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Discussion: Future Directions

De Moraes, Carlos Gustavo MD*,†

doi: 10.1097/IJG.0b013e3182934bd6

The previous chapters - and lectures they refer to - provided an update on what is new in the relationship between the brain and glaucoma and yielded information needed to plan future studies capable of translating this knowledge into clinical practice. During the second day of the Think Tank, our panel of scientists spent the time synthesizing and interpreting the material presented, examining new conceptual relationships, developing concepts for future directions and collaborations, discovering new areas for research, and elaborating on experiments that could be performed in the coming years to address unanswered questions and generate translational information. The following topics were merited special focus and a summary of their content is present below.

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Given the strong arguments that the pressure gradient between the prelaminar optic nerve tissue and the subarachnoid CSF space may be more relevant than the ‘estimated’ intraocular pressure (IOP), the development of non-invasive methods to measure intracranial CSF pressure is warranted. Lumbar puncture is unsuitable as a routine procedure, particularly as an office procedure by ophthalmologists, given the risks of discomfort, infection and cerebral herniation. It is also possible that CSF pressure in the lumbar region may differ substantially from that in the subarachnoid space around the orbital portion of the optic nerve. Thus a technique for measurement of CSF pressure at the cranial level would be a valuable addition to our research and clinical armamentarium. Some of the proposed techniques are:

  • Ophthalmodynamometry: since the central retinal venous pressure correlates with the subarachnoid space CSF pressure, the pressure exerted to the eye to cause cessation of venous pulsations seen during ophthalmoscopy could be a surrogate measure of the pressure in that compartiment.1,2 One limitation is the lack of information on venous resistance, how it correlates with the pressure need to cease pulsation, and more importantly, what systemic variables (eg: systemic hypertension, use of medications) can interfere with venous resistance and its correlation with CSF pressure.
  • Magnetic resonance imaging (MRI): recent studies have shown that the cross-sectional width of the optic nerve – including its meningeal sheets - can provide information on the pressure level in the subarachnoid space.3 Some of its disadvantages are cost and the fact that this technique does not provide numeric, objective measurements of CSF pressure, but rather a subjective dichotomized conclusion to be correlated with IOP measurements.
  • Intracranial pressure measurement using tympanic membrane displacement (TMD) and infrasonic emissions: by measuring infrasonic emissions from the tympanic membrane researchers have be able to estimate in vivo and non-invasively whether the intracranial pressure is high or low.4 Low intracranial pressure is associated with an initial high peak followed by peaks with smaller amplitudes whereas elevated intracranial pressure is associated with a significant decrease in the number of peaks and in the amplitude difference between initial and last measured peaks. This method, nevertheless, does not provide objective, numeric measurements of intracranial pressure levels, even though it could potentially be used as a screening tool and for the continuous intracranial pressure monitoring.
  • Transcranial Doppler Ultrasonography (TCD): the basic principle behind TCD is to apply ultrasound to measure the blood flow velocity in the middle cerebral artery and thus the difference between systolic and diastolic flow velocity, divided by the mean flow velocity - named the pulsatility index (PI) – correlates with invasively measured intracranial pressure. However, the correlation coefficients (r) ranged between 0.43 and 0.93 and the technique has better reliability in assessing intracranial pressure values lower than 30 mmHg.5

In any of the methods above, normative databases need to be validated to allow further application into clinical practice and replication of results from different research groups. Moreover, clinicians should be aware of the subjectivity of some of these methods and the fact that they often disregard the compartmentalization of the CSF space, that is, intracranial pressure measurements may not be similar to optic nerve subarachnoid CSF measurements.

One potential application of these techniques would be to measure CSF pressure in patients with normal-tension glaucoma (NTG). For diagnostic and prognostic purposes, all patients with NTG should have their CSF pressure assessed in the same manner, as mean arterial ocular perfusion pressure determination has been increasingly recommended for these patients.

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Similar to the circadian rhythm known to occur with IOP and systemic blood pressure (SBP), CSF pressure varies during the day and between days. A single, snapshot CSF pressure measurement may be insufficient to determine whether a patient with NTG is at risk of progression or even to decide whether increased gradient pressure between the intraocular and orbital portions of optic nerve plays a role in disease onset.

It is very likely that continuous or semi-continuous methods to monitor CSF pressure will be required as an analogy of what has happened with 24-hour IOP monitoring. In that case, clinicians should be instructed on which patients would benefit the most. For instance, if CSF pressure becomes a modifiable risk factor, clinicians will need to evaluate the pressure before and after some type of intervention to confirm treatment effectiveness. Also, nocturnal CSF pressure monitoring to investigate the relationship between SBP dips and IOP elevation and how the CSF fluctuates in response to these other variables may be warranted.

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Even though recent cross-sectional studies revealed an association between low lumbar CSF pressure and glaucoma - particularly NTG –6,7 the causal relationship between CSF pressure and glaucoma has yet to be elucidated.

One potential study would be to select glaucoma patients (in particular NTG patients), perform baseline CSF pressure measurements using one of the modalities described above in combination with SBP measurements, and follow these patients over a long period of time (2-5 years) to investigate whether having a lower CSF pressure at baseline and during multiple visits increases the risk of progressive visual field and/or retinal nerve fiber layer loss. This particular covariate should be tested in a multivariable model along with other known risk factors in glaucoma, such as IOP, translaminar IOP gradient, low SBP, central corneal thickness, baseline level of glaucoma damage, age, and occurrence of disc hemorrhage, for instance. Such a study would provide the first level of evidence to test whether CSF pressure is a modifiable risk factor. As pointed out above, a better understanding of the short- and long-term fluctuation of the CSF pressure in the subarachnoid space, its changes with body position and variation in SBP, are need prior to performing a longitudinal study.

The next experiment, following the same principles of the one described above, would be testing whether CSF pressure elevating interventions can prevent or slow glaucoma progression. Before this can be done, however, experimental studies of safety of potential drugs and how blood flow and pressure may affect the dynamic of CSF need to be substantiated.

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The concept of “compartment syndrome” appears to be one plausible model to explain the relationship between CSF pressure, blood pressure, and IOP. Although there is evidence that CSF pressure increases with elevated SBP, it is still indefinite whether therapies aimed to elevate CSF pressure can lead to decreased arterial perfusion pressure at the optic nerve due to increased resistance from the CSF space. Since the ophthalmic artery and posterior ciliary branches share inherent anatomical relationships with the subarachnoid space, one should cautious when planning to intervene on CSF pressure to treat glaucoma. This could in turn affect the pressure and blood flow to the optic nerve in detrimental ways. Therefore, experimental studies in animal models – preferably primates - should investigate how these three compartments (vascular system, subarachnoid space, and IOP) relate with one another in physiologic states and under stress. In humans, enhanced-depth imaging optical coherence tomography (OCT) can help study how elasticity and thickness of the lamina cribrosa alter the translaminar pressure gradient. By applying this technology in patients with NTG with or without altered CSF pressure, one can come up with a model that is able to estimate this translaminar pressure gradient based on deformations of the posterior laminar surface due to IOP and CSF pressure changes. The results of these types of research may shed light more effective methods to intervene in IOP-independent mechanisms of glaucoma damage.

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Not only the optic nerve but also post-chiasmal structures also undergo structural changes in glaucoma.8–10 MRI can detect changes in the lateral geniculate nucleus (LGN) consistent with anterograde (‘Wallerian’) degeneration of the visual pathways secondary to glaucomatous damage. Even though this finding confirms that glaucoma is another CNS disease, there is still limited application of LGN imaging in clinical practice for glaucoma diagnosis and monitoring. In spite of high-resolution imaging of this intracranial structure, inter-subject variability, imprecision of measurements, and high cost pose as main limitations for its routine use. Moreover, it remains questionable whether changes in LGN structure seen with MRI can be detected prior to changes in the optic nerve and retinal nerve fiber layer in early stages of the disease. Various ocular imaging technologies, such as spectral-domain optical coherence tomography (SDOCT) have long been employed to aid glaucoma diagnosis and monitoring of progression, with well-established databases, precise measurements, and correlations with functional tests. On the other hand, LGN imaging is a potentially key tool for research on neuroprotective therapies, as has been suggested recently in a primate model.11 To enhance the performance and application of this technology in glaucoma research, functional markers that correlate with neuronal activity in the LGN may prove useful when studying effectiveness of therapy and disease progression. More studies in this field are needed to develop specific markers and allow precise measurements to be used in comparative studies.

More recently, two photon laser scanning microscopy (TPLSM) has allowed high-resolution, real-time imaging of the functioning visual cortex,12 which allows a novel insight into the dynamics of neurons and glia in vivo. This technology provides a direct view of ‘dendritic spines’, which are the postsynaptic structures of the majority of excitatory synapses in the CNS. TPLSM has changed the way scientists look at the roles of neurons and glial cells in the visual cortex: while the former are traditionally seen as the mediators of plastic changes in the brain, investigators are now first realizing that glial cells also play important roles in CNS function, disease, and plasticity.13 TPLSM could be used to track changes in cortical visual function in animal models of glaucoma, including better understanding of how glaucoma affects the visual cortex, what and how neuroprotective agents could boost the already existing synapses, including more dendritic ramifications with higher order neurons which could potentially help improve vision.

In particular, studies have shown that vision restoration after brain damage is possible based on the “Residual Vision Activation Theory”. This means that neurons in glaucoma (retinal ganglion cells or neurons in the visual cortex) are not either ‘dead’ or ‘alive’, as some may still be alive but malfunctioning, given numerous hazardous factors (eg: elevated IOP, low ocular and cerebral perfusion pressure). With TPLSM, scientists may be able to objectively image the activity of the visual cortex of glaucoma patients and test whether it is possible to activate residual vision by electrical current stimulation – namely applied repetitive, transorbital, alternating current stimulation (rtACS).14 Based on principles of CNS plasticity which are now better understood with TPLSM, scientists may be able to activate malfunctioning neurons, stimulate increased ramification of dendrites, and possibly magnify the visual field of glaucoma patients.

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The 18th Optic Nerve Rescue and Restoration Think Tank on “The Brain and Glaucoma” brought together a panel with the most prominent researchers in the field of glaucoma, neurology, and neuro-imaging for a high-level discussion on the state-of-the-art and share immediately-applicable knowledge among those who work independently in the different fields. This was a unique opportunity to in fact translate knowledge into new research that will ultimately bring benefit to patients. The main points that still need deeper investigation are:

  • How do CSF pressure, IOP, and ocular perfusion pressure correlate in physiologic and pathologic states?
  • Are we ready to use non-invasive, safe, and precise methods to measure CSF pressure in the orbital subarachnoid space?
  • Is translaminar gradient pressure a modifiable glaucoma risk factor if we are able to safely manipulate CSF pressure?
  • How can we make better use of ocular and brain imaging technologies to study visual function and monitor changes due to glaucoma progression or new forms of neuroprotective therapy?
  • Can retrograde electric stimulation help recover or improve quality of vision?
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© 2013 by Lippincott Williams & Wilkins.