Original Article
Intracranial Hypertension Without Papilledema in Children
Journal of Child Neurology 1-7 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073815587029 jcn.sagepub.com
Shawn C. Aylward, MD1, Catherine Aronowitz2, and E. Steve Roach, MD1
Abstract This study aims to determine the frequency of intracranial hypertension without papilledema in children. Charts of patients evaluated in a pediatric intracranial hypertension clinic at our institution were retrospectively reviewed. The patients were divided into 2 groups depending on whether they had presence or absence of optic nerve edema at the time of presentation. Age, body mass index, and opening cerebrospinal fluid pressures were considered continuous variables and compared by Wilcoxon rank sum test because of non-normality. A P-value of 0.05 was considered significant. A total of 228 charts were reviewed; 152 patients met the criteria for intracranial hypertension, and 27 patients (17.8%) met the criteria of headache without optic nerve edema. There was no clinically significant difference in age, body mass index, opening pressure, and modified opening pressure between the 2 groups. Keywords pseudotumor cerebri, intracranial hypertension, pediatric, headache Received January 12, 2015. Received revised March 30, 2015. Accepted for publication April 21, 2015.
There are scattered case reports in the literature of patients suffering from chronic headaches or migraines and absence of papilledema that are eventually diagnosed with increased intracranial pressure.1,2 Reports of the rates of intracranial hypertension without papilledema range from 5.6% to 48% depending on the study size.3-6 The largest study at the University of Utah included 353 patients with 5.7% (20/353) lacking edema.3 They found age matched comparison patients with edema, the average age at diagnosis was 32 years for both groups. The age ranges were 15 to 56 and 10 to 49 years for those with and without edema, respectively. They noted the opening pressures were lower in the patients without edema (30.9 cm of water vs 37.3 cm, P ¼ 0.031) yet headache characteristics were similar between the 2 groups. A small pediatric study from the University of Texas Houston noted 48% (13/27) of their patients lacked optic edema and met the remainder of the criteria for primary (idiopathic) intracranial hypertension.6 Obesity rates in the pediatric studies range from 16.4% to 30%.4-6 Mathew et al7 evaluated a series of 85 patients (mainly adult) with chronic headache followed in a Houston headache clinic. All patients lacked optic edema, and 12 (14%) had elevated opening pressure on lumbar puncture. Seven of these (58%) were considered obese by the Metropolitan Life Insurance criteria. This study also noted no differences in headache symptoms between those with and without edema.
The aim of our study is to determine the prevalence of intracranial hypertension without papilledema in a subspecialty pediatric neurology clinic.
Methods We analyzed the clinical charts of individuals evaluated between May 2010 and June 2013 in a pediatric multidisciplinary specialty clinic devoted to primary (idiopathic) and secondary intracranial hypertension. IRB approval was obtained prior to study initiation. To reduce potential referral bias, only patients from Ohio and the contiguous states were included. This also allowed most patients to be seen in close proximity to their initial diagnosis for confirmation of the original optic nerve findings by ophthalmology. To ensure inclusion of widespread hospital use of the electronic health record, only those diagnosed after January 2009 were included. Using the electronic
1
Department of Neurology, Nationwide Children’s Hospital, Ohio State University College of Medicine, Columbus, OH, USA 2 Haverford College, Haverford, PA, USA Corresponding Author: Shawn C. Aylward, MD, Division of Child Neurology ED526, Nationwide Children’s Hospital, Ohio State University College of Medicine, 700 Children’s Drive, Columbus, OH 43205, USA. Email: [email protected]
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Table 1. Pediatric Diagnostic Criteria Used for Primary Intracranial Hypertension. Modified Dandy Criteria8,a 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 bilateral abducens nerve palsy 3. CSF opening pressure of >25 cm H2O with normal composition 4. Normal to small ventricles as demonstrated by computed tomography Prepubertal primary intracranial hypertension criteria9,b 1. CSF opening pressure of >18 cm H2O in children 25 cm H2O in children 8 years or 99th percentiles with a median of 87.5. In this group, 40.9% (9/22) were considered obese and 13.6% (3/22) considered overweight. This compared to percentiles ranging from 99th percentiles with a median of 95.5 for group 2. In group 2, 51.9% (55/106) were obese, 18.9% (20/106) were overweight, and 3.8% (4/106) were considered underweight. Opening pressure mean was 32.97 cm of water (+5.64) for group 1. In group 2, the mean opening pressure was 33.57 cm water (+10.5). This was not clinically significant with a P value of 0.5. There was 1 patient in group 1 that had outside records noting elevated treatment pressures but we were unable to find the initial pre-treatment pressure. There were 10 patients in group 2 without initial, diagnostic opening pressures, 2 had clear issues with measurement from the procedure notes, one clotted off, the other had a large amount of cerebrospinal fluid loss prior to attachment of the manometer. Three had no initial opening pressure found in the provided notes; however, subsequent measurements were elevated. Two patients had normal opening pressures, one was on therapeutic acetazolamide (Diamox) and the other had stopped minocycline 2 weeks before their lumbar puncture. Three lumbar punctures were deferred because of clinical indications; 1 with spinal anatomic abnormalities limiting lumbar puncture, 1 with hydrocephalus, and 1 was on growth hormone replacement, which was stopped 2 weeks prior to initial evaluation in neurology. All patients had documented optic nerve edema, which resolved with treatment, the patient with growth hormone replacement was monitored without treatment as the growth hormone was stopped and likewise improvement in the edema was noted. In groups 1 and 2, there were 1 and 17 patients, respectively, that exceeded the measuring capability of the manometer. Additionally, 1 and 2 patients in each respective group had readings that fell between the unmarked opaque adapter on the 2 piece manometer and were recorded as a range of 36 to 38 cm water. These patients were not included in the initial comparison. To
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Figure 1. (A) Group 1, patient 8, 9.42 years, opening pressure 40 cm water, normal optic nerves. (B) Group 2, patient 89, 8.08 years, opening pressure 19 cm water, bilateral optic nerve edema.
allow inclusion to see if there would be a clinically significant difference, the measurements at the manometer’s upper limit and the average of the range (37 cm water) were used. This ‘‘modified’’ opening pressure mean was 33.97 cm water (+6.95) and 34.91 cm water (+10.65) for groups 1 and 2, respectively. This was also not clinically significant with a P-value of 0.89. All patients in group 1 and 118 of 125 (94.4%) of group 2 patients took at least 1 medication commonly used for treatment of intracranial hypertension. Twenty-six (96.3%) in group 1 took acetazolamide, 7 (25.9%) topiramate, 5 (18.5%) furosemide, and 1 (3.7%) methazolamide. There were 2 (7.4%) that took multiple combinations of these medicines. Eight (29.6%) also took other migraine medications. In the comparison group, 113 of 125 (90.4%) took acetazolamide, 23 (18.4%) tried topiramate, and 19 (15.2%) tried furosemide. Two (1.6%) took combinations of these medications, 15 (12%) also took other migraine medications. Seven patients (5.6%) in group 2 did not receive medications for their intracranial hypertension at the discretion of the attending neurologist; 5 of these were considered secondary intracranial hypertension. None of the patients in group 1 required surgical intervention compared to 13 (10.4%) in group 2. Two (4.8%) patients
had lumbar peritoneal shunting, 6 (4.8%) received ventricular peritoneal shunting, 1 (3%) patient received both types of shunt, 5 (4%) received optic nerve sheath fenestration, 1 with craniofacial syndrome had a cranial reconstruction, and 1 with hydrocephalus had a third ventriculostomy (in addition to optic nerve sheath fenestration).
Discussion In review of our patients with both primary (idiopathic) and secondary intracranial hypertension, we noted 27 of 152 (17.8%) met the criteria of intracranial hypertension without papilledema. These results are in line with previous published rates,3-6 although ours was lower than the single small pediatric study.6 The exact mechanism as to why some patients do not develop edema is not clear as the exact mechanism responsible for development of edema is not understood. The concept of disc edema is thought to represent axonal swelling, with increased fluid surrounding the axons. It has been shown that papilledema develops in those with potential space in the subarachnoid space that surrounds the optic nerve. If this potential space is blocked by adhesions, such as that seen following optic
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Table 2. Patient Demographics and Characteristics.
Age at diagnosis Number Mean Standard deviation Range Female Secondary intracranial hypertension Body mass index Number Mean Standard deviation Range Opening pressure Number Mean Standard deviation Range Modified opening pressure Number Mean Standard deviation Range Headaches meet criteria for migraine History of migraines History of headaches
Group 1 (no ONE) (n ¼ 27)
Group 2 (þ ONE) (n ¼ 125)
27 12.65 3.34 5-18.42 18 (66.7%) 6
125 12.9 4.45 2.17-22.75 81 (64.8%) 31
22 25.88 9.13 15-43.83
106 27.97 11.74 12.64-95.51
24 32.97 5.64 23.8-45
96 33.57 10.5 19-67
26 33.97 6.95 23.8-55
115 34.91 10.65 19-67
Table 3. Causes for Secondary Intracranial Hypertension in Each Group. P value
0.55
0.51
0.5
0.89
69.2% (18/26) 51.4% (56/109) 11.5% (3/26) 11.9% (13/109) 34.6% (9/26) 30.3% (33/109)
Abbreviation: ONE, optic nerve edema.
nerve sheath fenestration, papilledema does not develop. It is felt that papilledema requires increased pressure at the distal optic nerve sheath, reduced perfusion of axons as they exit the lamina cribrosa, elevated central retinal venous pressure, and disruption/stasis of axoplasmic transport to develop.13,14 It is conceivable that those with intracranial hypertension without edema have an anatomic variant that offers a level of protection from development of edema, yet still experience the other symptoms associated with the condition. There has been recent debate on the normal values for pediatrics with regards to opening pressure. Two recent publications attempted to determine the normal pressure for a pediatric patient.15,16 Lee et al16 included only sedated patients in an effort to have a more controlled study population, whereas Avery et al15 included sedated and nonsedated study patients. These studies found a slightly higher average opening pressure. Both studies also included patients with white matter and/or demyelinating disorders as normal patients. However, these patients by nature of their disease state have direct central nervous system inflammation and typically increased cerebrospinal fluid protein, which will result in higher than normal cerebrospinal fluid opening pressure and thus likely skew the average results in their study samples.17,18 In a recent comparison, Narula et al19 found
Intracranial thrombosis Superior vena cava thrombosis Acute lymphoblastic leukemia/lymphoma Infectious Behc¸et disease Hydrocephalus Muckle-Wells Craniofacial syndrome Medication Minocycline Steroids Growth hormone Lithium
Group 1 (no ONE)
Group 2a (þ ONE)
0 0 1 0 0 0 2 0
7 1 4 4 1 2 1 1
2 1 0 0
6 2 4 1
Abbreviation: ONE, optic nerve edema. a One patient each had both ALL with sinus venous thrombosis, ALL with superior vena cava thrombosis, and minocycline with sinus venous thrombosis as cause for their secondary intracranial hypertension.
Table 4. Subtle Magnetic Resonance Imaging (MRI) Findings in Cohort of Patients With Intracranial Hypertension Without Optic Nerve Edema.a Normal
18
Dilated optic nerve sheaths Empty sella or compressed pituitary Tortuous optic nerve Fattening of posterior globe Transverse venous stenosis Patients with 2 of the above Patients with 3 of the above
4 4 2 1 0 4 1
a Four patients were considered unknown, 3 due to no imaging reports found in chart, 1 had braces artifact.
that 28% of the demyelination patients had an elevated pressure when using the proposed higher normal value. They did not include in their discussion the proportion that would be elevated using the older criteria, which likely would have resulted in a higher percentage. With the lack of a more homogeneous sample population, we used the currently held convention in determination of an elevated pressure to avoid missing probable cases (see Figure 2). There have been attempts to modernize the diagnostic criteria for intracranial hypertension with the newer proposed opening pressure limits for pediatric cases and imaging findings if edema is absent.20 This has been met with criticism pointing out that such a strict set of criteria will ultimately lead to missed cases.21-23 If the criteria set forth by Friedman et al20 were applied to our cohort, only one would meet their criteria with elevated opening pressure, and satisfy 3 of the 4 imaging criteria (see Table 4) required for diagnosis of intracranial hypertension in absence of optic edema.20 Although these are good indicators of increased intracranial pressure, their absence
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Figure 2. Distribution of opening pressure versus age: (A) intracranial hypertension with optic nerve edema and (B) intracranial hypertension without optic nerve edema. Solid line notes 28 cm water cutoff proposed in recent articles.
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does not exclude the diagnosis.24,25 Thus, application of these strict criteria would result in exclusion of many patients in our cohort that otherwise have intracranial hypertension without optic nerve edema. If the higher opening pressure cutoff only was used, there would still be 3 and 29 patients excluded from groups 1 and 2, respectively. Our study noted no clinically significant difference in age, body mass index, opening pressure, and modified opening pressure between those patients diagnosed with intracranial hypertension (primary or secondary) with or without papilledema. We found similar rates of obesity (51.9% vs 40.9%) and being overweight (18.9% vs 13.6%) in those with and without edema. In our study, this was above the rate reported in the literature.4-6 The similar rates of obesity and opening pressure values between those with and without edema suggests that obesity and intracranial pressure value do not play a leading role in the development of papilledema. Those without papilledema were more likely to be on a concomitant typical migraine medication. This is likely due to these patients initially being diagnosed with migraine given the lack of edema. Headache characteristics alone cannot be used to distinguish headache due to migraine versus intracranial hypertension.3 In group 1, 69.2% (18/26) of their headaches met the criteria for migraine compared to 51.4% (56/109) in group 2. Prior to diagnosis, 11.5% (3/26) and 11.9% (13/109) had a diagnosis of migraine in groups 1 and 2, respectively. There were 34.6% (9/26) and 30.3% (33/109) in groups 1 and 2, respectively, that had a diagnosis of headache prior to diagnosis. None of the patients in group 1 received surgical interventions compared to 13/125 (10.4%) in group 2. The main weakness in this study is the missing variables for body mass index (15.8%) and initial opening pressure (9.3%). Acknowledgments This study was carried out at Nationwide Children’s Hospital. Columbus, Ohio.
Author Contributions SA was the study designer, performed the major data analysis, and wrote a majority of the manuscript. CA performed the data collection and first pass analysis. ESR was the primary manuscript reviewer.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval This study was approved by Nationwide Children’s Hospital institutional review board (IRB13-00342).
References 1. Beri S, Gosalakkal JA, Hussain N, Balky AP, Parepalli S. Idiopathic intracranial hypertension without papilledema. Pediatr Neurol. 2010;42:56-58. 2. Huff AL, Hupp SL, Rothrock JF. Chronic daily headache with migrainous features due to papilledema-negative idiopathic intracranial hypertension. Cephalalgia. 1996;16:451-452. 3. Digre KB, Nakamoto BK, Warner JE, Langeberg WJ, Baggaley SK, Katz BJ. A comparison of idiopathic intracranial hypertension with and without papilledema. Headache. 2009; 49:185-193. 4. Tibussek D, Schneider DT, Vandemeulebroecke N, et al. Clinical spectrum of the pseudotumor cerebri complex in children. Child Nerv Syst. 2010;26:313-321. 5. Tibussek D, Distelmaier F, von Kries R, Mayatepek E. Pseudotumor cerebri in childhood and adolescence—results of a Germanywide ESPED-survey. Klinische Padiatrie. 2013;225:81-85. 6. 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: 1389-1392. 7. Mathew NT, Ravishankar K, Sanin LC. Coexistence of migraine and idiopathic intracranial hypertension without papilledema. Neurology. 1996;46:1226-1230. 8. Smith JL. Whence pseudotumor cerebri? J Clin Neuroophthalmol. 1985;5:55-56. 9. Aylward SC. Pediatric idiopathic intracranial hypertension: a need for clarification. Pediatr Neurol. 2013;49:303-304. 10. Euling SY, Herman-Giddens ME, Lee PA, et al. Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings. Pediatrics. 2008;121(suppl 3):S172-S191. 11. Frisen L. Swelling of the optic nerve head: a staging scheme. J Neurol Neurosurg Psychiatry. 1982;45:13-18. 12. Kuczmarski RJ, Ogden CL, Guo SS, et al. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 11. 2002;(246):1-190. 13. Schirmer CM, Hedges TR 3rd. Mechanisms of visual loss in papilledema. Neurosurg Focus. 2007;23:E5. 14. Van Stavern GP. Optic disc edema. Sem Neurol. 2007;27: 233-243. 15. Avery RA, Shah SS, Licht DJ, et al. Reference range for cerebrospinal fluid opening pressure in children. N Engl J Med. 2010;363:891-893. 16. Lee MW, Vedanarayanan VV. Cerebrospinal fluid opening pressure in children: experience in a controlled setting. Pediatr Neurol. 2011;45:238-240. 17. Newman NJ, Selzer KA, Bell RA. Association of multiple sclerosis and intracranial hypertension. J Neuroophthalmol. 1994;14: 189-192. 18. Williams BJ, Skinner HJ, Maria BL. Increased intracranial pressure in a case of pediatric multiple sclerosis. J Child Neurol. 2008;23:699-702. 19. Narula S, Liu GT, Avery RA, Banwell B, Waldman AT. Elevated cerebrospinal fluid opening pressure in a pediatric demyelinating disease cohort. Pediatr Neurol. 2015;52:446-449.
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20. Friedman DI, Liu GT, Digre KB. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2013;81:1159-1165. 21. 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;82:1011-1012. 22. Liguori C, Romigi A, Albanese M, et al. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2014;82:1752-1753.
23. Wall M, Corbett JJ. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2014;83: 198-199. 24. Gorkem SB, Doganay S, Canpolat M, et al. MR imaging findings in children with pseudotumor cerebri and comparison with healthy controls. Child Nerv Syst. 2015;31:373-380. 25. Maralani PJ, Hassanlou M, Torres C, et al. Accuracy of brain imaging in the diagnosis of idiopathic intracranial hypertension. Clin Radiol. 2012;67:656-663.
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Intracranial Hypertension Without Papilledema in Children
Journal of Child Neurology 1-7 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073815587029 jcn.sagepub.com
Shawn C. Aylward, MD1, Catherine Aronowitz2, and E. Steve Roach, MD1
Abstract This study aims to determine the frequency of intracranial hypertension without papilledema in children. Charts of patients evaluated in a pediatric intracranial hypertension clinic at our institution were retrospectively reviewed. The patients were divided into 2 groups depending on whether they had presence or absence of optic nerve edema at the time of presentation. Age, body mass index, and opening cerebrospinal fluid pressures were considered continuous variables and compared by Wilcoxon rank sum test because of non-normality. A P-value of 0.05 was considered significant. A total of 228 charts were reviewed; 152 patients met the criteria for intracranial hypertension, and 27 patients (17.8%) met the criteria of headache without optic nerve edema. There was no clinically significant difference in age, body mass index, opening pressure, and modified opening pressure between the 2 groups. Keywords pseudotumor cerebri, intracranial hypertension, pediatric, headache Received January 12, 2015. Received revised March 30, 2015. Accepted for publication April 21, 2015.
There are scattered case reports in the literature of patients suffering from chronic headaches or migraines and absence of papilledema that are eventually diagnosed with increased intracranial pressure.1,2 Reports of the rates of intracranial hypertension without papilledema range from 5.6% to 48% depending on the study size.3-6 The largest study at the University of Utah included 353 patients with 5.7% (20/353) lacking edema.3 They found age matched comparison patients with edema, the average age at diagnosis was 32 years for both groups. The age ranges were 15 to 56 and 10 to 49 years for those with and without edema, respectively. They noted the opening pressures were lower in the patients without edema (30.9 cm of water vs 37.3 cm, P ¼ 0.031) yet headache characteristics were similar between the 2 groups. A small pediatric study from the University of Texas Houston noted 48% (13/27) of their patients lacked optic edema and met the remainder of the criteria for primary (idiopathic) intracranial hypertension.6 Obesity rates in the pediatric studies range from 16.4% to 30%.4-6 Mathew et al7 evaluated a series of 85 patients (mainly adult) with chronic headache followed in a Houston headache clinic. All patients lacked optic edema, and 12 (14%) had elevated opening pressure on lumbar puncture. Seven of these (58%) were considered obese by the Metropolitan Life Insurance criteria. This study also noted no differences in headache symptoms between those with and without edema.
The aim of our study is to determine the prevalence of intracranial hypertension without papilledema in a subspecialty pediatric neurology clinic.
Methods We analyzed the clinical charts of individuals evaluated between May 2010 and June 2013 in a pediatric multidisciplinary specialty clinic devoted to primary (idiopathic) and secondary intracranial hypertension. IRB approval was obtained prior to study initiation. To reduce potential referral bias, only patients from Ohio and the contiguous states were included. This also allowed most patients to be seen in close proximity to their initial diagnosis for confirmation of the original optic nerve findings by ophthalmology. To ensure inclusion of widespread hospital use of the electronic health record, only those diagnosed after January 2009 were included. Using the electronic
1
Department of Neurology, Nationwide Children’s Hospital, Ohio State University College of Medicine, Columbus, OH, USA 2 Haverford College, Haverford, PA, USA Corresponding Author: Shawn C. Aylward, MD, Division of Child Neurology ED526, Nationwide Children’s Hospital, Ohio State University College of Medicine, 700 Children’s Drive, Columbus, OH 43205, USA. Email: [email protected]
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Table 1. Pediatric Diagnostic Criteria Used for Primary Intracranial Hypertension. Modified Dandy Criteria8,a 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 bilateral abducens nerve palsy 3. CSF opening pressure of >25 cm H2O with normal composition 4. Normal to small ventricles as demonstrated by computed tomography Prepubertal primary intracranial hypertension criteria9,b 1. CSF opening pressure of >18 cm H2O in children 25 cm H2O in children 8 years or 99th percentiles with a median of 87.5. In this group, 40.9% (9/22) were considered obese and 13.6% (3/22) considered overweight. This compared to percentiles ranging from 99th percentiles with a median of 95.5 for group 2. In group 2, 51.9% (55/106) were obese, 18.9% (20/106) were overweight, and 3.8% (4/106) were considered underweight. Opening pressure mean was 32.97 cm of water (+5.64) for group 1. In group 2, the mean opening pressure was 33.57 cm water (+10.5). This was not clinically significant with a P value of 0.5. There was 1 patient in group 1 that had outside records noting elevated treatment pressures but we were unable to find the initial pre-treatment pressure. There were 10 patients in group 2 without initial, diagnostic opening pressures, 2 had clear issues with measurement from the procedure notes, one clotted off, the other had a large amount of cerebrospinal fluid loss prior to attachment of the manometer. Three had no initial opening pressure found in the provided notes; however, subsequent measurements were elevated. Two patients had normal opening pressures, one was on therapeutic acetazolamide (Diamox) and the other had stopped minocycline 2 weeks before their lumbar puncture. Three lumbar punctures were deferred because of clinical indications; 1 with spinal anatomic abnormalities limiting lumbar puncture, 1 with hydrocephalus, and 1 was on growth hormone replacement, which was stopped 2 weeks prior to initial evaluation in neurology. All patients had documented optic nerve edema, which resolved with treatment, the patient with growth hormone replacement was monitored without treatment as the growth hormone was stopped and likewise improvement in the edema was noted. In groups 1 and 2, there were 1 and 17 patients, respectively, that exceeded the measuring capability of the manometer. Additionally, 1 and 2 patients in each respective group had readings that fell between the unmarked opaque adapter on the 2 piece manometer and were recorded as a range of 36 to 38 cm water. These patients were not included in the initial comparison. To
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Aylward et al
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Figure 1. (A) Group 1, patient 8, 9.42 years, opening pressure 40 cm water, normal optic nerves. (B) Group 2, patient 89, 8.08 years, opening pressure 19 cm water, bilateral optic nerve edema.
allow inclusion to see if there would be a clinically significant difference, the measurements at the manometer’s upper limit and the average of the range (37 cm water) were used. This ‘‘modified’’ opening pressure mean was 33.97 cm water (+6.95) and 34.91 cm water (+10.65) for groups 1 and 2, respectively. This was also not clinically significant with a P-value of 0.89. All patients in group 1 and 118 of 125 (94.4%) of group 2 patients took at least 1 medication commonly used for treatment of intracranial hypertension. Twenty-six (96.3%) in group 1 took acetazolamide, 7 (25.9%) topiramate, 5 (18.5%) furosemide, and 1 (3.7%) methazolamide. There were 2 (7.4%) that took multiple combinations of these medicines. Eight (29.6%) also took other migraine medications. In the comparison group, 113 of 125 (90.4%) took acetazolamide, 23 (18.4%) tried topiramate, and 19 (15.2%) tried furosemide. Two (1.6%) took combinations of these medications, 15 (12%) also took other migraine medications. Seven patients (5.6%) in group 2 did not receive medications for their intracranial hypertension at the discretion of the attending neurologist; 5 of these were considered secondary intracranial hypertension. None of the patients in group 1 required surgical intervention compared to 13 (10.4%) in group 2. Two (4.8%) patients
had lumbar peritoneal shunting, 6 (4.8%) received ventricular peritoneal shunting, 1 (3%) patient received both types of shunt, 5 (4%) received optic nerve sheath fenestration, 1 with craniofacial syndrome had a cranial reconstruction, and 1 with hydrocephalus had a third ventriculostomy (in addition to optic nerve sheath fenestration).
Discussion In review of our patients with both primary (idiopathic) and secondary intracranial hypertension, we noted 27 of 152 (17.8%) met the criteria of intracranial hypertension without papilledema. These results are in line with previous published rates,3-6 although ours was lower than the single small pediatric study.6 The exact mechanism as to why some patients do not develop edema is not clear as the exact mechanism responsible for development of edema is not understood. The concept of disc edema is thought to represent axonal swelling, with increased fluid surrounding the axons. It has been shown that papilledema develops in those with potential space in the subarachnoid space that surrounds the optic nerve. If this potential space is blocked by adhesions, such as that seen following optic
Downloaded from jcn.sagepub.com at FLORIDA INTERNATIONAL UNIV on May 27, 2015
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Table 2. Patient Demographics and Characteristics.
Age at diagnosis Number Mean Standard deviation Range Female Secondary intracranial hypertension Body mass index Number Mean Standard deviation Range Opening pressure Number Mean Standard deviation Range Modified opening pressure Number Mean Standard deviation Range Headaches meet criteria for migraine History of migraines History of headaches
Group 1 (no ONE) (n ¼ 27)
Group 2 (þ ONE) (n ¼ 125)
27 12.65 3.34 5-18.42 18 (66.7%) 6
125 12.9 4.45 2.17-22.75 81 (64.8%) 31
22 25.88 9.13 15-43.83
106 27.97 11.74 12.64-95.51
24 32.97 5.64 23.8-45
96 33.57 10.5 19-67
26 33.97 6.95 23.8-55
115 34.91 10.65 19-67
Table 3. Causes for Secondary Intracranial Hypertension in Each Group. P value
0.55
0.51
0.5
0.89
69.2% (18/26) 51.4% (56/109) 11.5% (3/26) 11.9% (13/109) 34.6% (9/26) 30.3% (33/109)
Abbreviation: ONE, optic nerve edema.
nerve sheath fenestration, papilledema does not develop. It is felt that papilledema requires increased pressure at the distal optic nerve sheath, reduced perfusion of axons as they exit the lamina cribrosa, elevated central retinal venous pressure, and disruption/stasis of axoplasmic transport to develop.13,14 It is conceivable that those with intracranial hypertension without edema have an anatomic variant that offers a level of protection from development of edema, yet still experience the other symptoms associated with the condition. There has been recent debate on the normal values for pediatrics with regards to opening pressure. Two recent publications attempted to determine the normal pressure for a pediatric patient.15,16 Lee et al16 included only sedated patients in an effort to have a more controlled study population, whereas Avery et al15 included sedated and nonsedated study patients. These studies found a slightly higher average opening pressure. Both studies also included patients with white matter and/or demyelinating disorders as normal patients. However, these patients by nature of their disease state have direct central nervous system inflammation and typically increased cerebrospinal fluid protein, which will result in higher than normal cerebrospinal fluid opening pressure and thus likely skew the average results in their study samples.17,18 In a recent comparison, Narula et al19 found
Intracranial thrombosis Superior vena cava thrombosis Acute lymphoblastic leukemia/lymphoma Infectious Behc¸et disease Hydrocephalus Muckle-Wells Craniofacial syndrome Medication Minocycline Steroids Growth hormone Lithium
Group 1 (no ONE)
Group 2a (þ ONE)
0 0 1 0 0 0 2 0
7 1 4 4 1 2 1 1
2 1 0 0
6 2 4 1
Abbreviation: ONE, optic nerve edema. a One patient each had both ALL with sinus venous thrombosis, ALL with superior vena cava thrombosis, and minocycline with sinus venous thrombosis as cause for their secondary intracranial hypertension.
Table 4. Subtle Magnetic Resonance Imaging (MRI) Findings in Cohort of Patients With Intracranial Hypertension Without Optic Nerve Edema.a Normal
18
Dilated optic nerve sheaths Empty sella or compressed pituitary Tortuous optic nerve Fattening of posterior globe Transverse venous stenosis Patients with 2 of the above Patients with 3 of the above
4 4 2 1 0 4 1
a Four patients were considered unknown, 3 due to no imaging reports found in chart, 1 had braces artifact.
that 28% of the demyelination patients had an elevated pressure when using the proposed higher normal value. They did not include in their discussion the proportion that would be elevated using the older criteria, which likely would have resulted in a higher percentage. With the lack of a more homogeneous sample population, we used the currently held convention in determination of an elevated pressure to avoid missing probable cases (see Figure 2). There have been attempts to modernize the diagnostic criteria for intracranial hypertension with the newer proposed opening pressure limits for pediatric cases and imaging findings if edema is absent.20 This has been met with criticism pointing out that such a strict set of criteria will ultimately lead to missed cases.21-23 If the criteria set forth by Friedman et al20 were applied to our cohort, only one would meet their criteria with elevated opening pressure, and satisfy 3 of the 4 imaging criteria (see Table 4) required for diagnosis of intracranial hypertension in absence of optic edema.20 Although these are good indicators of increased intracranial pressure, their absence
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Figure 2. Distribution of opening pressure versus age: (A) intracranial hypertension with optic nerve edema and (B) intracranial hypertension without optic nerve edema. Solid line notes 28 cm water cutoff proposed in recent articles.
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Journal of Child Neurology
does not exclude the diagnosis.24,25 Thus, application of these strict criteria would result in exclusion of many patients in our cohort that otherwise have intracranial hypertension without optic nerve edema. If the higher opening pressure cutoff only was used, there would still be 3 and 29 patients excluded from groups 1 and 2, respectively. Our study noted no clinically significant difference in age, body mass index, opening pressure, and modified opening pressure between those patients diagnosed with intracranial hypertension (primary or secondary) with or without papilledema. We found similar rates of obesity (51.9% vs 40.9%) and being overweight (18.9% vs 13.6%) in those with and without edema. In our study, this was above the rate reported in the literature.4-6 The similar rates of obesity and opening pressure values between those with and without edema suggests that obesity and intracranial pressure value do not play a leading role in the development of papilledema. Those without papilledema were more likely to be on a concomitant typical migraine medication. This is likely due to these patients initially being diagnosed with migraine given the lack of edema. Headache characteristics alone cannot be used to distinguish headache due to migraine versus intracranial hypertension.3 In group 1, 69.2% (18/26) of their headaches met the criteria for migraine compared to 51.4% (56/109) in group 2. Prior to diagnosis, 11.5% (3/26) and 11.9% (13/109) had a diagnosis of migraine in groups 1 and 2, respectively. There were 34.6% (9/26) and 30.3% (33/109) in groups 1 and 2, respectively, that had a diagnosis of headache prior to diagnosis. None of the patients in group 1 received surgical interventions compared to 13/125 (10.4%) in group 2. The main weakness in this study is the missing variables for body mass index (15.8%) and initial opening pressure (9.3%). Acknowledgments This study was carried out at Nationwide Children’s Hospital. Columbus, Ohio.
Author Contributions SA was the study designer, performed the major data analysis, and wrote a majority of the manuscript. CA performed the data collection and first pass analysis. ESR was the primary manuscript reviewer.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval This study was approved by Nationwide Children’s Hospital institutional review board (IRB13-00342).
References 1. Beri S, Gosalakkal JA, Hussain N, Balky AP, Parepalli S. Idiopathic intracranial hypertension without papilledema. Pediatr Neurol. 2010;42:56-58. 2. Huff AL, Hupp SL, Rothrock JF. Chronic daily headache with migrainous features due to papilledema-negative idiopathic intracranial hypertension. Cephalalgia. 1996;16:451-452. 3. Digre KB, Nakamoto BK, Warner JE, Langeberg WJ, Baggaley SK, Katz BJ. A comparison of idiopathic intracranial hypertension with and without papilledema. Headache. 2009; 49:185-193. 4. Tibussek D, Schneider DT, Vandemeulebroecke N, et al. Clinical spectrum of the pseudotumor cerebri complex in children. Child Nerv Syst. 2010;26:313-321. 5. Tibussek D, Distelmaier F, von Kries R, Mayatepek E. Pseudotumor cerebri in childhood and adolescence—results of a Germanywide ESPED-survey. Klinische Padiatrie. 2013;225:81-85. 6. 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: 1389-1392. 7. Mathew NT, Ravishankar K, Sanin LC. Coexistence of migraine and idiopathic intracranial hypertension without papilledema. Neurology. 1996;46:1226-1230. 8. Smith JL. Whence pseudotumor cerebri? J Clin Neuroophthalmol. 1985;5:55-56. 9. Aylward SC. Pediatric idiopathic intracranial hypertension: a need for clarification. Pediatr Neurol. 2013;49:303-304. 10. Euling SY, Herman-Giddens ME, Lee PA, et al. Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings. Pediatrics. 2008;121(suppl 3):S172-S191. 11. Frisen L. Swelling of the optic nerve head: a staging scheme. J Neurol Neurosurg Psychiatry. 1982;45:13-18. 12. Kuczmarski RJ, Ogden CL, Guo SS, et al. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 11. 2002;(246):1-190. 13. Schirmer CM, Hedges TR 3rd. Mechanisms of visual loss in papilledema. Neurosurg Focus. 2007;23:E5. 14. Van Stavern GP. Optic disc edema. Sem Neurol. 2007;27: 233-243. 15. Avery RA, Shah SS, Licht DJ, et al. Reference range for cerebrospinal fluid opening pressure in children. N Engl J Med. 2010;363:891-893. 16. Lee MW, Vedanarayanan VV. Cerebrospinal fluid opening pressure in children: experience in a controlled setting. Pediatr Neurol. 2011;45:238-240. 17. Newman NJ, Selzer KA, Bell RA. Association of multiple sclerosis and intracranial hypertension. J Neuroophthalmol. 1994;14: 189-192. 18. Williams BJ, Skinner HJ, Maria BL. Increased intracranial pressure in a case of pediatric multiple sclerosis. J Child Neurol. 2008;23:699-702. 19. Narula S, Liu GT, Avery RA, Banwell B, Waldman AT. Elevated cerebrospinal fluid opening pressure in a pediatric demyelinating disease cohort. Pediatr Neurol. 2015;52:446-449.
Downloaded from jcn.sagepub.com at FLORIDA INTERNATIONAL UNIV on May 27, 2015
Aylward et al
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20. Friedman DI, Liu GT, Digre KB. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2013;81:1159-1165. 21. 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;82:1011-1012. 22. Liguori C, Romigi A, Albanese M, et al. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2014;82:1752-1753.
23. Wall M, Corbett JJ. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2014;83: 198-199. 24. Gorkem SB, Doganay S, Canpolat M, et al. MR imaging findings in children with pseudotumor cerebri and comparison with healthy controls. Child Nerv Syst. 2015;31:373-380. 25. Maralani PJ, Hassanlou M, Torres C, et al. Accuracy of brain imaging in the diagnosis of idiopathic intracranial hypertension. Clin Radiol. 2012;67:656-663.
Downloaded from jcn.sagepub.com at FLORIDA INTERNATIONAL UNIV on May 27, 2015
