on the vein of Galen or occlusion of the posterior sagittal sinus.380 The most common tumors associated with childhood papilledema are midbrain and cerebellar glioma, medulloblastoma, and ependymoma.161 Pediatric brain tumors and their neuro-ophthalmologic sequelae are detailed in Chap. 11.

Idiopathic Intracranial Hypertension (IIH)

in Children

IIH is a condition characterized by symptoms and signs of increased intracranial pressure without evidence of a mass lesion or hydrocephalus.108 It differs from other causes of increased intracranial pressure in that the level of consciousness is not altered. The diagnosis of primary IIH is usually established when the modified Dandy criteria are met:

·· Signs and symptoms of increased intracranial pressure ·· Absence of localizing findings on neurologic examination ·· Absence of deformity, displacement, or obstruction of the

ventricular system and otherwise normal neurodiagnostic studies, except for increased CSF pressure

·· Alert and oriented patient

·· No other cause of increased intracranial pressure present

Older children with IIH may complain of headache, neck pain, diplopia, intracranial noises, or transient visual obscurations, whereas younger children may present with apathy or irritability.565 Although IIH headaches have been described as characteristically frontal, severe, pulsatile, and worse on lying down, most experts suggest that they are similar to migraine headaches, except that IIH headaches tend to be continuous, whereas migrainous headaches are generally more severe and intermittent.524 More precise criteria for diagnosis of elevated intracranial pressure are needed. For example, some consider the upper limit of normal opening CSF pressure in young children to be 180 mmHg,445 while others have found opening pressures of 275 mmHg in children who were identified as having pseudopapilledema.385

Pathophysiology

The complex, multifactorial causes of IIH have been studied at both basic and clinical levels. There is no doubt that multiple contributory factors can downregulate CSF outflow and eventuate in elevated intracranial pressure. Johnson et al269 proposed a classification of IIH that reflects the concept of IIH as a disorder of CSF outflow. We have modified this model (Table 3.1) to apply it to the different forms of IIH of childhood. By expanding the diagnosis of IIH to include

Table 3.1  Classification of idiopathic intracranial hypertension in children (Adapted from Johnston et al272)

Primary idiopathic intracranial hypertension

·  No recognized cause (idiopathic intracranial hypertension or benign intracranial hypertension)

Secondary idiopathic intracranial hypertension

·Idiopathic intracranial hypertension associated with neurological disease

–Dural venous sinus thrombosis (associated with otitis media, mastoiditis, or head trauma)

–Altered cerebrospinal fluid composition (meningitis)

–Arteriovenous malformation draining into a venous sinus

–Gliomatosis cerebri

Idiopathic intracranial hypertension secondary to systemic disease

·Malnutrition or renutrition

·Systemic lupus erythematosis

·Severe anemia (iron deficiency, aplastic, sickle cell)

·Addison disease

·Bone marrow transplantation

·Retinal transplantation

·Down syndrome

·Sleep apnea

Postinfectious (following chickenpox or measles)

Idiopathic intracranial hypertension secondary to ingestion or withdrawal of exogenous agents

·Corticosteroid withdrawal

·Thyroxine replacement therapya

·Nalidixic acid (used in the treatment of urinary tract infection and bacillary dysentery)

·Tetracycline or minocycline therapy (used in teenagers to suppress acne)

·Vitamin A intoxication – often in adolescents who take vitamin A or the synthetic vitamin A derivative isoretinoin for acne

·Danazol, danocrine (used for endometriosis or autoimmune hemolytic anemia)

·Recombinant growth hormone

·All-trans retinoic acid

·Chemotherapy (cyclosporine, cytarbine)

Atypical idiopathic intracranial hypertension

Occult idiopathic intracranial hypertension (no papilledema) Normal pressure idiopathic intracranial hypertension Infantile idiopathic intracranial hypertension

intracranial hypertension without ventriculomegaly from a defect of CSF absorption (of any cause), one can begin to synthesize the numerous and disparate causes into a single conceptual framework; in such a framework, the finding of clinical or neuroimaging abnormalities would not preclude the diagnosis of IIH as long as the mechanism of decreased CSF absorption is present.

Until recently, the accumulated evidence best supported a blockage of CSF absorption that can occur at the level of the Pacchionian granulations or the venous sinuses. Decreased absorption at the level of the arachnoid villi has been demonstrated by radioisotope cisternography, although it is unclear whether it is secondary to compression of the arachnoid villi

or the result of elevated intracranial pressure itself.355 This hypothesis is consistent with the absence of tight junctions in the ependymal cells surrounding the lateral ventricles, which allows high-pressure fluid to move transependymally into the extracellular space.

The absence of tight junctions in pial cells that cover the cerebral convexities allows high-pressure fluid to communicate from the lateral ventricles to the subarachnoid space and vice versa. This flow may lead to the establishment of an equilibrium between raised CSF outflow resistance and increased brain stiffness (occurring as a consequence of increased cerebral blood volume, mild interstitial cerebral edema, or both), which would explain the absence of ventriculomegaly in IIH. The development of such a steady state of CSF fluid migration would also help explain the inability of some studies to demonstrate increased periventricular brain water content on MR imaging.99,512 Although some studies have found increased periventricular signal intensity (presumably signifying low-grade edema) in patients with IIH, the increased white matter signal intensity was demonstrable only by statistical analysis of periventricular signal intensities.

It has now been shown that a significant portion of CSF passes through the olfactory bulb and through the foramina in the cribriform plate into an extensive network of lymphatic vessels in the nasal submucosa.267,268,595,597 These findings have refocused our attention on a possible predominant role of nasal lymphatic drainage pathways for intracranial and perioptic CSF. Elucidation of the relative contribution of these CSF pathways under normal and pathophysiologic conditions may change the way we conceptualize this condition and offer new avenues of treatment. Some CSF dysfunction may be attributable to changes of molecular flux and CSF flow rate.450,515

Corbett103 proposed that elevated levels of free vitamin A in obese patients may damage arachnoidal granulations and lead to decreased CSF absorption in primary IIH. Evidence of an adverse effect of high vitamin A intake on intracranial pressure is well-recognized. Acute swelling of the anterior fontanelle, with vomiting, agitation, and insomnia, develops in infants given large oral doses of vitamin A. These changes occur after only a few hours and usually subside 24–48 h later.367 Although 98% of vitamin A is said to be stored in the liver, there is evidence that this fat-soluble vitamin may be stored in fat to a greater degree than generally appreciated. Unbound vitamin A (retinyl esters) is a toxic agent that triggers cell death by activating lysosomal enzymes. Therefore, it is attached to different carrier proteins throughout the body. In the blood, it is bound to retinol-binding protein. In the CSF, it is attached to prealbumin (transthyretin), a carrier protein synthesized at the choroid plexus.

Warner et al562 found increased levels of unbound retinal in the CSF of subjects with IIH, providing further evidence that vitamin A metabolism might be involved in the pathogenesis of IIH and that IIH could result from vitamin A toxicity localized to the CSF.349

Any condition leading to elevated levels of unbound vitamin A in the CSF, such as endogenous obesity, excess ingestion, or renal failure (which results in decreased excretion of retinol-binding protein and, secondarily, high levels of total vitamin A), could exceed the capacity of transthyretin to bind it. Free vitamin A in the CSF would then percolate into the Pacchionian granulations, where it damages the endothelial cells, which results in decreased CSF absorption. Because CSF transthyretin also binds thyroxine, the occurrence of IIH during thyroxine replacement in hypothyroidism (which would deplete CSF transthyretin and increase the level of unbound vitamin A in the CSF) is consistent with this hypothetical mechanism; the same is true for the association of IIH with obesity and its occurrence in women (who have more body fat). The changing hormonal status at menarche may contribute to vitamin A storage and binding. Drugs and toxins associated with IIH may affect absorption, binding, storage, or transmission of vitamin A.

Recently, attention has been focused on the possible causative role of elevated venous sinus pressure in decreasing CSF absorption.445 MR venography has shown elevated venous sinus pressure in patients with IIH, which could be the primary cause, a contributory cause, or a secondary phenomenon. Elevated venous pressure may increase resistance to CSF absorption, causing the cerebrospinal pressure to increase as well. Karahalios et al276 found dural venous outflow obstruction in five of ten patients with IIH using angiography and manometry. The patients who had an obstruction had a high-pressure gradient across the stenosis. Angioplasty or thrombolytic infusion improved the outlet obstruction but not the clinical picture. Studies using cerebral venography and manometry showed elevated venous pressure in the superior sagittal and proximal transverse sinuses.309 However, King et al309 and other researchers have shown that venous sinus stenoses reverses with correction of the elevated intracranial pressure, suggesting that elevated venous pressure could be the effect rather than the cause of intracranial pressure.513 Bateman32 has proposed that reduced venous sinus pulsatility may be a marker for IIH secondary to elevated venous sinus pressure. Increased intraabdominal pressure that is transmitted through the thorax to the cerebral draining veins has also been proposed as the cause of IIH in morbid obesity, and bariatric surgery has shown to be efficacious in treating IIH in adults.534

Neuroimaging

MR imaging is usually sufficient to rule out central nervous system disease, gliomatosis cerebri, leptomeningeal spread of lymphoma, leukemia, germ cell tumors (which may produce­ meningeal enhancement on MR imaging or CSF elevation in protein, pleocytosis, or abnormal CSF cytology) and spinal cord tumors, which usually produce back pain, upper motor neuron signs, or a sensory level. Although MR imaging does not show changes in the volume of the brain or ventricles in IIH, it is extremely helpful in identifying elevated intracranial pressure (Figs. 3.3 and

3.4).497 In a study of 20 patients with IIH, Brodsky and Vaphiades found flattening of the posterior sclera in 80%, empty sella in 70%, distension of the perioptic subarachnoid space in 45%, enhancement of the prelamnar optic nerve in 50%, vertical tortuousity of the orbital optic nerve in 40%, and intraocular protrusion of the prelaminar optic nerve in 30% (Fig. 3.4). MR imaging showed an empty sella in 71% of adults with IIH.373 Empty sella is thought to result from a pressure-induced, downward herniation of the suprasellar subarachnoid space into the sella, with secondary compression and flattening of the pituitary gland.373 Following normalization of intracranial pressure,

Fig. 3.4  MR imaging in IIH. (a) Enhanced T1-weighted MR image demonstrating distended perioptic nerve sheath (large open arrows), vertical tortuousity of the orbital optic nerve, and intraocular protrusion of the enhanced papilla (small open arrow). (b) Enhanced T1-weighted axial MR image demonstrating distension of the perioptic CSF space, vertical tortuousity of the optic nerves, and more severe protrusion of the papilla into

the globes (OS > OD). (c) Axial T1-weighted MR image demonstrating bilateral distension of the perioptic CSF space and flattening of the posterior sclera. (d) Empty sella. T1-weighted sagittal MR image shows compressed pituitary gland (lower arrow) assuming a concave shape within the lower sella. Upper arrow denotes chiasm, middle arrow denotes infundibulum. Used with permission from Brodsky and Vaphiades65

the pituitary gland may reexpand to assume its normal configuration.596

Primary IIH in Children

Although IIH is generally considered a disease of obese women of child-bearing age, its occurrence in children has been documented in numerous studies.23,25,343 Numerous studies have noted that the clinical profile of pediatric IIH differs in many respects from the adult variety (Table 3.2), suggesting that the precipitating factors may also be different. In younger age groups, there are more boys and nonobese children with IIH, and children may be more likely to be asymptomatic.93,128,445,492 Unlike adults, in whom there is a strong female predominance, the male-female ratio for IIH in prepubescent children is approximately equal.23,25,343 Starting at puberty, however, there is a distinct female predominance. A self-limited form of IIH may develop in girls following the onset of menstruation.213 Spontaneous remission appears to be more common in children and may even follow a diagnostic lumbar puncture.567 Some cases of IIH are familial.102

Infants and young children may present with irritability, listlessness, and somnolence.26,220,349 Dizziness or ataxia may also be evident.220,343 Irritability, nervousness, or apathy may be observed in older children.220 Generalized seizures have even been reported.220 Papilledema may still develop in infants with open fontanelles who have elevated intracranial pressure.343 Complaints of earache or roaring tinnitus are relatively common in children as well as adults.210 These associated symptoms should raise the diagnostic consideration of lateral venous sinus thrombosis.210 The incidence of certain neurologic deficits appear to be more common in children than in adults. Such deficits include lateral rectus paresis and atypical neurologic manifestations, such as skew deviation, facial paresis, and neck, shoulder, and back pain.343 Rarely, IIH can produce a comitant esotropia that is worse at distance without abduction deficits, internuclear ophthalmoplegia, transient bilateral oculomotor palsy,546 diffuse ophthalmoparesis, and nystagmus.175,595 It has been suggested that facial nerve paresis in IIH results from traction on the extra-axial facial nerves associated with small brainstem shifts caused by elevated intracranial pressure.501

Until recently, the consensus from clinical studies was that young patients with IIH tolerate chronic papilledema well and that visual loss from IIH is extremely rare in the pediatric age group.210–212,220,466,567 In summarizing 23 cases of childhood IIH, Rose and Matson466 concluded that “benign intracranial hypertension (in children) thus emerges as a clinical syndrome of varied etiology, generally with a short course, good prognosis, little tendency to

recurrence, and only rarely requiring surgical intervention.” It is now established that permanent visual loss may occur in both the adult and the pediatric variants of IIH23,26,108,343 and that children and adults share similar risks.24,26,342 Recognition of this visual morbidity has led to discarding the term benign intracranial hypertension in favor of the term IIH.

Optic atrophy as a consequence of chronic papilledema causes visual loss in IIH. In severe cases, loss of vision may evolve over a period of weeks; therefore, the finding of decreased vision demands aggressive, urgent intervention. In addition to chronic atrophic papilledema, rarer causes of visual loss, such as central retinal artery occlusion, peripapillary subretinal neovascularization, anterior ischemic optic neuropathy, and macular edema, should also be sought.26 Assessment of progressive visual loss is more difficult in children who are unable to cooperate for visual field testing. Although optical coherence tomography (OCT) has been reported to be of value in monitoring retinal nerve fiber layer in pediatric IIH (with increasing peripapillary nerve fiber layer thickness corresponding to worsening papilledema), the gradual development of optic atrophy can produce a significant confounding variable.142

Secondary IIH

Once the diagnosis of IIH has been established, one must exclude the presence of associated neurologic disorders, systemic disease, or ingestion of vitamins or other medications that are known to precipitate IIH (Table 3.2). The latter two categories may merge in patients in whom an exogenous agent is used to treat a systemic disease (e.g., thyroid replacement for hypothyroidism),77,442 danazol therapy for anemia,223,343 or recombinant growth hormone for growth hormone deficiency94,113,169,315,464 (Table 3.1). The three most commonly recognized causes of childhood IIH are dural venous thrombosis, steroid withdrawal, and malnutrition associated with refeeding.

IIH Secondary to Neurological Disease

The importance of otitis media, mastoiditis, and lateral sinus thrombosis in childhood IIH has long been recognized.211,539 Such cases of otitic hydrocephalus have decreased in recent decades as the incidence of mastoiditis has diminished with the advent of effective antibiotics.108,343 The differential diagnostic considerations of otitis media (with or without mastoiditis) associated with elevated intra­ cranial pressure include dural venous sinus thrombosis,

venous sinus compression by a regional abscess, and contiguous meningitis. The prevailing belief is that increased intracranial pressure may also follow an acute, uncomplicated otitis media.

Several earlier studies identified otitis media with mastoiditis as a major cause. During mastoidectomy in 11 such children, Greer211 consistently found compression of the junction between the lateral and sigmoid sinus from overlying necrotic material or abscess. The primary channel for intracranial venous drainage is the sagittal sinus, which normally drains into the right lateral sinus. This

explains the preponderance of right-sided infections in children with otitis-associated IIH.211 Lateral sinus thrombosis, although less common today, remains an important consideration in childhood IIH because children with dural sinus thrombosis may be at increased risk for visual loss compared to those with primary IIH.26 Lateral sinus thrombosis, mastoiditis, and cerebral abscess can usually be identified on MR imaging (Fig. 3.5). Obstruction of the transverse, sagittal, or straight sinus may follow seemingly­ insignificant head trauma in children and cause intracranial hypertension. Surprisingly, a recent multicenter­