Journal of Glaucoma:
Compartment Syndromes of the Optic Nerve and Open-Angle Glaucoma
Killer, Hanspeter Esriel MD
University of Basel, Head of Neuro-ophthalmology, Kantonsspital Aarau, Aarau, Switzerland
Disclosure: The author declares no conflict of interest.
A compartment is a space or volume that is separated from its environment. The cause for separation can be manifold. It can be expressed as a difference ∆ in parameters, such as size, area, volume, color or pressure. The border of a compartment can be rigid or flexible (compliance). The optic nerve is located within the subarachnoid space and is covered by the dura mater, the arachnoid and the pia mater that cover the brain as well. As is the brain, the optic nerve is bathed in cerebrospinal fluid (CSF). Optic nerve compartmentalization has been demonstrated in papilledema, anterior ischemic optic neuropathy, posterior ischemic optic neuropathy, and normal tension glaucoma. Anatomically the optic nerve can be described as located in a cul de sac with a steady inflow of CSF from the pituitary cistern via the optic canal. This specific anatomy raises questions concerning the mechanism of CSF recycling from the confined perioptic space.
The basic causes and mechanisms of glaucomatous damage remain poorly understood. Among the most important known risk factors are elevated intraocular pressure and vascular dysregulation. The search for additional risk factors is ongoing.
Unlike other cranial nerves, the optic nerve is a white matter tract of the brain located in the orbit within its own subarachnoid space (SAS). It is enveloped by the dura mater, the arachnoid and the pia; basically the same covering as in the brain. Menigothelial cells cover both the arachnoid and the pia and face cerebrospinal fluid (CSF). As is the brain, the optic nerve is bathed in CSF that is recycled up to five times daily in order to fulfill its physiological functions (nutrition of axons and glial cells as well as removal of toxic metabolites). There is a steady inflow of CSF from the intracranial CSF spaces (pituitary cistern) via the optic canal into the SAS of the optic nerve. Due to the the large volume gradient of CSF, reversal of CSF flow is unlikely. Lymphatic clefts in the dura are thought to be a possible outflow pathway for CSF from this cul-de-sac anatomy with its blind end at the lamina cribrosa.1,2 Menigothelial cells are capable of phagocytosis and might therefore contribute to CSF clearing and recycling, which is of high importance for the integrity of axons and glia (oligodendrocyes and astrocytes). Outflow mechanisms have been demonstrated both in vitro and in vivo.3,4
Alteration in the content and concentration of CSF proteins can be harmful to astrocyte proliferation and to adenosine triphosphate (ATP) production.5 The integrity of the outflow system was shown to be impaired in patients with papilledema and normal-tension glaucoma (NTG).6 In both diseases, concentration gradients of lipocalin-type prostaglandin D2 synthase (L-PGDS, a betatrace protein) between the lumbar CSF and the CSF from the SAS of the optic nerve have been measured. Compartmentalization of the SAS of the optic nerve, with either reduced CSF exchange or augmented production of L-PGDS can explain such a gradient. Compartmentalization can best be demonstrated with computed tomography (CT) cisternography after intrathecal application of a contrast medium (Iopamidol, molecular weight 778 D) by lumbar puncture.7 The distribution of contrast loaded CSF can be measured in Hounsfield units at various locations.
Differences of contrast loaded CSF concentrations are indicators for compartmentalization. According to the second law of thermodynamics, the injected contrast agent is expected to diffuse homogenously throughout all CSF spaces (ventricles, subarachnoid spaces, cisterns), given that these spaces communicate freely. In a series of 18 NTG patients, large concentration gradients of contrast loaded CSF were measured between the basal cisterns and the SAS of the optic nerve (paper in review). Similar results have been recently reported in patients with longstanding papilledema, in whom conventional medical treatment was ineffective and who underwent optic nerve sheath decompression.8
Compartmentalization of CSF spaces can lead to dissociation/discontinuation of CSF flow and content and also to pressure gradients between the different CSF spaces. Evidence for such a dissociation of pressure between the lumbar CSF space and the SAS of the optic nerve is based on the relationship between intracranial pressure and the diameter of the optic nerve sheath. Previous studies have shown a relationship between the intracranial pressure and the optic nerve sheath diameter in patients with brain tumors and increased intracranial pressure due to high altitude.9–11
Enlargement of the SAS of the optic nerve in patients with NTG have also been measured.12 In all these patients, however, the intracranial pressure determined with lumbar puncture was in the normal range and the reason for the distension of optic nerve sheath is unclear. The question therefore is whether NTG patients might have a local elevated pressure confined to the SAS of the affected and compartmentalized optic nerves. This idea seems to conflict with previous data that reported lower intracranial pressure (measured with lumbar puncture) in patients with NTG.13,14 In these series of patients the diameter of the optic nerve sheath was not measured. The reason for this contradiction may be do to the current, but incomplete, understanding of the patency of the CSF pathways and the limitation of the value of lumbar spinal tap.
It is still generally assumed that lumbar pressure represents the intracranial pressure and the pressure in the SAS of the optic nerve as well, i.e. measuring at one point in the CSF system allows for extrapolation to other points. Given the high complexity of the SAS anatomy in the CSF pathways15 as well as the long distance from the lumber spine to the SAS of the optic nerve, it is indeed questionable whether this assumption is true, especially in patients with diseases of the optic nerve sheath, such as compartmentalization. In a small study performed on patients with normal-pressure hydrocephalus, a high correlation of lumbar pressure and parenchymal pressure of the brain was demonstrated.16 The authors concluded that lumbar puncture is an accurate technique to determine the intracranial pressure in patients with communicating CSF systems.16 This assumption, however, might not be true in patients with NTG that demonstrate impaired CSF flow on CT cisternography.
Compartmentalization inhibits free CSF communication due to altered anatomic structures in the SAS of the optic nerve, mainly thickening of the menigothelial cell layer, as shown in patients with glaucoma.17 The mechanism leading to compartmentalization is currently under investigation. Several pathways may be included in this process, such as failure of CSF drainage due to insufficient lymphatic drainage, impaired phagocytosis of menigothelial cells, or thickening of the menigothelial cell layer following low grade inflammatory processes.3,4
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