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and 183 (64%) had no infantile esotropia. Wide nasal bridge and broad epicanthal folds were recorded in 98 (34%) non-Chinese children. The PPV of referrals for infantile esotropia in Chinese patients was 5.9% (95% CI, 1.0%-27.0%), which was significantly lower than that in non-Chinese patients (PPV 5 36.0%; 95% CI, 30.7%-41.7%). The false referral rate in Chinese patients was 94.1% (95% CI, 73.0%-99.0%), which was significantly higher than that in non-Chinese patients (false referral 5 64.0%; 95% CI, 58.3%-69.3%). There were no significant differences in the mean age of onset and mean refractive errors between the two groups (Table 1).
Discussion After addressing potential confounders such as other comorbidities, age of onset, and difference in refractive errors, the major finding of this study is a very low positive predictive value (5.9%) and a very high false referral rate (94.1%) among Chinese children referred for early-onset esotropia. We acknowledge the limitations of using a list of surnames to identify people of Chinese descent. For example, some people from Southeast Asia may have Chinese surnames but they are not necessarily ethnic Chinese. Also, children from multiracial couples may or may not adopt a Chinese surname. Nevertheless, the use of a list of Chinese surnames is a validated methodology10 and it alone could not account for the large difference in PPV of referral for infantile esotropia between Chinese and non-Chinese patients. This difference is also unlikely to be due to baseline patient characteristics, because the mean age of onset and mean refractive errors did not differ significantly. The poor PPV and high false referral rate among Chinese children could be explained by the observation that 88% of Chinese children exhibited typical facial features associated with pseudo-esotropia (eg, wide nasal bridge and broad epicanthal folds). A secondary finding—a probable 6-fold lower prevalence of infantile esotropia in the Chinese population—is suggested by the low incidence of true positives in Chinese (5.9%) vs non-Chinese children (36.0%); however, this finding is only indirectly supported by the evidence because our data was based on referrals rather than the general population. More studies are needed to investigate whether the prevalence of infantile esotropia (and esotropia of all types) is truly lower in the general Chinese population. References 1. Chew E, Remaley NA, Tamboli A, Zhao J, Podgor MJ, Klebanoff M. Risk factors for esotropia and exotropia. Arch Ophthalmol 1994;112: 1349-55. 2. Yu CB, Fan DS, Wong VW, Wong CY, Lam DS. Changing patterns of strabismus: a decade of experience in Hong Kong. Br J Ophthalmol 2002;86:854-6. 3. Matsuo T, Matsuo C. The prevalence of strabismus and amblyopia in Japanese elementary school children. Ophthalmic Epidemiol 2005; 12:31-6. 4. Lambert SR. Are there more exotropes than esotropes in Hong Kong? Br J Ophthalmol 2002;86:835-6.
Volume 18 Number 5 / October 2014 5. Friedman Z, Neumann E, Hyams SW, Peleg B. Ophthalmic screening of 38,000 children, age 1 to 2 1/2 years, in child welfare clinics. J Pediatr Ophthalmol Strabismus 1980;17:261-7. 6. Pike MG, Holmstrom G, de Vries LS, et al. Patterns of visual impairment associated with lesions of the preterm infant brain. Dev Med Child Neurol 1994;36:849-62. 7. Shapiro MB, France TD. The ocular features of Down’s syndrome. Am J Ophthalmol 1985;99:659-63. 8. People and Culture—Population Densities. http://www.ontario.ca/ en/about_ontario/EC001035.html. 9. City of Toronto. Toronto Facts: Diversity. 2014. http://www. toronto.ca/toronto_facts/diversity.htm. 10. Choi BC, Hanley AJ, Holowaty EJ, Dale D. Use of surnames to identify individuals of Chinese ancestry. Am J Epidemiol 1993;138:723-34.
Intracranial hypertension due to levothyroxine use Casey J. Beal, MD,a Kristina Y. Pao, MD,a and R. Nick Hogan, MD, PhDb,c We report a case of intracranial hypertension in a 13-year-old boy on levothyroxine therapy for hypothyroidism and review the literature describing this rare association. He presented with severe headaches and was found to have bilateral optic disk edema and elevated intracranial pressure shortly after an increase in his dosage of levothyroxine. The optic disk edema and headaches resolved with decreasing the levothyroxine and initiating acetazolamide.
I
diopathic intracranial hypertension, or pseudotumor cerebri, is defined clinically as the signs and symptoms of increased intracranial pressure with normal neuroanatomy and cerebral spinal fluid studies and an elevated opening pressure on lumbar puncture. Optic disk edema is a characteristic clinical finding in idiopathic intracranial hypertension and is often associated with visual field defects. The most common symptoms include postural headache, nausea, amarosis fugax, diplopia, and pulsatile tinnitus.1 Treatment is aimed at decreasing intracranial pressure and preventing permanent vision loss. The list of reported secondary causes of elevated intracranial pressure is long and ever expanding and includes hypervitaminosis A, retinoic acid, tetracyclines, nitrofurantoin, fluoroquinolones, lithium, oral contraceptives,
Author affiliations: Departments of aOphthalmology, bNeuro-ophthalmology, and cOcular Pathology, University of Texas Southwestern Medical Center, Dallas, Texas Submitted September 28, 2013. Revision accepted June 12, 2014. Published online September 27, 2014. Correspondence: R. Nick Hogan, MD, PhD, Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd. Dallas, TX (email: Nick. [email protected]). J AAPOS 2014;18:504-507. Copyright Ó 2014 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2014.06.017
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Table 1. THRT associated with intracranial hypertension: review of published cases Secondary IH
Author 3
Patient age,b years (sex) BMI THRT 8/12
Van Wyk
12
Prendes4 Van Dop5
(F)
Opening pressure, Duration of treatmenta Presenting symptoms mm H2O
24.6
T3
4.5 months
89/12 (F) 119/12 (M)
17.3 N/A
DT T4
2 months 1 month
Van Dop5
87/12 (F)
N/A
T4
5 weeks
McVie6
9 (F)
Huseman7
136/12 (M)
Headache, scotoma, vomiting 17.9 LT 2 months; 5 Headache, vomiting days on recurrence 40.5 Liotrix 3 months Headache
Huseman7
133/12 (F)
N/A
LT
2 months
Rohn8
66/12 (F)
N/A
LT
1.5 months
Campos1
77/12 (F)
16.1
LT
1 week
Raghavan9
3 wks (F)
N/A
LT
4 months
N/A 31.9
LT LT
N/A 3 months
12 (F) Strickler10 Present case 1311/12 (M)
Blurred vision, enlarged blind spot Headache Headache
350 N/A 280 480 N/A 260
Headache, horizontal 274 diplopia, transient visual obscurations Headache, transient N/A visual obscurations Headache, eye pain, 280 nausea, vomiting, tinnitus None Elevated (value N/A) Headache N/A Headache 380
Treatment change 1/2 grain DT daily, increased to 1.5 None AZ (250 mg BID), T4 decrease Dexamethasone, AZ (250 mg BID) LT decrease
Duration of treatment and/or Follow- up, resolution of IH months 3 weeks
12
5 months 1 month
16 N/A
10 months
N/A
2 weeks
N/A
Cortisone acetate, 5 months glycerin, Liotrix to LT (100 mcg/day) Glycerin, LT decrease, 8 months prednisone
36
N/A
N/A
N/A
AZ (250 mg BID)
2 months
N/A
None
4-8 months
12
AZ (250 mg BID) AZ (250 mg TID), LT decrease to 50 mcg/day
N/A 12 months
6 12
12
AZ, acetazolamide; BID, twice daily; BMI, body mass index; DT, dessicated thyroid; IH, intracranial hypertension; LT, levothyroxine; N/A, not available or unknown; T3, triiodothyroxine; T4, thyroxine; THRT, thyroid replacement therapy; TID, thrice daily. a Before diagnosis of secondary IH. b Age at diagnosis of thyroid abnormality.
immunizations, pregnancy, infection, weight gain in nutritionally deprived children, thyroid dysfunction, parathyroid dysfunction, adrenal dysfunction, Addison’s disease, hypocalcemia, panhypopituitarism, iron deficiency, steroid use or withdrawal, and, rarely, levothyroxine.2 We report the case of a 13-year-old boy on levothyroxine who developed elevated intracranial pressure and review the current English literature of levothyroxine-induced intracranial hypertension.
Case Report A 13-year-old Hispanic boy presented at the Endocrinology Center at Children’s Medical Center of Dallas with a chief symptom of intermittent headaches for the previous 2 years. The patient’s family noted weight gain, generalized fatigue, and growth restriction. Systemic endocrinological work-up revealed a body mass index (BMI) of 39.1, with an elevated thyroid-stimulating hormone (TSH) and low free T4. Hemoglobin A1C and oral glucose tolerance test were normal. He was diagnosed with chronic lymphocytic thyroiditis and prescribed oral levothyroxine 50 mcg daily (0.72 mcg/kg/day).
Journal of AAPOS
Two months after the initiation of levothyroxine therapy his dosage was titrated to 75 mcg per day (1.17mcg/kg/ day). One month after the increase, he reported severely worsening headaches. He was initially seen by an outside eye care provider for a routine eye examination and was noted to have bilateral optic disk edema. The patient was referred to Children’s Medical Center of Dallas ophthalmology clinic for further evaluation. On examination, the patient’s corrected distance visual acuity was 20/15 in both eyes. The pupils were equal and briskly reactive, with no afferent pupillary defect. Ishihara pseudo-isochromatic plates were normal in both eyes. The patient was orthophoric, with full ductions and versions. Confrontational visual fields and intraocular pressure were normal. Slit-lamp examination was unremarkable. Dilated fundus examination showed bilateral optic disk edema without hemorrhages or hard exudates. Cycloplegic refraction showed a 2.00 D refractive error in both eyes. Humphrey visual field testing was unreliable in both eyes. Lumbar puncture in the left lateral decubitus position revealed an opening pressure of 380 mm H2O (normal, \200 mm H2O). Radiographic and cerebral spinal fluid
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studies were unremarkable. Oral acetazolamide, 250 mg three times daily, was initiated, and the patient’s levothyroxine dosage was decreased to 50 mcg daily, with marked improvement in his headaches. Three months later, the patient’s visual acuity was 20/20 in both eyes, with trace residual nasal elevation of his optic disks. His acetazolamide dose was decreased to 125 mg twice daily, and his levothyroxine dosage was increased to 88 mcg daily. The patient continued to do well at 12 months’ follow-up, with no residual visual deficits and resolution of his optic disk edema.
Discussion Reports of thyroid replacement therapy associated with intracranial hypertension are rare. Our review of the literature identified 11 other cases that support the association between thyroid replacement therapy and intracranial hypertension (Table 1). Of the 12 cases (9 females), including the present one, 1 involved congenital hypothyroidism9; the rest, juvenile hypothyroidism. The average age of onset of symptoms was 9 3.9 years (standard deviation). The initial TSH and thyroxine levels on hypothyroidism diagnosis did not correlate with duration of symptoms, treatment, or outcomes. The most common presenting symptom was headache, occurring in 10 of the 12 patients. Headaches were characterized as throbbing, pressure, and boring-type pain. Only 5 of the 12 patients reported visual symptoms on presentation. When visual symptoms were reported, they included transient visual obscurations, blurred vision, scotoma, and horizontal diplopia.7 Our review implicates several types of thyroid replacement therapy, including liotrix, dessicated thyroid, triiodothyroxine, thyroxine, and levothyroxine. This suggests that the underlying cause of the secondary intracranial hypertension is not specific to levothyroxine alone. Currently, levothyroxine is the treatment of choice for hypothyroidism. The duration of thyroid treatment prior to the diagnosis of intracranial hypertension ranged from 1-18 weeks, averaging of 8-12 weeks. The length of treatment for the intracranial hypertension varied widely. In 2 patients signs and symptoms resolved spontaneously, with no treatment of their intracranial hypertension, over 4-8 months and continuance of the same dosage of thyroid hormone replacement.4,9 Other treatment regimens included temporarily decreasing the dosage of thyroid replacement therapy, changing to another medication, and treating the increased intracranial pressure with corticosteroids, glycerin, or acetazolamide. The length of treatment for the increased intracranial pressure ranged from 2 weeks to 12 months, depending upon the patient’s signs and symptoms. Only 1 patient showed a permanent visual deficit (persistent enlarged blind spots) during follow-up.10 This patient was lost to follow-up after 6 months. The length of follow-up of the other cases ranged from 6 months to 3 years.
Volume 18 Number 5 / October 2014 Our patient developed worsening headaches after his levothyroxine dosage was increased and was found to have bilateral optic disk edema, with an opening pressure of 380 mm H2O. However, due to our patient’s BMI and history of headaches, we cannot exclude the possibility that papilledema was present prior to the initiation of levothyroxine. A baseline ophthalmic examination was not obtained, because the patient had no visual complaints. A thorough literature review revealed that visual symptoms were present in less than half of the patients with secondary elevated intracranial pressure. Thus visual symptoms cannot be a reliable indicator of the presence of increased intracranial pressure in children. The most common presenting symptom was headache. One might suggest that a baseline ocular examination be obtained prior to initiation of thyroid replacement therapy in patients with a history of obesity and headaches, because thyroid replacement therapy may cause or worsen preexisting signs and symptoms of elevated ICP. The pathophysiology of secondary intracranial hypertension associated with thyroid replacement is unknown. It is important to be aware of this association between levothyroxine and intracranial hypertension because a delay in diagnosis may lead to permanent vision loss. A coordinated effort between ophthalmology and endocrinology should be undertaken to help ensure proper management of both the intracranial hypertension and the patient’s underlying thyroid abnormality.
Literature Search PubMed was searched on August 20, 2014, without date restriction for English-language results using combinations of the following terms: levothyroxine, idiopathic intracranial hypertension, elevated ICP, hypothyroidism, pediatric, and pseudotumor cerebri. All articles with sufficient evidence to associate thyroid replacement with intracranial hypertension were included. References 1. Campos SP, Olitsky S. Idiopathic intracranial hypertension after Lthyroxine therapy for acquired primary hypothyroidism. Clin Pediatr 1995;34:334-7. 2. Robertson WC, Chawla J. Pediatric idiopathic intracranial hypertension. http://www.emedicine.medscape.com/article/1179733-overview. Accessed August 19, 2012. 3. Van Wyk JJ, Grumbach MM. Syndrome of precocious menstruation and galactorrhea in juvenile hypothyroidism: an example of hormonal overlap in pituitary feedback. J Pediatr 1960;57:416-35. 4. Prendes JL, McLean WT. Pseudotumor cerebri during treatment for hypothyroidism. South Med J 1978;71:977. 5. Van Dop C, Conte FA, Koch TK, Clark SJ, Wilson-Davis SL, Grumbach MM. Pseudotumor cerebri associated with initiation of levothyroxine therapy for juvenile hypothyroidism. N Engl J Med 1983;308:1076-80. 6. McVie R. Abnormal TSH regulation, pseudotumor cerebri, and empty sella after replacement therapy in juvenile hypothyroidism. J Pediatr 1984;105:768-70. 7. Huseman CA, Torkelson RD. Pseudotumor cerebri following treatment of hypothalamic and primary hypothyroidism. Am J Dis Child 1984;138:927-31.
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8. Rohn R. Pseudotumor cerebri following treatment of hypothyroidism. Am J Dis Child 1985;139:752. 9. Raghavan S, DiMartino-Nardi J, Saenger P, Linder B. Pseudotumor cerebri in an infant after L-thyroxine therapy for transient neonatal hypothyroidism. J Pediatr 1997;130:478-80. 10. Strickler C, Pilon AF. Presumed levothyroxine-induced pseudotumor cerebri in a pediatric patient being treated for congenital hypothyroidism. Clin Ophthalmol 2007;1:545-9.
Congenital oculomotor nerve palsy due to effects of carotid artery agenesis Lakshmi Cherungottil, MS,a Shashikant Shetty, MS,a Perumalsamy Vijayalakshmi, MS,a Malay Kumar Dwivedi, MS,a Kaliappan Gurusamy Srinivasan, MD,b and Muniasamy Saravanan, MRCPc Isolated carotid artery agenesis is not generally recognized as a cause of congenital oculomotor nerve palsy. We report this rare association in 2 children and examine the underlying mechanism.
Case 1
A
7-year-old South Indian girl presented at the Paediatric Ophthalmology Department of Aravind Eye Hospital and Post Graduate Institute with a history of right upper eyelid ptosis and squinting of the same eye since birth. She had a normal perinatal period and normal milestones. Her medical history was unremarkable. There was no family history of any significant eye disease. On ophthalmological examination, visual acuity was 20/ 80 in the right eye, with no improvement with refractive correction or pinhole, and 20/20 in the left eye. There was an upper lid notch, with ptosis in the right eye and an epibulbar dermoid (Figure 1A). The right eye was exotropic and hypotropic; ocular motility was restricted in all directions except abduction. The pupil was dilated and fixed at 5 mm, with no signs of aberrant regeneration. Ocular motility in the left eye was full and unrestricted.
FIG 1. Patient 1. A, The right eye in exotropic and hypotropic position showing ptosis and temporal lid notch. B, T2-weighted cranial magnetic resonance (MR) imaging (axial view) showing the right posterior communicating artery aneurysm. C, 3D time-of-flight (TOF) cerebral angiogram axial view, superior) showing a deficient flow in the left internal carotid artery, normal flow in the right internal carotid artery, and the absence of high intensity signal flow void in the aneurysm. D, 3D TOF angiogram of the neck (coronal view) showing absent flow in the left internal carotid artery.
Retinal examination of both eyes was normal, but she showed perifoveal fixation in the right eye. She had no binocularity in primary or downgaze. There were no neurocutaneous abnormalities or other neurologic signs, and a thorough evaluation performed by the pediatrician ruled out systemic diseases. She was diagnosed with pupilinvolving congenital third (oculomotor) nerve palsy with amblyopia in her right eye. Magnetic resonance (MR) imaging and MR angiography revealed a right posterior communicating artery aneurysm (Figure 1B) compressing the oculomotor nerve, which explained the clinical features, but the aneurysm was already thrombosed, as indicated by the absence of flow void in the MR angiogram (Figure 1C). Additionally, she had a left internal carotid artery agenesis (Figure 1C,D), which led us to conclude that the lesion was a thrombosed “flow aneurysm,” which was congenital and did not mandate emergency intervention.
Case 2 Author affiliations: aAravind Eye Hospital and Post Graduate Institute of Ophthalmology, Madurai, Tamil Nadu, India; bKGS Advanced Scan Centre, Madurai, Tamil Nadu; cRio Advanced Children’s Hospital Madurai, Tamil Nadu Submitted December 30, 2013. Revision accepted June 12, 2014. Correspondence: Lakshmi Cherungottil, MS, Aravind Eye Hospital, 1 Anna Nagar, Madurai 625020, Tamil Nadu, India (email: [email protected]). J AAPOS 2014;18:507-509. Copyright Ó 2014 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2014.06.014
Journal of AAPOS
A 40-day-old female infant was referred with a history of right upper eyelid ptosis, since birth. She had an uneventful perinatal history except for a patent ductus arteriosus which closed spontaneously and a small Atrial septal defect with left to right shunt, assessed by the cardiologist that was under observation. There was no family history of ptosis or eye disease. On initial examination, she had complete ptosis of the right eye (Figure 2A), which was fixed in the abducted
Beal, Pao, and Hogan
and 183 (64%) had no infantile esotropia. Wide nasal bridge and broad epicanthal folds were recorded in 98 (34%) non-Chinese children. The PPV of referrals for infantile esotropia in Chinese patients was 5.9% (95% CI, 1.0%-27.0%), which was significantly lower than that in non-Chinese patients (PPV 5 36.0%; 95% CI, 30.7%-41.7%). The false referral rate in Chinese patients was 94.1% (95% CI, 73.0%-99.0%), which was significantly higher than that in non-Chinese patients (false referral 5 64.0%; 95% CI, 58.3%-69.3%). There were no significant differences in the mean age of onset and mean refractive errors between the two groups (Table 1).
Discussion After addressing potential confounders such as other comorbidities, age of onset, and difference in refractive errors, the major finding of this study is a very low positive predictive value (5.9%) and a very high false referral rate (94.1%) among Chinese children referred for early-onset esotropia. We acknowledge the limitations of using a list of surnames to identify people of Chinese descent. For example, some people from Southeast Asia may have Chinese surnames but they are not necessarily ethnic Chinese. Also, children from multiracial couples may or may not adopt a Chinese surname. Nevertheless, the use of a list of Chinese surnames is a validated methodology10 and it alone could not account for the large difference in PPV of referral for infantile esotropia between Chinese and non-Chinese patients. This difference is also unlikely to be due to baseline patient characteristics, because the mean age of onset and mean refractive errors did not differ significantly. The poor PPV and high false referral rate among Chinese children could be explained by the observation that 88% of Chinese children exhibited typical facial features associated with pseudo-esotropia (eg, wide nasal bridge and broad epicanthal folds). A secondary finding—a probable 6-fold lower prevalence of infantile esotropia in the Chinese population—is suggested by the low incidence of true positives in Chinese (5.9%) vs non-Chinese children (36.0%); however, this finding is only indirectly supported by the evidence because our data was based on referrals rather than the general population. More studies are needed to investigate whether the prevalence of infantile esotropia (and esotropia of all types) is truly lower in the general Chinese population. References 1. Chew E, Remaley NA, Tamboli A, Zhao J, Podgor MJ, Klebanoff M. Risk factors for esotropia and exotropia. Arch Ophthalmol 1994;112: 1349-55. 2. Yu CB, Fan DS, Wong VW, Wong CY, Lam DS. Changing patterns of strabismus: a decade of experience in Hong Kong. Br J Ophthalmol 2002;86:854-6. 3. Matsuo T, Matsuo C. The prevalence of strabismus and amblyopia in Japanese elementary school children. Ophthalmic Epidemiol 2005; 12:31-6. 4. Lambert SR. Are there more exotropes than esotropes in Hong Kong? Br J Ophthalmol 2002;86:835-6.
Volume 18 Number 5 / October 2014 5. Friedman Z, Neumann E, Hyams SW, Peleg B. Ophthalmic screening of 38,000 children, age 1 to 2 1/2 years, in child welfare clinics. J Pediatr Ophthalmol Strabismus 1980;17:261-7. 6. Pike MG, Holmstrom G, de Vries LS, et al. Patterns of visual impairment associated with lesions of the preterm infant brain. Dev Med Child Neurol 1994;36:849-62. 7. Shapiro MB, France TD. The ocular features of Down’s syndrome. Am J Ophthalmol 1985;99:659-63. 8. People and Culture—Population Densities. http://www.ontario.ca/ en/about_ontario/EC001035.html. 9. City of Toronto. Toronto Facts: Diversity. 2014. http://www. toronto.ca/toronto_facts/diversity.htm. 10. Choi BC, Hanley AJ, Holowaty EJ, Dale D. Use of surnames to identify individuals of Chinese ancestry. Am J Epidemiol 1993;138:723-34.
Intracranial hypertension due to levothyroxine use Casey J. Beal, MD,a Kristina Y. Pao, MD,a and R. Nick Hogan, MD, PhDb,c We report a case of intracranial hypertension in a 13-year-old boy on levothyroxine therapy for hypothyroidism and review the literature describing this rare association. He presented with severe headaches and was found to have bilateral optic disk edema and elevated intracranial pressure shortly after an increase in his dosage of levothyroxine. The optic disk edema and headaches resolved with decreasing the levothyroxine and initiating acetazolamide.
I
diopathic intracranial hypertension, or pseudotumor cerebri, is defined clinically as the signs and symptoms of increased intracranial pressure with normal neuroanatomy and cerebral spinal fluid studies and an elevated opening pressure on lumbar puncture. Optic disk edema is a characteristic clinical finding in idiopathic intracranial hypertension and is often associated with visual field defects. The most common symptoms include postural headache, nausea, amarosis fugax, diplopia, and pulsatile tinnitus.1 Treatment is aimed at decreasing intracranial pressure and preventing permanent vision loss. The list of reported secondary causes of elevated intracranial pressure is long and ever expanding and includes hypervitaminosis A, retinoic acid, tetracyclines, nitrofurantoin, fluoroquinolones, lithium, oral contraceptives,
Author affiliations: Departments of aOphthalmology, bNeuro-ophthalmology, and cOcular Pathology, University of Texas Southwestern Medical Center, Dallas, Texas Submitted September 28, 2013. Revision accepted June 12, 2014. Published online September 27, 2014. Correspondence: R. Nick Hogan, MD, PhD, Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd. Dallas, TX (email: Nick. [email protected]). J AAPOS 2014;18:504-507. Copyright Ó 2014 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2014.06.017
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Table 1. THRT associated with intracranial hypertension: review of published cases Secondary IH
Author 3
Patient age,b years (sex) BMI THRT 8/12
Van Wyk
12
Prendes4 Van Dop5
(F)
Opening pressure, Duration of treatmenta Presenting symptoms mm H2O
24.6
T3
4.5 months
89/12 (F) 119/12 (M)
17.3 N/A
DT T4
2 months 1 month
Van Dop5
87/12 (F)
N/A
T4
5 weeks
McVie6
9 (F)
Huseman7
136/12 (M)
Headache, scotoma, vomiting 17.9 LT 2 months; 5 Headache, vomiting days on recurrence 40.5 Liotrix 3 months Headache
Huseman7
133/12 (F)
N/A
LT
2 months
Rohn8
66/12 (F)
N/A
LT
1.5 months
Campos1
77/12 (F)
16.1
LT
1 week
Raghavan9
3 wks (F)
N/A
LT
4 months
N/A 31.9
LT LT
N/A 3 months
12 (F) Strickler10 Present case 1311/12 (M)
Blurred vision, enlarged blind spot Headache Headache
350 N/A 280 480 N/A 260
Headache, horizontal 274 diplopia, transient visual obscurations Headache, transient N/A visual obscurations Headache, eye pain, 280 nausea, vomiting, tinnitus None Elevated (value N/A) Headache N/A Headache 380
Treatment change 1/2 grain DT daily, increased to 1.5 None AZ (250 mg BID), T4 decrease Dexamethasone, AZ (250 mg BID) LT decrease
Duration of treatment and/or Follow- up, resolution of IH months 3 weeks
12
5 months 1 month
16 N/A
10 months
N/A
2 weeks
N/A
Cortisone acetate, 5 months glycerin, Liotrix to LT (100 mcg/day) Glycerin, LT decrease, 8 months prednisone
36
N/A
N/A
N/A
AZ (250 mg BID)
2 months
N/A
None
4-8 months
12
AZ (250 mg BID) AZ (250 mg TID), LT decrease to 50 mcg/day
N/A 12 months
6 12
12
AZ, acetazolamide; BID, twice daily; BMI, body mass index; DT, dessicated thyroid; IH, intracranial hypertension; LT, levothyroxine; N/A, not available or unknown; T3, triiodothyroxine; T4, thyroxine; THRT, thyroid replacement therapy; TID, thrice daily. a Before diagnosis of secondary IH. b Age at diagnosis of thyroid abnormality.
immunizations, pregnancy, infection, weight gain in nutritionally deprived children, thyroid dysfunction, parathyroid dysfunction, adrenal dysfunction, Addison’s disease, hypocalcemia, panhypopituitarism, iron deficiency, steroid use or withdrawal, and, rarely, levothyroxine.2 We report the case of a 13-year-old boy on levothyroxine who developed elevated intracranial pressure and review the current English literature of levothyroxine-induced intracranial hypertension.
Case Report A 13-year-old Hispanic boy presented at the Endocrinology Center at Children’s Medical Center of Dallas with a chief symptom of intermittent headaches for the previous 2 years. The patient’s family noted weight gain, generalized fatigue, and growth restriction. Systemic endocrinological work-up revealed a body mass index (BMI) of 39.1, with an elevated thyroid-stimulating hormone (TSH) and low free T4. Hemoglobin A1C and oral glucose tolerance test were normal. He was diagnosed with chronic lymphocytic thyroiditis and prescribed oral levothyroxine 50 mcg daily (0.72 mcg/kg/day).
Journal of AAPOS
Two months after the initiation of levothyroxine therapy his dosage was titrated to 75 mcg per day (1.17mcg/kg/ day). One month after the increase, he reported severely worsening headaches. He was initially seen by an outside eye care provider for a routine eye examination and was noted to have bilateral optic disk edema. The patient was referred to Children’s Medical Center of Dallas ophthalmology clinic for further evaluation. On examination, the patient’s corrected distance visual acuity was 20/15 in both eyes. The pupils were equal and briskly reactive, with no afferent pupillary defect. Ishihara pseudo-isochromatic plates were normal in both eyes. The patient was orthophoric, with full ductions and versions. Confrontational visual fields and intraocular pressure were normal. Slit-lamp examination was unremarkable. Dilated fundus examination showed bilateral optic disk edema without hemorrhages or hard exudates. Cycloplegic refraction showed a 2.00 D refractive error in both eyes. Humphrey visual field testing was unreliable in both eyes. Lumbar puncture in the left lateral decubitus position revealed an opening pressure of 380 mm H2O (normal, \200 mm H2O). Radiographic and cerebral spinal fluid
506
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studies were unremarkable. Oral acetazolamide, 250 mg three times daily, was initiated, and the patient’s levothyroxine dosage was decreased to 50 mcg daily, with marked improvement in his headaches. Three months later, the patient’s visual acuity was 20/20 in both eyes, with trace residual nasal elevation of his optic disks. His acetazolamide dose was decreased to 125 mg twice daily, and his levothyroxine dosage was increased to 88 mcg daily. The patient continued to do well at 12 months’ follow-up, with no residual visual deficits and resolution of his optic disk edema.
Discussion Reports of thyroid replacement therapy associated with intracranial hypertension are rare. Our review of the literature identified 11 other cases that support the association between thyroid replacement therapy and intracranial hypertension (Table 1). Of the 12 cases (9 females), including the present one, 1 involved congenital hypothyroidism9; the rest, juvenile hypothyroidism. The average age of onset of symptoms was 9 3.9 years (standard deviation). The initial TSH and thyroxine levels on hypothyroidism diagnosis did not correlate with duration of symptoms, treatment, or outcomes. The most common presenting symptom was headache, occurring in 10 of the 12 patients. Headaches were characterized as throbbing, pressure, and boring-type pain. Only 5 of the 12 patients reported visual symptoms on presentation. When visual symptoms were reported, they included transient visual obscurations, blurred vision, scotoma, and horizontal diplopia.7 Our review implicates several types of thyroid replacement therapy, including liotrix, dessicated thyroid, triiodothyroxine, thyroxine, and levothyroxine. This suggests that the underlying cause of the secondary intracranial hypertension is not specific to levothyroxine alone. Currently, levothyroxine is the treatment of choice for hypothyroidism. The duration of thyroid treatment prior to the diagnosis of intracranial hypertension ranged from 1-18 weeks, averaging of 8-12 weeks. The length of treatment for the intracranial hypertension varied widely. In 2 patients signs and symptoms resolved spontaneously, with no treatment of their intracranial hypertension, over 4-8 months and continuance of the same dosage of thyroid hormone replacement.4,9 Other treatment regimens included temporarily decreasing the dosage of thyroid replacement therapy, changing to another medication, and treating the increased intracranial pressure with corticosteroids, glycerin, or acetazolamide. The length of treatment for the increased intracranial pressure ranged from 2 weeks to 12 months, depending upon the patient’s signs and symptoms. Only 1 patient showed a permanent visual deficit (persistent enlarged blind spots) during follow-up.10 This patient was lost to follow-up after 6 months. The length of follow-up of the other cases ranged from 6 months to 3 years.
Volume 18 Number 5 / October 2014 Our patient developed worsening headaches after his levothyroxine dosage was increased and was found to have bilateral optic disk edema, with an opening pressure of 380 mm H2O. However, due to our patient’s BMI and history of headaches, we cannot exclude the possibility that papilledema was present prior to the initiation of levothyroxine. A baseline ophthalmic examination was not obtained, because the patient had no visual complaints. A thorough literature review revealed that visual symptoms were present in less than half of the patients with secondary elevated intracranial pressure. Thus visual symptoms cannot be a reliable indicator of the presence of increased intracranial pressure in children. The most common presenting symptom was headache. One might suggest that a baseline ocular examination be obtained prior to initiation of thyroid replacement therapy in patients with a history of obesity and headaches, because thyroid replacement therapy may cause or worsen preexisting signs and symptoms of elevated ICP. The pathophysiology of secondary intracranial hypertension associated with thyroid replacement is unknown. It is important to be aware of this association between levothyroxine and intracranial hypertension because a delay in diagnosis may lead to permanent vision loss. A coordinated effort between ophthalmology and endocrinology should be undertaken to help ensure proper management of both the intracranial hypertension and the patient’s underlying thyroid abnormality.
Literature Search PubMed was searched on August 20, 2014, without date restriction for English-language results using combinations of the following terms: levothyroxine, idiopathic intracranial hypertension, elevated ICP, hypothyroidism, pediatric, and pseudotumor cerebri. All articles with sufficient evidence to associate thyroid replacement with intracranial hypertension were included. References 1. Campos SP, Olitsky S. Idiopathic intracranial hypertension after Lthyroxine therapy for acquired primary hypothyroidism. Clin Pediatr 1995;34:334-7. 2. Robertson WC, Chawla J. Pediatric idiopathic intracranial hypertension. http://www.emedicine.medscape.com/article/1179733-overview. Accessed August 19, 2012. 3. Van Wyk JJ, Grumbach MM. Syndrome of precocious menstruation and galactorrhea in juvenile hypothyroidism: an example of hormonal overlap in pituitary feedback. J Pediatr 1960;57:416-35. 4. Prendes JL, McLean WT. Pseudotumor cerebri during treatment for hypothyroidism. South Med J 1978;71:977. 5. Van Dop C, Conte FA, Koch TK, Clark SJ, Wilson-Davis SL, Grumbach MM. Pseudotumor cerebri associated with initiation of levothyroxine therapy for juvenile hypothyroidism. N Engl J Med 1983;308:1076-80. 6. McVie R. Abnormal TSH regulation, pseudotumor cerebri, and empty sella after replacement therapy in juvenile hypothyroidism. J Pediatr 1984;105:768-70. 7. Huseman CA, Torkelson RD. Pseudotumor cerebri following treatment of hypothalamic and primary hypothyroidism. Am J Dis Child 1984;138:927-31.
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8. Rohn R. Pseudotumor cerebri following treatment of hypothyroidism. Am J Dis Child 1985;139:752. 9. Raghavan S, DiMartino-Nardi J, Saenger P, Linder B. Pseudotumor cerebri in an infant after L-thyroxine therapy for transient neonatal hypothyroidism. J Pediatr 1997;130:478-80. 10. Strickler C, Pilon AF. Presumed levothyroxine-induced pseudotumor cerebri in a pediatric patient being treated for congenital hypothyroidism. Clin Ophthalmol 2007;1:545-9.
Congenital oculomotor nerve palsy due to effects of carotid artery agenesis Lakshmi Cherungottil, MS,a Shashikant Shetty, MS,a Perumalsamy Vijayalakshmi, MS,a Malay Kumar Dwivedi, MS,a Kaliappan Gurusamy Srinivasan, MD,b and Muniasamy Saravanan, MRCPc Isolated carotid artery agenesis is not generally recognized as a cause of congenital oculomotor nerve palsy. We report this rare association in 2 children and examine the underlying mechanism.
Case 1
A
7-year-old South Indian girl presented at the Paediatric Ophthalmology Department of Aravind Eye Hospital and Post Graduate Institute with a history of right upper eyelid ptosis and squinting of the same eye since birth. She had a normal perinatal period and normal milestones. Her medical history was unremarkable. There was no family history of any significant eye disease. On ophthalmological examination, visual acuity was 20/ 80 in the right eye, with no improvement with refractive correction or pinhole, and 20/20 in the left eye. There was an upper lid notch, with ptosis in the right eye and an epibulbar dermoid (Figure 1A). The right eye was exotropic and hypotropic; ocular motility was restricted in all directions except abduction. The pupil was dilated and fixed at 5 mm, with no signs of aberrant regeneration. Ocular motility in the left eye was full and unrestricted.
FIG 1. Patient 1. A, The right eye in exotropic and hypotropic position showing ptosis and temporal lid notch. B, T2-weighted cranial magnetic resonance (MR) imaging (axial view) showing the right posterior communicating artery aneurysm. C, 3D time-of-flight (TOF) cerebral angiogram axial view, superior) showing a deficient flow in the left internal carotid artery, normal flow in the right internal carotid artery, and the absence of high intensity signal flow void in the aneurysm. D, 3D TOF angiogram of the neck (coronal view) showing absent flow in the left internal carotid artery.
Retinal examination of both eyes was normal, but she showed perifoveal fixation in the right eye. She had no binocularity in primary or downgaze. There were no neurocutaneous abnormalities or other neurologic signs, and a thorough evaluation performed by the pediatrician ruled out systemic diseases. She was diagnosed with pupilinvolving congenital third (oculomotor) nerve palsy with amblyopia in her right eye. Magnetic resonance (MR) imaging and MR angiography revealed a right posterior communicating artery aneurysm (Figure 1B) compressing the oculomotor nerve, which explained the clinical features, but the aneurysm was already thrombosed, as indicated by the absence of flow void in the MR angiogram (Figure 1C). Additionally, she had a left internal carotid artery agenesis (Figure 1C,D), which led us to conclude that the lesion was a thrombosed “flow aneurysm,” which was congenital and did not mandate emergency intervention.
Case 2 Author affiliations: aAravind Eye Hospital and Post Graduate Institute of Ophthalmology, Madurai, Tamil Nadu, India; bKGS Advanced Scan Centre, Madurai, Tamil Nadu; cRio Advanced Children’s Hospital Madurai, Tamil Nadu Submitted December 30, 2013. Revision accepted June 12, 2014. Correspondence: Lakshmi Cherungottil, MS, Aravind Eye Hospital, 1 Anna Nagar, Madurai 625020, Tamil Nadu, India (email: [email protected]). J AAPOS 2014;18:507-509. Copyright Ó 2014 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2014.06.014
Journal of AAPOS
A 40-day-old female infant was referred with a history of right upper eyelid ptosis, since birth. She had an uneventful perinatal history except for a patent ductus arteriosus which closed spontaneously and a small Atrial septal defect with left to right shunt, assessed by the cardiologist that was under observation. There was no family history of ptosis or eye disease. On initial examination, she had complete ptosis of the right eye (Figure 2A), which was fixed in the abducted
