Cerebrospinal fluid (CSF) pressure and composition are generally thought to be homogeneous within small limits throughout all CSF compartments. CSF sampled during lumbar puncture therefore should be representative for all CSF compartments. On the basis of clinical findings, histology and biochemical markers, we present for the first time strong evidence that the subarachnoid spaces (SAS) of the optic nerve (ON) can become separated from other CSF compartments in certain ON disorders, thus leading to an ON sheath compartment syndrome. This may result in an abnormal concentration gradient of CSF molecular markers determined in locally sampled CSF compared with CSF taken during lumbar punctur

Flammer, J.

Huber, A. R.

Jaggi, G. P.

Killer, H. E.

Miller, N. R.

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doi:10.1093/brain/awl045 Brain (2006), 129, 1027–1030The optic nerve: a new window into cerebrospinalfluid composition?H. E. Killer,1,2 G. P. Jaggi,2 J. Flammer,1 N. R. Miller4 and A. R. Huber31University of Basel, Eye Institute, 2Department of Ophthalmology and 3Department of Laboratory Medicine, KantonsspitalAarau, Switzerland and 4Wilmer Ophthalmological Institute, Johns Hopkins Hospital, Baltimore, MD, USACorrespondence to: PD Dr. H.E. Killer, Kantonsspital Aarau, CH-5001 Aarau, SwitzerlandE-mail: Killer@ksa.chCerebrospinal fluid (CSF) pressure and composition are generally thought to be homogeneous withinsmall limits throughout all CSF compartments. CSF sampled during lumbar puncture therefore should berepresentative for all CSF compartments. On the basis of clinical findings, histology and biochemical markers,we present for the first time strong evidence that the subarachnoid spaces (SAS) of the optic nerve (ON) canbecome separated from other CSF compartments in certain ON disorders, thus leading to an ON sheathcompartment syndrome. This may result in an abnormal concentration gradient of CSF molecular markersdetermined in locally sampled CSF compared with CSF taken during lumbar puncture.Keywords: beta trace protein; cerebrospinal fluid; optic nerve; subarachnoid spaceAbbreviations: CSF = cerebrospinal fluid; ON = optic nerve; SAS = subarachnoid space; ONSF = optic nerve sheathfenestration; MRI = magnetic resonance imaging; PGD = prostaglandin D; NSE = neuron-specific enolaseReceived November 28, 2005. Revised January 24, 2006. Accepted January 27, 2006. Advance Access publication February 27, 2006.IntroductionCerebrospinal fluid (CSF) is mainly produced by the choroidplexus epithelium in the ventricles, from where it flows intointerconnecting chambers, namely, the cisterns and the sub-arachnoid spaces (SAS), including the SAS of the optic nerves(ONs) (Dichiro, 1964; Bito and Vavson, 1966; Milohart,1972; Wood, 1982). Recent findings demonstrate that CSFdysfunction might be caused by changes of molecular fluxand CSF flow rate (Reiber, 2001), which in turn could resultin accumulation of toxic components. For example, abnor-mal flow rates are thought to be the main cause for thepathological protein concentrations seen in neurological dis-orders such as Alzheimer’s disease (Felgenhauer, 1980; Reiberand Felgenhauer, 1987; Tumani et al., 1998; Reiber, 2001).Furthermore, recent studies have allowed for description oftheoretical models of CSF flux that are well supported byempirically measured protein concentrations in the CSF(Reiber, 1994, 2001). The CSF contains a variety of proteins,of which 85% are derived from the blood, for example, albu-min, immunoglobulin (Ig) G, whereas approximately 15%are synthesized primarily in the brain, for example, beta-traceprotein, tau protein, S100 B protein and neuron-specificenolase (NSE) (Reiber, 2001). Beta-trace protein (molecularmass 25 kDa) is the most abundant synthesized protein in theCSF. On the basis of amino acid sequencing it has beenidentified as prostaglandin D (PGD) synthase and thereforehas biological active properties (Hoffman et al., 1993).In contrast to all other cranial nerves, the ON (a whitematter tract of the central nervous system) is covered by themeninges and surrounded by CSF throughout its entirelength. A rise in intracranial pressure thus may cause impair-ment of axoplasmic transport leading to papilloedema(Hayreh, 1964). Because CSF is assumed to communicatefreely among the different CSF compartments, it has beenconcluded that there also exists a homogeneous pressure andhomogeneous concentration of CSF components. However,to date, no data on measurements of actual protein concen-trations in the perioptic CSF space (a subarachnoid space)have been reported. Certainly, the fact that most patients withpapilloedema have more or less symmetric swelling of theoptic discs supports the assumption of free communicationamong the CSF compartments; however, cases of asymmetricand even completely unilateral papilloedema have beenreported (Killer et al., 1999, 2003a, b; Killer and Flammer,2001), and a satisfactory pathophysiological explanation forthese phenomena is lacking. As the pressure gradient of CSF isdirected from intracranial towards the SAS of the ON, it isdifficult to understand how CSF can recycle from there, as achange of direction of fluid in order to return to the site of# The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.orgresorption at the arachnoid villi is unlikely because of thevolume gradient of CSF. A CSF outflow pathway from theSAS of the ON is therefore of physiological relevance toprevent fluid accumulation. The recent discovery of lympha-tic vessels in the dura of the human ON—and their ability todrain CSF as demonstrated with a marker substance—mayoffer a CSF outflow route from the perioptic space (Killeret al., 1999, 2003). The results of experimental studies inanimals describe CSF drainage into lymphatic vessels(Boulton et al., 1998; Johnston, 2000, 2003; Zakharov et al.,2003). In cats CSF outflow from cisternal infusion to thedistal portion of the ON has been demonstrated(Lu¨demann et al., 2005). In addition, the anatomy and thearrangement of trabecula and septae in the SAS of the ONoffer the possibility that a one-way valve mechanism explainslocal CSF entrapment as well as reduced influx of CSF into theSAS of the ON (Killer et al., 1999, 2003) (Fig. 1). Unilateraland highly asymmetric dilation of the SAS of the ON canpartly be explained by reduced local drainage on the side ofthe more pronounced papilloedema or by a bigger resistanceto influx of CSF on the side of the less marked papilloedema.Owing to the small size of the SAS of the ON, local pressuremeasurements are difficult and to date have been performedonly in cadavers (Liu and Kahn, 1993).Material and methodsWe performed ON sheath fenestration (ONSF) (Galbraith andSullivan, 1973) in six patients after ophthalmological and neurolo-gical examination including lumbar puncture in five patients. In fivepatients MRI imaging of the brain and orbit was performed.One patient underwent high-resolution computed tomography.In one patient ONSF was performed on both ON. All patientswere operated at the same institution (Kantonsspital Aarau) bythe same surgeon (H. E. Killer). Three had unilateral optic discswelling: one from anterior ischaemic optic neuropathy, one fromON sheath meningioma and one idiopathic optic disc swelling(presumed from a local vascular cause). The other three patientshad highly asymmetric papilloedema: one from pachymeningitis,one from idiopathic intracranial hypertension and one followinga cerebral haemorrhage.Marked dilation of the perioptic CSF spaces was present on MRimaging in all three patients with papilloedema. These MRI findingswere first described by Brodsky et al. (1998). Less-marked dilationwas present in the three patients with unilateral optic disc swelling.CSF was collected in all patients from the SAS of the ON after the‘CSF gush’ following the incision of the dura and from the lumbarSAS at the time of the lumbar puncture. The CSF from both com-partments was examined for the content of albumin, IgG and beta-trace protein. For the determination of serum and CSF albumin, IgGand beta-trace proteins, nephelometric methods were employedusing polyclonal antibodies and a nephelometer (BNII) fromDade Behring, Marburg, Germany.ResultsBeta-trace concentrations of CSF obtained from the SAS ofthe ON was 79.84 6 27.14 mg/l, whereas the CSF : serumratio of albumin and IgG was 0.24 6 0.17 and 0.21 6 0.15,respectively. Further, beta-trace concentrations and albuminand IgG ratio in CSF obtained from a spinal tap were17.53 6 3.06, and 0.02 6 0.02 and 0.01 6 0.01 mg/l,respectively. Reference values for beta-trace protein are15.3 mg/l (Link and Olsson, 1972; Rubenstein, 1998)(Figs 2 and 3).DiscussionThis paper describes six cases with unilateral optic discswelling and asymmetric papilloedema with distension ofthe perioptic nerve sheath on orbital MRI or CT scan.The CSF findings strongly suggest that the ON can developinto a separate CSF compartment under certain pathologicalconditions. In addition, despite different aetiologies of opticdisc swelling, the CSF obtained from the SAS of the ON in allof these cases demonstrated markedly different biomarkerconcentrations compared with those in the CSF obtainedfrom the corresponding lumbar SAS. These findings are con-sistent with the compartmentalization of the SAS of the ON.In addition, they suggest that additional mechanical damage(e.g. elevated local pressure) as well as biochemical injurythrough an accumulation of biologically active moleculesmay contribute to disease progression and tissue damage toFig. 1 Histological studies of the meninges of the human ON.(Courtesy of P. Groscurth, Department of Anatomy, University ofZu¨rich, Switzerland). (A) Scanning electron microscopy of theretrobulbar portion of the SAS of the ON. Note the complexnetwork of trabeculae bridging the SAS. (B) Transmission electronmicroscopy of arachnoid trabeculae. Note the thin layer ofmeningoepithelial cells surrounding each trabeculum and thecytoplasmic bridges connecting adjacent trabeculae. Theanatomical arrangement of trabeculae and cytoplasmatic bridgesallow for local CSF entrapment in the SAS causing an ON sheathcompartment syndrome. (C) Lymphatic capillary in the dura ofthe human ON sheath. Marker particles are visible in the lumen ofthe vessel (asterisk). (D) Arachnoid layer with pore for CSFoutflow into the dura. Note the macrophage entering the pore.1028 Brain (2006), 129, 1027–1030 H. E. Killer et al.blood vessels, axons and neurons (Link and Olsson, 1972;Logdberg and Wester, 2000; Urade and Hayaishi, 2000;Reiber, 2001; Fujitani et al., 2002; Taniike et al., 2002;Ragolia et al., 2003; Zakharov et al., 2003).Although elevated concentrations of IgG and albumin,seen in patients with blood-brain barrier dysfunction,might have been caused by the surgical procedure, theincreased concentration of CSF beta-trace protein in theSAS of the ON can only be due to abnormal local synthesisor pathological flow dynamics (reduced beta-trace clearing)in the occluded compartment. Whether or not this markedlyincreased concentration of beta-trace further aggravatescompartmentalization is not known at this time. Ours isthe first report to provide information concerning thebiochemical constituents of the CSF in the SAS of the ONand the difference between the concentrations of theseconstituents in the perioptic SAS versus the lumbar SAS.Furthermore, the results provide strong evidence forcompartmentalization of the SAS of the ON, thus leadingunder certain circumstances to the development of anON sheath compartment syndrome. Several studies havedemonstrated apoptosis-inducing properties of beta-tracein neuronal tissues (Link and Olsson, 1972; Logdbergand Wester, 2000; Urade and Hayaishi, 2000; Fujitani et al.,2002; Taniike et al., 2002; Ragolia et al., 2003). Given thebiological potential of some molecules in the CSF, it could bepostulated that the accumulation of these biologically activemolecules (e.g. beta-trace) in blocked compartments of theCSF space would cause significant, possibly devastating,damage to the tissues in the vicinity of the affected area.A relationship between an impaired CSF circulatory system,impaired clearance of noxious substances in the CSFand dementias of the aged has recently been proposed(Rubenstein, 1998; Silverberg et al., 2003). Following thisline of thought, our findings may prove helpful to shed anew light onto the pathophysiology of progressive anteriorand posterior ischaemic optic neuropathy or more commonON disorders, such as chronic open-angle and normal-tension glaucoma, which in many cases show progressivevisual field loss despite well-regulated intraocular pressure,0102030405060708090100110120LP ON LP ON LP ON0.000.010.101.00A B CPatient   M.E. S.A. S.A. K.H. H.H. H.U. P.M. Age [years]  39 23 23 61 48 52 20 Gender    f m m m m f f Diagnosis    ONSM PM PM IODS SPC AION PC ON Side   l l r l l r l LP Pressure  [cm H2O]  24 50 50 none  34 20 43 Beta-Trace LP  [mg/L]  18.60 18.10 18.10 none 11.80 21.00 17.60 Beta-Trace ON [mg/L]  49.90 103.00 124.00 81.10 71.10 80.90 48.90 Albumin Ratio LP  (CSF/Serum)  0.01 0.03 0.03 none  0.03 0.00 0.00 Albumin Ratio ON  (CSF/Serum)  0.52 0.20 0.11 0.14 0.09 0.43 0.21 IgG Ratio LP  (CSF/Serum)  0.00 0.01 0.01 none  0.02 0.00 0.00 IgG Ratio ON  (CSF/Serum)  0.45 0.13 none  0.12 0.05 0.32 0.17 Fig. 2 Table and graph of CSF data from six patients. Table: The CSF samples are taken from seven SAS of the left (l) or/and theright (r) ON from three male (m) (mean age 44.0 6 19.3 years) and three female (f ) (mean age 37.0 6 16.0 years) patients after informedconsent. Clinical diagnosis: pseudotumour cerebri (PC) and secondary pseudotumour cerebri (SPC), anterior ischaemic optic neuropathy(AION), pachymeningitis (PM), idiopathic optic disc swelling (IODS) and ON sheath meningioma (ONSM). Lumbarpuncture (LP) was performed in five patients and markers determined as described. Graph: Beta trace (A; light bars) in (mg/l) 6 SD,CSF/serum ratio of albumin (B, dark bars), and of IgG (C, hatched bars) of mean 6 SD and logarithmic from six patientsobtained by spinal tap (LP) and puncture of the SAS of the ON.A new window into cerebrospinal fluid composition Brain (2006), 129, 1027–1030 1029suggesting additional pathophysiological components(Gliklich et al., 1989).AcknowledgementWe would like to thank Ronald M. Burde—former headof Department of Ophthalmology, Albert Einstein Collegeof Medicine, New York—for continued inspiration andfriendship.Conflict of interest statement. None declared.ReferencesBito LZ, VavsonH. 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Neuropathol Appl Neurobiol 2003; 29: 563–73.Fig. 3 Fundus photography and MRI studies of a patient withunilateral papilloedema (due to nerve sheath meningioma).(A) Unremarkable optic disc on the right. (B) Unilateral optic discswelling due to left ON sheath meningioma. (C) Distendedperioptic nerve sheath on the left with accumulation of CSF(white on T2-weighted magnetic resonance image, axial view).These radiological features meet the criteria for papilloedemaas described previously by Brodsky and Vaphiades (1998).(D) Coronal view of the left orbit. Note marked distension ofthe SAS and accumulation of CSF.1030 Brain (2006), 129, 1027–1030 H. E. Killer et al.

The optic nerve: a new window into cerebrospinal fluid composition?

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