Edited by: Heather Moss, Stanford University, United States
Reviewed by: Christopher Charles Glisson, Michigan State University, United States; Melissa Wang Ko, Upstate Medical University, United States
This article was submitted to Neuro-Ophthalmology, a section of the journal Frontiers in Neurology
†These authors have contributed equally to this work.
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Idiopathic intracranial hypertension (IIH) is a neurological disorder characterized by elevated intracranial pressure (ICP) in the absence of any known causative factor (mass lesion, inflammation, central venous thrombosis). The patients typically present with headache, visual disturbances (transient visual obscurations), tinnitus and diplopia. Mainly affected are obese women of childbearing age (
By definition papilledema refers to a swelling of the optic disc resulting from increased ICP. The development of papilledema is thought to depend on the transmission of elevated ICP via the subarachnoid space (SAS) to the lamina cribrosa with resulting damage to axonal transport (
Papilledema is usually bilateral but highly asymmetric cases and even unilateral cases have been described (
The understanding of the pathophysiology in patients with IIH and persistent papilledema is of great importance as in these patients visual impairment progresses and can result in permanent visual loss (
Although several studies (
In the current study the contrast loaded CSF (CLCSF) density was measured by computer tomographic (CT) assisted cisternography at three regions along the optic nerve (orbital optic nerve portion: bulbar segment and mid-orbital segment, intracranial optic nerve portion) and in the basal cistern in 16 patients with history of IIH and papilledema with visual impairment. A group of 12 patients without known history of elevated ICP and papilledema that underwent CT cisternography for various reasons served as controls.
This study should add to the understanding of the complex CSF dynamics in the SAS along the entire optic nerve in patients with IIH and papilledema.
This study was approved by the local ethical commission (Ethikkommission Nordwest- und Zentralschweiz) and follows the tenets of the Declaration of Helsinki. The informed consent from the subjects was checked before inclusion in this study.
From 2005 to 2015 16 patients (32 optic nerves), 14 women and 2 men with an established diagnosis of IIH were admitted to our department for CT cysternography because of a therapy-resistant papilledema and progressive visual impairment (visual acuity and/or visual field). Mean age was 49 ± 16 years, 47 ± 15 years in women and 68 ± 15 years in men. All patients underwent a full neuro-opthalmological examination, magnetic resonance imaging (MRI) and lumbar puncture to establish the diagnosis. This was based on the updated modified Dandy criteria (
At initially presentation all patients had bilateral papilledema (no information about grade). The mean CSF opening pressure measured by lumbar puncture was 40.0 ± 12.7 cmH2O (in 5 patients the lumbar CSF pressure was documented from the performing doctor as >25 cmH2O) at time of diagnosis.
At time of cisternography in all patients both optic nerves were involved whereas in 8 patients papilledema was slightly asymmetrical and 2 patients showed atrophic optic discs. The average visual field mean deviation was 6.6 ± 8.5 dB on the right and 6.9 ± 7.9 dB on the left side using standard automated perimetry (SAP, Program G2 Octopus Haag-Streit, Switzerland) whereas in 5 patients only the Goldman visual field perimetry was used. The visual acuity using the logMAR chart was 0.3 ± 0.5 right and 0.2 ± 0.3 left. The mean body mass index (BMI) was 31 ± 5. The mean CSF opening pressure measured by lumbar puncture was 29.2 ± 8.6 cmH2O at time of cisternography (Table
Clinical parameters at time of cisternography of patients with Idiopathic Intracranial Hypertension (IIH).
1 | 60–65 | 36 | 0 | 0 | 3.9 | 4.3 | 21 |
2 | 26–30 | 37 | 0.1 | 0 | 2.8 | 0.7 | 18 |
3 | 75–80 | 25 | 1.3 | 0.1 | 25.2 | 25.9 | 24 |
4 | 56–60 | 38 | 0 | 0.1 | 1.4 | 9.2 | 26 |
5 | 20–25 | 24 | 0 | 0 | 19.4 | 13.7 | 29 |
6 | 56–60 | 32 | 0 | 0 | 0.9 | 0.3 | 34 |
7 | 20–25 | 33 | 0 | 0 | 2.1 | 2.7 | 45 |
8 | 46–50 | 36 | 0 | 0 | 2.9 | 2.2 | 34 |
9 | 46–50 | 33 | 0 | 1 | – | – | 29 |
10 | 40–45 | 33 | 0 | 0 | 5.3 | 7.2 | 25 |
11 | 36–40 | 35 | 0.1 | 0 | – | – | 28 |
12 | 60–65 | 30 | 1 | 0.5 | – | – | 23 |
13 | 56–60 | 29 | 0.3 | 0.2 | – | – | 50 |
14 | 56–60 | 24 | 0 | 0 | 2.4 | 2.3 | 34 |
15 | 30–35 | 27 | 1.3 | 1 | – | – | 27 |
16 | 60–65 | 27 | 0 | 0 | 12 | 12.2 | 21 |
AM ± SD | 49 ± 16 | 31 ± 5 | 0.3 ± 0.5 | 0.2 ± 0.3 | 6.6 ± 8.5 | 6.9 ± 7.9 | 29.2 ± 8.6 |
Clinical symptoms were visual symptoms (blurry vision, transient visual obscuration, visual field impairment) (16 patients), headache (12 patients), and diplopia from VIth cranial nerve palsy (1 patient). At time of cisternography all patients were treated with oral acetozolamide (10 patients: 1,500 mg/day, 6 patients: 1,000 mg/day due to side effects, mean dose: 1,313 mg/day) and 2 patients had additionally undergone a shunt procedure. The duration of the therapy was variable depending on the duration of the disease. Radiological signs showed flattening of the posterior globe (16 patients), an “empty sella” (6 patients), and stenosis of the transverse venous sinus (3 patients).
The indication for CT cysternography was progressive visual impairment and persistent papilledema (14 patients) or optic nerve atrophy development (2 patients) despite weight loss attempts and maximal therapy with systemic acetazolamide or additionally performed shunt procedures. The mean time from diagnosis to performed CT cisternography was highly variable and varied between 23 years and 3 months, the mean was 5 ± 6 years.
During CT cisternography all patients were hospitalized in our department and underwent a full ophthalmological and neuro-ophthalmological examination including slit lamp-assisted biomicroscopy and visual field testing.
As CT cisternography is an invasive and therefore potentially harmful technique, a healthy aged-matched control group is not available. We therefore included an inhomogeneous group of patients who underwent CT cisternography for a variety of indications. The same group was used as controls in a not yet published work about glaucoma.
From the database of the Department of Neuroradiology, Cantonal Hospital, Aarau, Switzerland, all patients who underwent CT cisternography for various diagnostic reasons in the period from 2010 to 2015 were used as the initial dataset. 12 patients (24 optic nerves), 9 women and 3 men without elevated intracranial pressure (<20cmH2O) and without papilledema were included and served as controls. Mean age was 60 ± 19 years, 61 ± 22 years in women and 55 ± 10 years in men. There was no significant difference (
The mean CSF opening pressure measured by lumbar puncture was 13.0 ± 4cmH2O (in 8 patients the lumbar CSF-p was documented as <20cmH2O) at time of cisternography.
At the beginning of cisternography a lumbar puncture was performed in the lateral decubitus position and CSF pressure was measured. The patient‘s legs were straightened and the patient was asked to remain calm and not to speak during the measurements in order to avoid Valsalva manoeuvers. In all patients with IIH during lumbar puncture 10 ml of CSF was sampled for biochemical analysis and then 10 ml iopamidol (molecular weight 778 D, Iopamiro 300, Bracco, Milano, Italy) was injected intrathecally. The total CSF volume was therefore not altered. The patient was then turned to the prone position. The time between iopamidol injection and CT was 15 min and was the same in both patients and controls. All patients underwent CT cisternography at the same institution, by the same neuro-radiologist (L.R.).
A 64-detector scanner (Aquillion 64, Toshiba, Tokyo, Japan) providing 0.5 mmX32 section collimation was used. Scanning parameters were a 25 cm field of view with a 512 × 512 matrix and a soft tissue and a bone reconstruction algorithm were employed. The field of view included the foramen magnum and the nose.
Multiplanar reconstruction images (MPR) were obtained in the axial, coronal and sagittal planes with a 0.5 mm slice thickness. CT images were analyzed using the program VitreaCore (Vital Images, Inc., Minnetonka, MN, USA) on the Advantage Workstation 4.1 software (General Electric, Milwaukee, Wisconsin, USA).
CLCSF density was measured in Hounsfield units (HU) on CT images. Measurements of the contrast agent were performed at three defined regions along the optic nerve and in the basal cistern. Region of interest (ROI) 1 (bulbar segment) was defined as the area 1–4 mm in distance from the lamina cribrosa, ROI 2 (mid-orbital segment), as the area 13–16 mm in distance from lamina cribrosa and ROI 3 (intracranial portion) was defined as the area from the optic chiasm to the cranial opening of the OC. ROI 4 corresponded to the basal cistern (Figure
Region of interests (ROI) where contrast loaded cerebrospinal fluid (CLCSF) density measurements were performed. ROI 1: bulbar segment of the orbital portion, ROI 2: mid-orbital segment of the orbital portion, ROI 3: intracranial portion, ROI 4: basal cistern.
Contrast loaded cerebrospinal fluid (CLCSF) density measurements in the mid-orbital segment of the orbital portion (ROI 2) of a right optic nerve. Axial
All CLCSF measurements were measured twice and reviewed by an experienced neuroradiologist blinded to the neuro-ophthalmological findings.
Statistical analysis was performed using SigmaPlot 10.0 (Systat Software, San Jose, CA, USA), Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA, USA) for Windows statistical package. Data were analyzed using paired or unpaired Student
In IIH patients the mean density of CLCSF measured 65 ± 53 HU in the right optic nerve and 63 ± 35 HU in the left optic nerve. In controls the mean CLCSF density measured 226 ± 131 HU in the right optic nerve and 205 ± 111 HU in the left optic nerve (Tables
Measurements of contrast loaded cerebrospinal fluid (CLCSF) along the entire optic nerve in patients with Idiopathic Intracranial Hypertension (IIH).
1 | 60–65 | 542 | 203 | 205 | 62 | 47 | 43 | 39 |
2 | 26–30 | 701 | 231 | 287 | 127 | 78 | 233 | 118 |
3 | 75–80 | 1070 | 689 | 769 | 33 | 42 | 40 | 40 |
4 | 56–60 | 820 | 492 | 317 | 74 | 75 | 81 | 86 |
5 | 20–25 | 488 | 247 | 243 | 41 | 20 | 30 | 28 |
6 | 56–60 | 529 | 240 | 235 | 175 | 71 | 47 | 59 |
7 | 20–25 | 642 | 305 | 318 | 65 | 92 | 33 | 101 |
8 | 46–50 | 433 | 152 | 138 | 40 | 35 | 29 | 29 |
9 | 46–50 | 382 | 377 | 601 | 79 | 54 | 121 | 84 |
10 | 40–45 | 515 | 203 | 211 | 82 | 77 | 105 | 101 |
11 | 36–40 | 635 | 222 | 262 | 45 | 91 | 47 | 131 |
12 | 60–65 | 578 | 319 | 323 | 52 | 50 | 37 | 35 |
13 | 56–60 | 448 | 206 | 183 | 39 | 31 | 32 | 32 |
14 | 56–60 | 791 | 350 | 350 | 58 | 65 | 43 | 45 |
15 | 30–35 | 895 | 402 | 520 | 46 | 72 | 43 | 50 |
16 | 60–65 | 520 | 207 | 209 | 73 | 54 | 76 | 29 |
AM ± SD | 49 ± 16 | 623 ± 188 | 303 ± 137 | 323 ± 169 | 68 ± 37 | 60 ± 21 | 65 ± 53 | 63 ± 35 |
Measurements of contrast loaded cerebrospinal fluid (CLCSF) along the entire optic nerve in controls without elevated intracranial pressure and without papilledema.
1 | 90–95 | 1,067 | 268 | 230 | 278 | 151 | 246 | 242 |
2 | 40–45 | 607 | 307 | 312 | 83 | 100 | 116 | 166 |
3 | 46–50 | 881 | 239 | 206 | 202 | 180 | 229 | 141 |
4 | 30–35 | 595 | 268 | 299 | 90 | 84 | 110 | 149 |
5 | 30–35 | 807 | 393 | 331 | 116 | 115 | 126 | 146 |
6 | 66–70 | 500 | 316 | 308 | 147 | 109 | 145 | 127 |
7 | 76–80 | 368 | 374 | 327 | 202 | 200 | 131 | 131 |
8 | 66–70 | 527 | 306 | 350 | 144 | 188 | 176 | 168 |
9 | 46–50 | 860 | 270 | 335 | 295 | 289 | 575 | 529 |
10 | 70–75 | 391 | 321 | 299 | 246 | 202 | 273 | 185 |
11 | 76–80 | 610 | 379 | 359 | 180 | 185 | 315 | 208 |
12 | 46–50 | 639 | 353 | 284 | 337 | 234 | 268 | 266 |
AM ± SD | 60 ± 19 | 654 ± 210 | 316 ± 50 | 303 ± 46 | 193 ± 82 | 170 ± 61 | 226 ± 131 | 205 ± 111 |
Scatterplot of contrast loaded cerebrospinal fluid (CLCSF) density measurements in Hounsfield Units (HU) in the bulbar- (ROI 1) and mid-orbital segment (ROI 2) of the optic nerve, the intracranial portion (ROI 3) of the optic nerve and in the basal cistern (ROI 4) in patients with idiopathic intracranial hypertension (IIH) and papilledema and controls, separated for right and left optic nerve. IIH patients (
In IIH patients the mean CLCSF density measured 68 ± 37 HU in the right optic nerve and 60 ± 21 HU in the left optic nerve. In controls the mean CLCSF density measured 193 ± 82 HU in the right optic nerve and 170 ± 61 HU in the left optic nerve (Tables
The difference between IIH patients and controls showed statistical significance for the right and for the left optic nerve (right optic nerve:
In IIH patients the mean CLCSF density measured 303 ± 137 HU in the right optic nerve and 323 ± 169 HU in the left optic nerve. In controls the mean CLCSF density measured 316 ± 50 HU in the right optic nerve and 303 ± 46 HU in the left optic nerve (Tables
In IIH patients the mean density of CLCSF measured 623 ± 188 HU and in controls 654 ± 210 HU (Tables
In IIH patients the mean difference between
In controls the mean difference between
The difference of CLCSF density between the right and the left optic nerve was not statistically significant in either group (IIH: ROI 1:
The current study uses CT cisternography to assess the CSF dynamics along the entire optic nerve in 16 patients with a history of IIH and papilledema and in 12 controls without elevated ICP and without papilledema. The measurements demonstrate a significant reduction of CLCSF concentrations within the intraorbital optic nerve segments in patients with IIH compared to controls.
The CSF pathway within the SAS of optic nerve is a closed circulatory system that ends behind the eye ball. CSF moves from the basal cistern to the intracranial optic nerve portion and then via the optic canal into the intraorbital segments (mid-orbital segment and retrobulbar segment) to the lamina cribrosa at the posterior end of the globe. Both the SAS diameter and the meshwork of trabeculae and septae that bridge the SAS differ in number and morphology within the different optic nerve portions. The narrowest diameter is measured within the intracanalicular portion where the SAS is confined by bone (
Cisternography is at present the only method that can provide information on CSF flow dynamics in the SAS of the optic nerve
The highest CLCSF density was measured in both IIH patients and controls in the basal cistern (ROI 4). This is not surprising as the volume of the chiasmal cistern is much larger than the SAS volume surrounding the optic nerve. Further, the density measured in the basal cistern is biased by the measurement method used. We measured the CLCSF as the mean of HU within a circle because CT imaging does not allow us to distinguish the exact borders of the optic nerve and the optic nerve sheath. The density measurements along the optic nerve therefore include the optic nerve sheath and the optic nerve itself which is not filled with CSF and is therefore lower than that in the basal cistern where the optic nerve density does not bias the measurement.
In both IIH patients and controls a significant reduction of CLCSF density was measured between the intracranial (ROI 3) and the mid-orbital segment of the orbital optic nerve portion (ROI 2). In controls the measured CLCSF density reduction through the optic canal is most likely to be due to the physiological diminution of the SAS diameter within the intracanalicular optic nerve portion. The SAS measured its smallest diameter within the optic canal (
Distribution of contrast loaded cerebrospinal fluid (CLCSF) along the entire optic nerve in patients with idiopathic intracranial hypertension (IIH) and papilledema and controls, separated for right and left optic nerve. ROI 1: bulbar segment of the orbital portion, ROI 2: mid-orbital segment of the orbital portion, ROI 3: intracranial portion. •, IIH patients; ◦, controls.
Computed tomographic (CT) cisternography in a patient with idiopathic intracranial hypertension (IIH) and papilledema and a control subject. In the patient with IIH
Evidence for the restricting effect of the optic canal on CSF dynamics in patients with IIH was provided by pro–and retrospective clinical studies (
The optic canal is confined by bone and the meninges. While bone represents the solid component, the structure of the meninges is more dynamic. The meningothelial cell (MEC) layer that forms the arachnoid and the pia layer of the meninges therefore play an important role for the anatomy of the optic canal. MECs are multifunctional cells that cover the pia and the arachnoid layer of the meninges in the entire central nervous system and thus the septae and trabeculae in the SAS of the optic nerve (
Such impaired CSF dynamics within the orbital optic nerve segments might be of clinical importance. Once CSF influx stagnates, the SAS of the optic nerve turns into a CSF compartment with a reduced in and outflow of CSF. This results in an accumulation of biologically active substances, such as L-PGDS, a multifactorial prostaglandin synthetase. CSF sampling during optic nerve sheath fenestration in patients with papilledema demonstrated exceedingly high concentrations of this protein (
Changes in the optic canal patency and formation of an optic nerve sheath compartment have also recently been considered to play a role in the development of the visual impairment intracranial pressure (VIIP) syndrome found in astronauts after prolonged space flight (
The present study further might be of interest for the treatment options in patients with IIH and persisting papilledema in spite of normalized ICP (
There are several obvious weaknesses in this study which need to be addressed. Firstly, the large differences in time from first diagnosis to cisternography and thus the differences in the duration of the disease in IIH patients. As cisternography is not a primary procedure in patients with IIH, cisternography was only performed in IIH patients with persistent papilledema and progressive visual impairment despite loss weight attempts and maximal therapy with systemic acetazolamide and or ventriculoperitoneal shunt surgery. The IIH patients in this study does therefore not present the “typical IIH patient.” The patients are not within the typically age range and the BMI is lower compared to the typical IIH cohort. If this is due to a cultural difference between different populations (Swiss with other countries) needs further studies. Secondly, the control group is not homogeneous and the controls underwent cisternography for various indications. Due to the invasive nature of cisternography we cannot, for obvious ethical considerations, provide a healthy aged- and gender matched control group of “normal.” However, the differences between IIH patients and the control group is clearly demonstrated. Thirdly, the density measurements in ROI 1, ROI 2, and ROI 3 are biased by including the optic nerve itself because it is still technically not possible for us to measure the CSF filled SAS alone. This however is the case in both groups and does therefore not compromise the comparison between controls and IIH. Fourthly, the number of patients in both the IIH- and the control group is rather small (IIH:
The current study demonstrates reduced CLCSF density within the orbital optic nerve segments in 16 (32 optic nerve) patients with history of IIH and papilledema. It is possible that impaired CSF dynamics are involved in the pathophysiology of IIH.
All authors listed have contributed significantly and are in agreement with the content of the manuscript. AP was mainly involved in study design, data analysis, data interpretation and manuscript preparation. MM was mainly involved in study design, data acquisition, data interpretation and manuscript preparation. AP and MM contributed equally to this work. JP was mainly involved in data analysis. JB was mainly involved in data acquisition. LR was mainly involved in data acquisition and data analysis. HK was mainly involved in study design, data interpretation and manuscript preparation.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank Dr. Julian Stekhoven for helpful comments on the manuscript as well as for assistance with the language.
cerebrospinal fluid
idiopathic intracranial hypertension
computed tomographic
contrast loaded cerebrospinal fluid
Hounsfield units
regions of interest
intracranial pressure
subarachnoid space
magnetic resonance imaging
body mass index
multiplanar reconstruction images
meningothelial cell
visual impairment intracranial pressure.