebri. Neurology. 1983;33(10):1386-1388. Bono F, Lupo MR, Serra P, et al. Obesity does not induce abnormal CSF pressure in subjects with normal cerebral MR venography. Neurology. 2002;59(10):1641-1643. Whiteley W, Al-Shahi R, Warlow CP, Zeidler M, Lueck CJ. CSF opening pressure: reference interval and the effect of body mass index. Neurology. 2006;67(9):1690-1691. Gilland O. CSF dynamic diagnosis of spinal block. II. The spinal CSF pressure-volume curve. Acta neurologica Scandinavica. 1965;41(5):487-496. Avery RA, Mistry RD, Shah SS, et al. Patient position during lumbar puncture has no meaningful effect on cerebrospinal fluid opening pressure in children. J Child Neurol. 2010;25(5):616-619. Ellis R, 3rd. Lumbar cerebrospinal fluid opening pressure measured in a flexed lateral decubitus position in children. Pediatrics. 1994;93(4):622-623. Lim MJ, Lin JP. The effects of carbon dioxide on measuring cerebral spinal fluid pressure. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery. 2009;25(7):783-784. Tschudy MM, Arcara KM, Johns Hopkins Hospital. Children's Medical and Surgical Center. The Harriet Lane handbook : a manual for pediatric house officers. 19th ed. Philadelphia, PA: Mosby Elsevier; 2012. Swaiman KF. Swaiman's pediatric neurology : principles and practice. 5th ed. Edinburgh: Elsevier Saunders; 2012. Rangwala LM, Liu GT. Pediatric idiopathic intracranial hypertension. Surv Ophthalmol. 2007;52(6):597-617. Avery RA, Shah SS, Licht DJ, et al. Reference range for cerebrospinal fluid opening pressure in children. N Engl J Med. 2010;363(9):891-893. Avery RA, Licht DJ, Shah SS, et al. CSF opening pressure in children with optic nerve head edema. Neurology. 2011;76(19):1658-1661. Lee MW, Vedanarayanan VV. Cerebrospinal fluid opening pressure in children: experience in a controlled setting. Pediatr Neurol. 2011;45(4):238-240. Newman NJ, Selzer KA, Bell RA. Association of multiple sclerosis and intracranial hypertension. J Neuroophthalmol. 1994;14(4):189-192.

AC C

12.

ACCEPTED MANUSCRIPT

41. 42. 43.

44. 45. 46. 47. 48. 49.

50. 51.

52. 53. 54. 55.

RI PT

40.

SC

39.

M AN U

38.

TE D

37.

EP

36.

Williams BJ, Skinner HJ, Maria BL. Increased intracranial pressure in a case of pediatric multiple sclerosis. J Child Neurol. 2008;23(6):699-702. Narula S, Liu GT, Avery RA, Banwell B, Waldman AT. Elevated cerebrospinal fluid opening pressure in a pediatric demyelinating disease cohort. Pediatr Neurol. 2015;52(4):446-449. Tibussek D, Schneider DT, Vandemeulebroecke N, et al. Clinical spectrum of the pseudotumor cerebri complex in children. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery. 2010;26(3):313-321. Babikian P, Corbett J, Bell W. Idiopathic intracranial hypertension in children: the Iowa experience. J Child Neurol. 1994;9(2):144-149. Distelmaier F, Sengler U, Messing-Juenger M, Assmann B, Mayatepek E, Rosenbaum T. Pseudotumor cerebri as an important differential diagnosis of papilledema in children. Brain & development. 2006;28(3):190-195. Cinciripini GS, Donahue S, Borchert MS. Idiopathic intracranial hypertension in prepubertal pediatric patients: characteristics, treatment, and outcome. Am J Ophthalmol. 1999;127(2):178182. Aylward SC, Waslo CS, Au JN, Tanne E. Manifestations of Pediatric Intracranial Hypertension From the Intracranial Hypertension Registry. Pediatr Neurol. 2016. Balcer LJ, Liu GT, Forman S, et al. Idiopathic intracranial hypertension: relation of age and obesity in children. Neurology. 1999;52(4):870-872. Beri S, Chandratre S, Chow G. Familial idiopathic intracranial hypertension with variable phenotype. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2011;15(1):81-83. Corbett JJ. The first Jacobson Lecture. Familial idiopathic intracranial hypertension. J Neuroophthalmol. 2008;28(4):337-347. Kharode C, McAbee G, Sherman J, Kaufman M. Familial intracranial hypertension: report of a case and review of the literature. J Child Neurol. 1992;7(2):196-198. Aylward SC, Aronowitz C, Reem R, Rogers D, Roach ES. Intracranial hypertension without headache in children. J Child Neurol. 2015;30(6):703-706. Bassan H, Berkner L, Stolovitch C, Kesler A. Asymptomatic idiopathic intracranial hypertension in children. Acta neurologica Scandinavica. 2008;118(4):251-255. Aylward SC, Aronowitz C, Roach ES. Intracranial Hypertension Without Papilledema in Children. J Child Neurol. 2016;31(2):177-183. Faz G, Butler IJ, Koenig MK. Incidence of papilledema and obesity in children diagnosed with idiopathic ''benign'' intracranial hypertension: case series and review. J Child Neurol. 2010;25(11):1389-1392. Huna-Baron R, Landau K, Rosenberg M, Warren FA, Kupersmith MJ. Unilateral swollen disc due to increased intracranial pressure. Neurology. 2001;56(11):1588-1590. Sher NA, Wirtschafter J, Shapiro SK, See C, Shapiro I. Unilateral papilledema in 'benign' intracranial hypertension (pseudotumor cerebri). JAMA : the journal of the American Medical Association. 1983;250(17):2346-2347. Hayreh SS. Pathogenesis of optic disc edema in raised intracranial pressure. Progress in retinal and eye research. 2016;50:108-144. Schirmer CM, Hedges TR, 3rd. Mechanisms of visual loss in papilledema. Neurosurg Focus. 2007;23(5):E5. Friedman DI. Papilledema and idiopathic intracranial hypertension. Continuum (Minneap Minn). 2014;20(4 Neuro-ophthalmology):857-876. Grant DN. Benign intracranial hypertension. A review of 79 cases in infancy and childhood. Archives of disease in childhood. 1971;46(249):651-655.

AC C

35.

ACCEPTED MANUSCRIPT

62. 63. 64.

65. 66. 67. 68. 69.

70.

71. 72. 73. 74. 75. 76.

RI PT

SC

61.

M AN U

60.

TE D

59.

EP

57. 58.

Kesler A, Fattal-Valevski A. Idiopathic intracranial hypertension in the pediatric population. J Child Neurol. 2002;17(10):745-748. Meador KJ, Swift TR. Tinnitus from intracranial hypertension. Neurology. 1984;34(9):1258-1261. Brainard L, Chen DA, Aziz KM, Hillman TA. Association of benign intracranial hypertension and spontaneous encephalocele with cerebrospinal fluid leak. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 2012;33(9):1621-1624. Rosenfeld E, Dotan G, Kimchi TJ, Kesler A. Spontaneous cerebrospinal fluid otorrhea and rhinorrhea in idiopathic intracranial hypertension patients. J Neuroophthalmol. 2013;33(2):113116. Kunte H, Schmidt F, Kronenberg G, et al. Olfactory dysfunction in patients with idiopathic intracranial hypertension. Neurology. 2013;81(4):379-382. Bershad EM, Urfy MZ, Calvillo E, et al. Marked olfactory impairment in idiopathic intracranial hypertension. Journal of neurology, neurosurgery, and psychiatry. 2014;85(9):959-964. Yri HM, Fagerlund B, Forchhammer HB, Jensen RH. Cognitive function in idiopathic intracranial hypertension: a prospective case-control study. BMJ open. 2014;4(4):e004376. Zur D, Naftaliev E, Kesler A. Evidence of multidomain mild cognitive impairment in idiopathic intracranial hypertension. J Neuroophthalmol. 2015;35(1):26-30. Roach ES, Golomb MR, Adams R, et al. Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke; a journal of cerebral circulation. 2008;39(9):2644-2691. deVeber G, Andrew M, Adams C, et al. Cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345(6):417-423. Isaacman DJ. Otitic hydrocephalus: an uncommon complication of a common condition. Annals of emergency medicine. 1989;18(6):684-687. Roach ES, Sinal SH. Increased intracranial pressure following treatment of cystic fibrosis. Pediatrics. 1980;66(4):622-623. Roach ES, Sinal SH. Initial treatment of cystic fibrosis. Frequency of transient bulging fontanel. Clinical pediatrics. 1989;28(8):371-373. Vaphiades MS, Eggenberger ER, Miller NR, Frohman L, Krisht A. Resolution of papilledema after neurosurgical decompression for primary Chiari I malformation. Am J Ophthalmol. 2002;133(5):673-678. Laviv Y, Michowitz S. Acute intracranial hypertension and shunt dependency following treatment of intracranial arachnoid cyst in a child: a case report and review of the literature. Acta neurochirurgica. 2010;152(8):1419-1423; discussion 1422-1413. Winn BJ, Liao YJ, Horton JC. Intracranial pressure returns to normal about a month after stopping tetracycline antibiotics. Arch Ophthalmol. 2007;125(8):1137-1138. Walters BN, Gubbay SS. Tetracycline and benign intracranial hypertension: report of five cases. Br Med J (Clin Res Ed). 1981;282(6257):19-20. Dhiravibulya K, Ouvrier R, Johnston I, Procopis P, Antony J. Benign intracranial hypertension in childhood: a review of 23 patients. Journal of paediatrics and child health. 1991;27(5):304-307. Kesler A, Goldhammer Y, Hadayer A, Pianka P. The outcome of pseudotumor cerebri induced by tetracycline therapy. Acta neurologica Scandinavica. 2004;110(6):408-411. Chiu AM, Chuenkongkaew WL, Cornblath WT, et al. Minocycline treatment and pseudotumor cerebri syndrome. Am J Ophthalmol. 1998;126(1):116-121. Friedman DI, Gordon LK, Egan RA, et al. Doxycycline and intracranial hypertension. Neurology. 2004;62(12):2297-2299.

AC C

56.

ACCEPTED MANUSCRIPT

82.

83. 84. 85. 86. 87. 88.

89.

90. 91.

92.

93. 94.

95.

RI PT

SC

81.

M AN U

80.

TE D

79.

EP

78.

Roux X, Sallansonnet-Froment M, De Greslan T, et al. [Idiopathic intracranial hypertension as a side effect of doxycycline]. La Revue de medecine interne / fondee ... par la Societe nationale francaise de medecine interne. 2009;30(12):1058-1060. Weese-Mayer DE, Yang RJ, Mayer JR, Zaparackas Z. Minocycline and Pseudotumor cerebri: The well-known but well-kept secret. Pediatrics. 2001;108(2):519-520. Giuseffi V, Wall M, Siegel PZ, Rojas PB. Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): a case-control study. Neurology. 1991;41(2 ( Pt 1)):239-244. Ireland B, Corbett JJ, Wallace RB. The search for causes of idiopathic intracranial hypertension. A preliminary case-control study. Arch Neurol. 1990;47(3):315-320. Warner JE, Bernstein PS, Yemelyanov A, Alder SC, Farnsworth ST, Digre KB. Vitamin A in the cerebrospinal fluid of patients with and without idiopathic intracranial hypertension. Annals of neurology. 2002;52(5):647-650. Warner JE, Larson AJ, Bhosale P, et al. Retinol-binding protein and retinol analysis in cerebrospinal fluid and serum of patients with and without idiopathic intracranial hypertension. J Neuroophthalmol. 2007;27(4):258-262. Morrice G, Jr., Havener WH, Kapetansky F. Vitamin A intoxication as a cause of pseudotumor cerebri. JAMA : the journal of the American Medical Association. 1960;173:1802-1805. Rodahl K. Toxicity of polar bear liver. Nature. 1949;164(4169):530. Digre K WJ. Is vitamin A implicated in the pathophysiology of increased intracranial pressure? Neurology. 2005;64(11):1827. Dotan G, Goldstein M, Stolovitch C, Kesler A. Pediatric Pseudotumor Cerebri Associated With Low Serum Levels of Vitamin A. J Child Neurol. 2013;28(11):1370-1377. Panozzo G, Babighian S, Bonora A. Association of xerophthalmia, flecked retina, and pseudotumor cerebri caused by hypovitaminosis A. Am J Ophthalmol. 1998;125(5):708-710. Holmes D, Vishnu P, Dorer RK, Aboulafia DM. All-Trans Retinoic Acid-Induced Pseudotumor Cerebri during Induction Therapy for Acute Promyelocytic Leukemia: A Case Report and Literature Review. Case reports in oncological medicine. 2012;2012:313057. Ray WZ, Lee A, Blackburn SL, Lueder GT, Leonard JR. Pseudotumor cerebri following tapered corticosteroid treatment in an 8-month-old infant. Journal of neurosurgery. Pediatrics. 2008;1(1):88-90. Neville BG, Wilson J. Benign intracranial hypertension following corticosteroid withdrawal in childhood. British medical journal. 1970;3(5722):554-556. Rogers AH, Rogers GL, Bremer DL, McGregor ML. Pseudotumor cerebri in children receiving recombinant human growth hormone. Ophthalmology. 1999;106(6):1186-1189; discussion 1189-1190. Malozowski S, Tanner LA, Wysowski DK, Fleming GA, Stadel BV. Benign intracranial hypertension in children with growth hormone deficiency treated with growth hormone. The Journal of pediatrics. 1995;126(6):996-999. Malozowski S, Tanner LA, Wysowski D, Fleming GA. Growth hormone, insulin-like growth factor I, and benign intracranial hypertension. N Engl J Med. 1993;329(9):665-666. Besch D, Makowski C, Steinborn MM, Bonfig W, Sadowski B. Visual loss without headache in children with pseudotumor cerebri and growth hormone treatment. Neuropediatrics. 2013;44(4):203-207. Noto R, Maneatis T, Frane J, Alexander K, Lippe B, Davis DA. Intracranial hypertension in pediatric patients treated with recombinant human growth hormone: data from 25 years of the Genentech National Cooperative Growth Study. J Pediatr Endocrinol Metab. 2011;24(9-10):627631.

AC C

77.

ACCEPTED MANUSCRIPT

102. 103. 104.

105.

106. 107. 108. 109. 110.

111.

112.

113. 114.

RI PT

101.

SC

100.

M AN U

99.

TE D

98.

EP

97.

Saul RF, Hamburger HA, Selhorst JB. Pseudotumor cerebri secondary to lithium carbonate. JAMA : the journal of the American Medical Association. 1985;253(19):2869-2870. Kelly SJ, O'Donnell T, Fleming JC, Einhaus S. Pseudotumor cerebri associated with lithium use in an 11-year-old boy. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus / American Association for Pediatric Ophthalmology and Strabismus. 2009;13(2):204-206. Boreus LO, Sundstrom B. Intracranial hypertension in a child during treatment with nalidixic acid. British medical journal. 1967;2(5554):744-745. Cohen DN. Intracranial hypertension and papilledema associated with nalidixic acid therapy. Am J Ophthalmol. 1973;76(5):680-682. Mukherjee A, Dutta P, Lahiri M, Sinha S, Mitra AK, Bhattacharya SK. Benign intracranial hypertension after nalidixic acid overdose in infants. Lancet. 1990;335(8705):1602. Galarza M, Gazzeri R. Cerebral venous sinus thrombosis associated with oral contraceptives: the case for neurosurgery. Neurosurg Focus. 2009;27(5):E5. Sheehan JP. Hormone replacement treatment and benign intracranial hypertension. Br Med J (Clin Res Ed). 1982;284(6330):1675-1676. Rogers DL. A review of pediatric idiopathic intracranial hypertension. Pediatric clinics of North America. 2014;61(3):579-590. Gili P, Flores-Rodriguez P, Yanguela J, Herreros Fernandez ML. Using autofluorescence to detect optic nerve head drusen in children. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus / American Association for Pediatric Ophthalmology and Strabismus. 2013;17(6):568-571. Group OCTS-SCfNIIHS, Auinger P, Durbin M, et al. Baseline OCT measurements in the idiopathic intracranial hypertension treatment trial, part I: quality control, comparisons, and variability. Investigative ophthalmology & visual science. 2014;55(12):8180-8188. Frisen L. Swelling of the optic nerve head: a staging scheme. Journal of neurology, neurosurgery, and psychiatry. 1982;45(1):13-18. Wong SH, White RP. The clinical validity of the spontaneous retinal venous pulsation. J Neuroophthalmol. 2013;33(1):17-20. Levin BE. The clinical significance of spontaneous pulsations of the retinal vein. Arch Neurol. 1978;35(1):37-40. Lorentzen SE. Incidence of spontaneous venous pulsation in the retina. Acta ophthalmologica. 1970;48(4):765-770. Auinger P, Durbin M, Feldon S, et al. Baseline OCT measurements in the idiopathic intracranial hypertension treatment trial, part II: correlations and relationship to clinical features. Investigative ophthalmology & visual science. 2014;55(12):8173-8179. El-Dairi MA, Holgado S, O'Donnell T, Buckley EG, Asrani S, Freedman SF. Optical coherence tomography as a tool for monitoring pediatric pseudotumor cerebri. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus / American Association for Pediatric Ophthalmology and Strabismus. 2007;11(6):564-570. Scott CJ, Kardon RH, Lee AG, Frisen L, Wall M. Diagnosis and grading of papilledema in patients with raised intracranial pressure using optical coherence tomography vs clinical expert assessment using a clinical staging scale. Arch Ophthalmol. 2010;128(6):705-711. Auw-Haedrich C, Staubach F, Witschel H. Optic disk drusen. Surv Ophthalmol. 2002;47(6):515532. Lam BL, Morais CG, Jr., Pasol J. Drusen of the optic disc. Current neurology and neuroscience reports. 2008;8(5):404-408.

AC C

96.

ACCEPTED MANUSCRIPT

120. 121. 122. 123. 124. 125.

126. 127. 128.

129. 130. 131.

132.

133.

RI PT

SC

119.

M AN U

118.

TE D

117.

EP

116.

Irazuzta JE, Brown ME, Akhtar J. Bedside Optic Nerve Sheath Diameter Assessment in the Identification of Increased Intracranial Pressure in Suspected Idiopathic Intracranial Hypertension. Pediatr Neurol. 2016;54:35-38. Maralani PJ, Hassanlou M, Torres C, et al. Accuracy of brain imaging in the diagnosis of idiopathic intracranial hypertension. Clinical radiology. 2012;67(7):656-663. Fraser JA, Leung AE. Reversibility of MRI features of pseudotumor cerebri syndrome. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques. 2014;41(4):530-532. Gorkem SB, Doganay S, Canpolat M, et al. MR imaging findings in children with pseudotumor cerebri and comparison with healthy controls. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery. 2015;31(3):373-380. Horev A, Hallevy H, Plakht Y, Shorer Z, Wirguin I, Shelef I. Changes in cerebral venous sinuses diameter after lumbar puncture in idiopathic intracranial hypertension: a prospective MRI study. Journal of neuroimaging : official journal of the American Society of Neuroimaging. 2013;23(3):375-378. Skyrman S, Fytagoridis A, Andresen M, Bartek J, Jr. Idiopathic intracranial hypertension and transverse sinus stenoses. BMJ case reports. 2013;2013. Johnston I, Paterson A. Benign intracranial hypertension. II. CSF pressure and circulation. Brain. 1974;97(2):301-312. Petersen KD, Landsfeldt U, Cold GE, et al. ICP is lower during propofol anaesthesia compared to isoflurane and sevoflurane. Acta neurochirurgica. Supplement. 2002;81:89-91. Eidlitz-Markus T, Stiebel-Kalish H, Rubin Y, Shuper A. CSF pressure measurement during anesthesia: an unreliable technique. Paediatric anaesthesia. 2005;15(12):1078-1082. Ben Yehuda Y, Watemberg N. Ketamine increases opening cerebrospinal pressure in children undergoing lumbar puncture. J Child Neurol. 2006;21(6):441-443. Bar-Joseph G, Guilburd Y, Tamir A, Guilburd JN. Effectiveness of ketamine in decreasing intracranial pressure in children with intracranial hypertension. Journal of neurosurgery. Pediatrics. 2009;4(1):40-46. Wall M, George D. Idiopathic intracranial hypertension. A prospective study of 50 patients. Brain. 1991;114 ( Pt 1A):155-180. Newborg B. Pseudotumor cerebri treated by rice reduction diet. Arch Intern Med. 1974;133(5):802-807. Sinclair AJ, Burdon MA, Nightingale PG, et al. Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension: prospective cohort study. BMJ. 2010;341:c2701. Ko MW, Chang SC, Ridha MA, et al. Weight gain and recurrence in idiopathic intracranial hypertension: a case-control study. Neurology. 2011;76(18):1564-1567. Kupersmith MJ, Gamell L, Turbin R, Peck V, Spiegel P, Wall M. Effects of weight loss on the course of idiopathic intracranial hypertension in women. Neurology. 1998;50(4):1094-1098. Johnson LN, Krohel GB, Madsen RW, March GA, Jr. The role of weight loss and acetazolamide in the treatment of idiopathic intracranial hypertension (pseudotumor cerebri). Ophthalmology. 1998;105(12):2313-2317. McCarthy KD, Reed DJ. The effect of acetazolamide and furosemide on cerebrospinal fluid production and choroid plexus carbonic anhydrase activity. The Journal of pharmacology and experimental therapeutics. 1974;189(1):194-201. Buhrley LE, Reed DJ. The effect of furosemide on sodium-22 uptake into cerebrospinal fluid and brain. Experimental brain research. 1972;14(5):503-510.

AC C

115.

ACCEPTED MANUSCRIPT

140.

141.

142.

143.

144.

145.

146.

147.

148. 149.

150. 151.

RI PT

SC

138. 139.

M AN U

137.

TE D

136.

EP

135.

Schoeman JF. Childhood pseudotumor cerebri: clinical and intracranial pressure response to acetazolamide and furosemide treatment in a case series. J Child Neurol. 1994;9(2):130-134. Lee AG, Anderson R, Kardon RH, Wall M. Presumed "sulfa allergy" in patients with intracranial hypertension treated with acetazolamide or furosemide: cross-reactivity, myth or reality? Am J Ophthalmol. 2004;138(1):114-118. Celebisoy N, Gokcay F, Sirin H, Akyurekli O. Treatment of idiopathic intracranial hypertension: topiramate vs acetazolamide, an open-label study. Acta neurologica Scandinavica. 2007;116(5):322-327. Liu GT, Glaser JS, Schatz NJ. High-dose methylprednisolone and acetazolamide for visual loss in pseudotumor cerebri. Am J Ophthalmol. 1994;118(1):88-96. Weisberg LA. Benign intracranial hypertension. Medicine. 1975;54(3):197-207. Deftereos SN, Panagopoulos G, Georgonikou D, Karageorgiou CE, Karageorgiou E, Piadites G. Treatment of idiopathic intracranial hypertension: Is there a place for octreotide? Cephalalgia : an international journal of headache. 2011;31(16):1679-1680. Alsuhaibani AH, Carter KD, Nerad JA, Lee AG. Effect of optic nerve sheath fenestration on papilledema of the operated and the contralateral nonoperated eyes in idiopathic intracranial hypertension. Ophthalmology. 2011;118(2):412-414. Corbett JJ, Nerad JA, Tse DT, Anderson RL. Results of optic nerve sheath fenestration for pseudotumor cerebri. The lateral orbitotomy approach. Arch Ophthalmol. 1988;106(10):13911397. Abubaker K, Ali Z, Raza K, Bolger C, Rawluk D, O'Brien D. Idiopathic intracranial hypertension: lumboperitoneal shunts versus ventriculoperitoneal shunts--case series and literature review. Br J Neurosurg. 2011;25(1):94-99. Liu A, Elder BD, Sankey EW, Goodwin CR, Jusue-Torres I, Rigamonti D. Are shunt series and shunt patency studies useful in patients with shunted idiopathic intracranial hypertension in the emergency department? Clinical neurology and neurosurgery. 2015;138:89-93. Liu A, Elder BD, Sankey EW, Goodwin CR, Jusue-Torres I, Rigamonti D. The Utility of Computed Tomography in Shunted Patients with Idiopathic Intracranial Hypertension Presenting to the Emergency Department. World neurosurgery. 2015;84(6):1852-1856. Higgins JN, Cousins C, Owler BK, Sarkies N, Pickard JD. Idiopathic intracranial hypertension: 12 cases treated by venous sinus stenting. Journal of neurology, neurosurgery, and psychiatry. 2003;74(12):1662-1666. Ahmed RM, Wilkinson M, Parker GD, et al. Transverse sinus stenting for idiopathic intracranial hypertension: a review of 52 patients and of model predictions. AJNR. American journal of neuroradiology. 2011;32(8):1408-1414. Radvany MG, Solomon D, Nijjar S, et al. Visual and neurological outcomes following endovascular stenting for pseudotumor cerebri associated with transverse sinus stenosis. J Neuroophthalmol. 2013;33(2):117-122. Kumpe DA, Bennett JL, Seinfeld J, Pelak VS, Chawla A, Tierney M. Dural sinus stent placement for idiopathic intracranial hypertension. J Neurosurg. 2012;116(3):538-548. Ahmed RM, Zmudzki F, Parker GD, Owler BK, Halmagyi GM. Transverse sinus stenting for pseudotumor cerebri: a cost comparison with CSF shunting. AJNR. American journal of neuroradiology. 2014;35(5):952-958. Digre KB, Bruce BB, McDermott MP, et al. Quality of life in idiopathic intracranial hypertension at diagnosis: IIH Treatment Trial results. Neurology. 2015;84(24):2449-2456. Mulla Y, Markey KA, Woolley RL, Patel S, Mollan SP, Sinclair AJ. Headache determines quality of life in idiopathic intracranial hypertension. The journal of headache and pain. 2015;16(1):521.

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Ravid S, Shahar E, Schif A, Yehudian S. Visual Outcome and Recurrence Rate in Children With Idiopathic Intracranial Hypertension. J Child Neurol. 2015;30(11):1448-1452. 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(2):279-283. Gospe SM, 3rd, Bhatti MT, El-Dairi MA. Anatomic and visual function outcomes in paediatric idiopathic intracranial hypertension. The British journal of ophthalmology. 2016;100(4):505-509. Friedman DI, Rausch EA. Headache diagnoses in patients with treated idiopathic intracranial hypertension. Neurology. 2002;58(10):1551-1553.

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ACCEPTED MANUSCRIPT Table 1: Distribution of risk factors based on puberty. Tibussek37 Dessardo3 Female-to-Male Ratio Pre-pubertal 3:4 1:1.5 Pubertal 1:2 2:1 No delineation 13:6

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Obesity Pre-pubertal Pubertal No delineation

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17%

Distelmaier39 Cinciripini40 Aylward41

16% 19%

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ACCEPTED MANUSCRIPT Table 2: Common Causes of Secondary Intracranial Hypertension

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Minocycline / Tetracycline / Doxycycline Growth hormone Corticosteroids (especially withdrawal) Cyclosporine A Cytarabine Lithium carbonate Nalidixic acid Oral contraceptives (likely secondary to venous thrombosis) Retinoic acid Vitamin A (excess or deficiency) Vitamin D (deficiency)

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Cerebral venous thrombosis Refeeding syndrome Adrenal insufficiency (often on steroids) Hypoparathyroidism (early in correction) Pregnancy/eclampsia Crohn’s disease Hydrocephalus Craniofacial syndrome Chiari Malformation Traumatic brain injury Brain tumor Conditions associated with abnormal CSF studies Meningitis/encephalitis Intracranial hemorrhage Lyme disease Demyelinating disease / multiple sclerosis Leukemia Lymphoma

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Figure 1: Superior sagittal sinus thrombosis (large arrows) and transverse sinus thrombosis (small arrow). Images are from different patients.

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Figure 2: Jugular thrombosis (small arrow) and sigmoid sinus stenosis (large arrow). Note presence of collaterals indicating these are old lesions.

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ACCEPTED MANUSCRIPT Figure 3: Optic nerve edema stages. Left to right. First row: Normal (0), stage 1. Second row: stage 2, stage 3 (note cotton wool spot with hemorrhage at 5 o’clock). Third row: stage 4 (note hemorrhages 1-2 and 6-8 o’clock, retinal striae due to severity of edema), stage 5

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Figure 4: MRI with dehiscence or downward displacement of the diaphragma sella (arrow).

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Figure 5: MRI with dilation of optic nerve sheaths (large arrow) and flattening of posterior globes (small arrow).