A baby with a lot of nerve

Accepted Manuscript A baby with a lot of nerve Hema L. Ramkumar, M.D., Rohan Verma, M.D., Janet Crow, M.D., Shira Robbins, M.D, David B. Granet, M.D., Claire A. Sheldon, M.D., PhD., Fred M. Henretig, M.D., Grant T. Liu, M.D. PII:

S0039-6257(15)00218-0

DOI:

10.1016/j.survophthal.2015.11.007

Reference:

SOP 6604

To appear in:

Survey of Ophthalmology

Received Date: 27 May 2015 Revised Date:

18 November 2015

Accepted Date: 23 November 2015

Please cite this article as: Ramkumar HL, Verma R, Crow J, Robbins S, Granet DB, Sheldon CA, Henretig FM, Liu GT, A baby with a lot of nerve, Survey of Ophthalmology (2015), doi: 10.1016/ j.survophthal.2015.11.007. 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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Clinical Challenges

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A baby with a lot of nerve

Hema L. Ramkumar, M.D.1, Rohan Verma, M.D.2, Janet Crow, M.D.4, Shira Robbins, M.D3., and David B. Granet, M.D.3* Claire A. Sheldon, M.D., PhD5., Fred M. Henretig, M.D.6 and Grant T. Liu, M.D.7 1

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Department of Ophthalmology, University of California, San Diego, 9415 Campus Point Drive, La Jolla, CA 92037-0946, USA 2 University of California, San Diego School of Medicine, 9500 Gilman Dr., San Diego, CA 92093 3 Pediatric Ophthalmology and Adult Re-Alignment Services, Ratner Children's Eye Center & Shiley Eye Center, University of California, San Diego, California, USA 4 Department of Pediatrics, University of California, San Diego, California, USA 5 Division of Neuro-Ophthalmology, Department of Ophthalmology & Visual Sciences, University of British Columbia, Vancouver, BC. 6 Section of Clinical Toxicology, Division of Emergency Medicine, Children’s Hospital of Philadelphia, and the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA. 7 Neuro-ophthalmology Service, Division of Ophthalmology, Children’s Hospital of Philadelphia and the Departments of Neurology and Ophthalmology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Institution: University of California, San Diego, California, USA

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Word count for entire manuscript, including abstract: 3,524

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Word count for abstract (introductory paragraph): 66 Conflicts of Interest: None of the authors have any conflicts of interest to disclose *Corresponding Author: David B. Granet, MD, FAAP, FACS, Anne F. Ratner Professor of Ophthalmology & Pediatrics, Ratner & Shiley Eye Centers, University of California San Diego, 9415 Campus Point Drive, La Jolla California 92037 Electronic address: [email protected]

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A 10-month-old girl was referred by her pediatrician for new onset esotropia. Her mother reported a five day history of intermittent inward turning of the left eye. One month prior to presentation, the patient had two episodes of vomiting. A pediatric physical examination at the time was normal. The infant was playful and had no history of fever, seizures, other gastrointestinal symptoms, or altered consciousness.

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The child was born after an unremarkable pregnancy at 40 weeks of gestation by uncomplicated spontaneous vaginal delivery at 3841 grams. The mother’s medications during the pregnancy included Lexapro for well-controlled depression as well as lysine, sunflower lecithin, calcium, fish oil, and a prenatal vitamin that contained 4000 IU vitamin A (retinal palmitate). She denied using alcohol or other drugs and continued to take the prenatal vitamin postnatally. The child was otherwise healthy, immunized, and met all developmental milestones. She was breastfed and was taking vitamin D supplementation prescribed by the pediatrician. There was no family history of strabismus or neurologic disease. Her refractive error was +2.00 +0.50 x 180 OU. She had a 30 prism diopter esotropia at near with a right eye preference that increased on left gaze and decreased on right gaze. Her ductions and versions revealed full range of motion OD with a -2.5 abduction deficit OS without nystagmus. Dilated fundus examination revealed mild hyperemia of both optic discs with blurred disc margins. The infant’s anterior fontanelle was open and soft. Because her ophthalmic examination was consistent with a left cranial nerve VI palsy in the setting of bilateral disc edema, she was transferred to the local children's hospital emergency room for further evaluation.

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Case Report

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(In keeping with the format of a clinical pathologic conference, the abstract and key words appear at the end of the article.)

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What are the diagnostic considerations? What would you do next? Comments by Claire A. Sheldon, M.D., PhD and Grant T. Liu, M.D.

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The authors describe the case of a 10-month-old child with vomiting, acute esotropia, and papilledema. Together, these clinical features are concerning for raised intracranial pressure. The differential diagnosis remains broad at this point and includes an intracranial mass lesion, hydrocephalus, intracranial hemorrhage, pseudotumor cerebri (PTC), venous thrombosis/obstruction, and meningitis.

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In light of the differential diagnosis, she requires urgent neuro-imaging. Given the child’s young age and the potential radiation exposure28 of CT, MRI imaging of the brain (with and without gadolinium) should be performed to rule out an intracranial mass lesion, hydrocephalus, or intracranial hemorrhage. Given her age, we would also recommend completing MR venography to exclude a venous thrombosis. If imaging is normal, a lumbar puncture is necessary to document elevated intracranial pressure and CSF composition. CSF fluid analysis should include, at minimum, cell count, cytology and concentrations of glucose and protein. Meningitis should be excluded.

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Case Report (continued)

Magnetic resonance imaging of the brain with and without gadolinium demonstrated no intracranial abnormalities, but protrusion of the optic nerve into the globes , consistent with the bilateral optic disc edema (Figure). Major vascular flow voids at the skull base suggested that there was no venous sinus thrombosis. An MRV was not performed because post-contrast images were deemed sufficient to rule-out a dural venous sinus thrombosis. A lumbar puncture performedin the left lateral decubitus position showed an elevated CSF opening pressure of 50 cm H20 with normal CSF composition. A serum vitamin A level was elevated to 52 mcg/dL. The normal range of vitamin A in children age 1-6 is 20-43 mcg/dL, but there is no acceptednormal range for infants.

Comments by Claire Sheldon, MD, PhD; Grant T. Liu, MD

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In the past, the diagnosis of PTC was based on the modified Dandy criteria; however, subsequent modifications have been made based on increasing recognition of typical signs and symptoms of this disorder. The most recent updated diagnostic criteria were published in 2013 and incorporated timely insights into common neuroimaging characteristics of raised ICP and reference ranges of normal CSF opening pressure.13 In the current case many criteria are fulfilled. First, the contrast-enhanced MRI revealed normal brain parenchyma and, with attention paid to the cerebral veins, there was no evidence of venous thrombosis/obstruction. The MRI did reveal at least two radiographic features of raised ICP, namely globe flattening and peri-optic distention (Figure). Second, an opening pressure of 50 cm H2O documents raised intracranial pressure. Opening pressure greater than 28 cm H2O in children is considered elevated;

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What is the relevance of this CSF opening pressure?

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however, greater than 25 cm H2O is considered elevated in those not sedated during the lumbar puncture and non-obese children.2 Third, there was normal CSF composition. In summary, as illustrated by this case, key diagnostic requirements for PTC include (i) papilledema, (ii) normal brain parenchyma on neuro-imaging with contrast-enhanced MRI or CT, (iii) normal venous imaging, in select cases, with MRI- or CT-venogram and (iv) normal CSF composition. With elevated ICP, a diagnosis of PTC can be made. We must re-emphasize that, given the atypical nature of this presentation, MR venography would have been important to establish a diagnosis of definite PTC.

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PTC is classified as either primary or secondary. Primary PTC includes idiopathic intracranial hypertension, a condition seen in adult, adolescent, and pediatric populations. Adolescents with PTC are more frequently obese and female.5 Young, prepubertal children, on the other hand, are less likely to be obese, equally male and female, and may present without symptoms of headache or visual blurring.4,8

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Secondary PTC refers to a clinical diagnosis of PTC attributable to one of a variety of identifiable cases: venous sinus thrombosis, medications and medical conditions other than obesity alone. Some of the most common causes of secondary PTC include anemia, exposure to tetracycline-related antibiotics, synthetic growth hormone, or Vitamin A derivative medications.12,13 The elevated vitamin A level documented in the current clinic case suggests that this may be a case of secondary PTC. Hypervitaminosis A reduces CSF absorption, possibly through a structural cellular change at the level of the arachnoid villi.19 Few studies have been focused on characterizing secondary pediatric PTC; however, a recent publication does outline that the initial clinical presentation is remarkably similar between primary and secondary PTC.22 What is the relevance of the vitamin A level?

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Comments by Fred M. Henretig, MD

The posited finding of an elevated serum vitamin A level in this infant raises the fascinating subject of this essential micronutrient’s relation to ocular health and disease. An early description of likely hypervitaminosis A-associated PTC was made by the 19th century Artic explorer Elisha Kane, who described the syndrome of headache, vomiting, drowsiness and irritability after ingesting polar bear liver.18

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The primary food sources of Vitamin A are liver, dairy products, egg yolk, and fish (retinol or retinyl esters) and yellow and green vegetables (carotene). Hepatic vitamin A storage is considerable, with typical content of 100-300 mcg/g as retinyl esters. When vitamin A ingestion becomes excessive, hepatic storage may be overwhelmed, resulting in hepatotoxicity from excessive retinyl ester and lipid accumulation, and elevated circulating vitamin A, both as retinol (which may exceed its retinol-binding protein capacity) and retinyl esters, resulting in systemic toxicity.20

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Such systemic effects include PTC, which may explain this infant’s illness, and for which the toxicologic etiology as discussed below. Other findings in children with vitamin A toxicity may include dematologic changes such as dry, pruritic, peeling skin, hair loss, cheilitis, stomatitis, and gingivitis, and skeletal system abnormalities including bone pain and tenderness, growth disturbance, radiographic changes such as osteoporosis, hypermineralization, cortical hyperostoss, and periosteal calcifications. Hypercalcemia may occur as a result of increased osteoclastic activity. Teratogenic effects of high dose vitamin A, and the vitamin A derivative acne medication, isotretinoin, are well described.

Comments by Claire Sheldon, MD, PhD; Grant T. Liu, MD

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The primary goal of treatment of PTC is to prevent vision loss and relieve symptoms of elevated ICP (e.g. nausea). The Idiopathic Intracranial Hypertension Treatment Trial was a multicenter, double-blind, randomized clinical trial illustrating the benefit of acetazolamide and weight loss to improve visual recovery in adult PTC; however, there are no randomized clinical trials to allow for evidence-based recommendations in the

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The treatment of chronic vitamin A toxicity consists primarily of cessation of exposure and supportive care, with the exception of significant PTC, which is discussed in detail elsewhere in this report. Occasional patients may require fluid, diuretic, and corticosteroid therapy for hypercalcemia.

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Typically, hypervitaminosis A in childhood involves much higher doses of vitamin A exposure than implicated in this infant, generally above 18,000 IU/day, given directly to the child. Such cases often involve well-meaning parents with an “alternative medicine” bent who feel that such supplementation will strengthen their child’s immune system or prevent chronic illnesses. In the case reported here, the mother received a vitamin A supplement providing 4000 IU /day, which is approximately the total daily recommended allowance for lactating women in the U.S 9, and it is suggested that this might have led to transfer of excessive amounts of vitamin A to the baby. Vitamin A content in breast milk does vary with maternal vitamin A intake, but the occurrence of vitamin A toxicity in breast fed infants whose mothers receive vitamin A supplementation is rare.1 Although the 10-month-old reported here had a retinol level of 52 mcg/dL, which was elevated per the normal range cited by the authors for older children (20-43 mcg/dL), another reference suggests that normal levels in infancy range from 20-50 mcg/dL, with higher values in older children and adults30, and thus the level in this case might be very close to normal for an “older infant”. On the other hand, cases of hypervitaminosis A have occurred with normal serum retinol levels. Thus, while possible, I am not yet convinced that this infant’s PTC is to the result of vitamin A toxicity, or if it was, that breast milk alone was the culprit. I wonder if it’s possible that additional sources of vitamin A, either dietary or thus far unreported supplements, were provided directly to this child?

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What is the management of PTC in the infantile and pediatric population?

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treatment of pediatric PTC. The two mainstays of treatment aremedications to lower ICP and weight management. Carbonic anhydrase inhibitors are frequently used in the treatment of pediatric patients with PTC.24 The recommended starting dose for acetazolamide is 15–25 mg/kg/day divided into 2–3 doses. This may be gradually increased up to 100 mg/kg (up to 2 g/day in children and 4 g/day in adolescents) as needed. Common side effects include paresthesias, metallic taste, gastrointestinal upset, and loss of appetite. Metabolic acidosis is a well-recognized adverse effect, but is typically asymptomatic, well tolerated, and generally does not require treatment.29 Alternatives to acetazolamide include furosemide (a loop diuretic), and topiramate (an anti-seizure drug).7 The duration of treatment is based on resolution of papilledema. We do not typically find repeat lumbar puncture informative and, rather, follow carefully the appearance of the optic nerves and visual fields. In children, when visual assessments cannot be made, then we follow optic nerve appearance, headache, and constitutional symptoms. When pediatric PTC is associated with obesity, weight management is essential. Finally, in the case of secondary PTC, removal of the offending agent is critical.

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Comments by Claire Sheldon, MD, PhD; Grant T. Liu, MD

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Surgical interventions are typically reserved for progressive vision loss despite maximal medical therapy or when there is severe visual loss at presentation. The two most commonly used surgical procedures are optic nerve sheath fenestration and CSF (ie.lumboperitoneal or ventriculoperitoneal) shunting.

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Why were optic nerves edematous in the setting of open sutures?

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Elevations in intracranial pressure, in the setting of open sutures, characteristically cause increases in head circumference.With rapid increases in intracranial pressure, however, there may be additional clinical features, including bulging fontanelle, papilledema, esodeviation and/or tonic downgaze. Case report concluded

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The final diagnosis was PTC associated with hypervitaminosis A. Maternal prenatal vitamin supplementation and infant vitamin D supplementations were discontinued. The patient was started on acetazolamide 25 mg/kg/day in three divided doses. Repeat lumbar puncture after two weeks revealed an opening pressure of 35 cm H20. At this time, there was no change in vitamin A level (50 mcg/dL). Follow-up eye examination revealed improving disc edema with complete resolution six weeks after initial presentation. Patching was instituted, and the left CN VI palsy improved over 10 months, after which she had a residual left abduction deficit of -0.5. The acetazolamide was tapered over the course of three months. Residual esophoria was 6 prism diopters in primary position at distance and near, with an esophoria of 4 prism diopters in right

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gaze and an esotropia of 8 prism diopters in left gaze. Her optic nerves remained flat without any evidence of optic atrophy or retinal nerve fiber layer loss.

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To our knowledge, this is the first case report of an infant with PTC from hypervitaminosis A associated with a prenatal vitamin taken at the recommended daily dose for breastfeeding mothers. This infant had a CN VI palsy and bilateral disc edema, both of which recovered without visual compromise after both the discontinuation of maternal prenatal vitamin supplementation and medical management with acetazolamide.

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Discussion

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The incidence of PTC in the general population is 1 out of 100,000, with an increased incidence of 19 per 100,000 for women aged 20-44 who are 20% or more over their ideal weight.9,6 Although there has been an increase in PTC being diagnosed among younger adolescents (12-15 years old), it is rare in infants14,15,25,26 where it isnot associated with obesity or female sex.4 An opening pressure greater than 28 cm H20 in children is considered abnormal,2 with revised criteria for PTC in pre-pubertal children proposed by Rangwala and Liu.13 In children signs of intracranial hypertension include vague symptoms such as stiff neck, photophobia, anorexia, retro-orbital pain, lightheadedness, myalgia, and head tilt. Headaches are the most common presenting sign, but this history cannot be elicited in infants. Psuedotumor patients have a normal level of consciousness, and a CN VI palsy occurs in up to 48% of cases.3,11,24 PTC is a diagnosis of exclusion with radiographic and laboratory evidence needed to rule out other causes of elevated ICP such as mass lesions, obstructive hydrocephalus, chronic meningitis, or dural sinus thrombosis.12

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In the pediatric population, many cases are associated with an identifiable condition (endocrine, medications, and infections). Hypervitaminosis A has been reported to cause PTC in children and adults with daily vitamin A intake of 1,500-150,000 IU/day,17,21 and infants are generally considered to be more susceptible to vitamin A toxicity.21 Breast milk retinol is highest during the first three months of lactation. One hypothesis is that the elevated serum retinol binding protein and retinol are transported to the CSF, where retinol acts as a toxin, damaging arachnoid granulation cells and decreasing CSF reabsorption in the ventricular system.27 Low Vitamin A levels, however, have also been found in children with PTC.10 Vitamin A metabolism dysregulation may be implicated, and further studies are warranted to better understand the pathophysiology. Treatment of PTC in children is extrapolated from adults with a key difference. If progressive visual field loss is observed on acetazolamide therapy, intravenous methylprednisolone may be used as adjunctive therapy.6 Medical therapy is almost always successful.16 If visual loss exists and medical therapy is failing, optic nerve sheath fenestration (ONSF) and/or lumboperitoneal shunting may prevent further visual field loss. While managing the cranial nerve VI palsy, amblyopia treatment with patching should also be considered.

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In infants papilledema is rare because open fontanelles lead to increased head circumference before the optic nerves are affected. This case demonstrates that papilledema may be present in infants when rapid or marked elevations in ICP may exceed the distensiblility of an infant’s skull, thereby increasing pressure within the optic nerve sheaths. The optic nerve sheath is not as rigid as other intracranial meningeal structures and can swell before changes in intracranial CSF spaces. For the ophthalmologist, judging vision, vision loss, and visual field loss can be difficult because of the lack of objective measures in infants. Permanent visual acuity deficits and visual field loss persist in 0-17% of treated patients, with a recurrence rate between 6-22%.8,23 Fortunately, pediatric and infantile PTC has an excellent prognosis with papilledema usually resolving in 4.7 months with treatment.8

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1. Disclosures

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The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.

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2. Method of Literature Search:

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A PubMed (1950-2014) database search was performed using the following keywords: vitamin A AND idiopathic intracranial hypertension OR pseudotumor cerebri AND infant. We included reports of idiopathic intracranial hypertension only if they were in the infant population. Additional studies were manually singled out by scrutinizing references from identified manuscripts, major ophthalmology journals, and texts.

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Legend:

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Figure: Magnetic Resonance Imaging (MRI) T2 axial section demonstrating edema of the optic nerve sheath and bilateral protrusion of the optic nerves into the globe consistent with clinical optic disc edema.

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Abstract

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An infant presented with bilateral disc edema and an acute left CN VI palsy due to pseudotumor cerebri (PTC). PTC is rare in infants where it is often associated with endocrine abnormalities, medications, viral infections, systemic conditions, and nutritional etiologies such as vitamin A toxicity. We report a case of PTC in an infant associated with hypervitaminosis A with an unlikely source—a common prenatal vitamin.

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Key words : pseudotumor cerebri, idiopathic intracranial hypertension, infant, vitamin A, acetazolamide, cranial neuropathy

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