The Interaction Between Intracranial Pressure, Intraocular Pressure and Lamina Cribrosal Compression in Glaucoma

CLINICAL AND EXPERIMENTAL OPTOMETRY

REVIEW

The interaction between intracranial pressure, intraocular pressure and lamina cribrosal compression in glaucoma

Clin Exp Optom 2016; 99: 219–226 DOI:10.1111/cxo.12333

Charles W McMonnies DSc This review examines some of the biomechanical consequences associated with the opposing School of Optometry and Vision Science, University of intraocular and intracranial forces. These forces compress the lamina cribrosa and are a poten- New South Wales, Kensington, Australia tial source of glaucomatous pathology. A difference between them creates a displacement E-mail: [email protected] force on the lamina cribrosa. Increasing intraocular pressure and/or decreasing intracranial pressure will increase the trans-lamina cribrosa pressure difference and the risk of its posterior displacement, canal expansion and the formation of pathological cupping. Both intraocular pressure and intracranial pressure can be elevated during a Valsalva manoeuvre with associated increases in both anterior and posterior lamina cribrosa loading as well as its compression. Any resulting thinning of or damage to the lamina cribrosa and/or retinal ganglion cell axons and/or astrocyte and glial cells attached to the matrix of the lamina cribrosa and/or reduction in blood ﬂow to the lamina cribrosa may contribute to glaucomatous neuropathy. Thinning of the lamina cribrosa reduces its stiffness and increases the risk of its posterior displacement. Optic nerve head posterior displacement warrants medical or surgical lowering of intraocular pressure; however, compared to intraocular pressure, the trans-lamina cribrosa pressure difference may be more important in pressure-related pathology of the optic nerve head region. Similarly important could be increased compression loading of the lamina cribrosa. Submitted: 15 April 2015 Reducing participation in activities which elevate intraocular and intracranial pressure will Revised: 30 May 2015 decrease lamina cribrosa compression exposure and may contribute to glaucoma management Accepted for publication: 23 June 2015 and may have prognostic signiﬁcance for glaucoma suspects.

Key words: glaucoma, intracranial pressure, intraocular pressure, lamina cribrosa

The glaucomas are multifactorial diseases, increased during a horizontal body position. to glaucomatous pathology rather than al- which result in a progressive loss of retinal It has been suggested that, as an alternative ways being concerned with the absolute ganglion cells (RGCs) and for which the to frequent lumbar punctures, non-invasive values for IOP, cerebrospinal fluid pressure aetiology remains unclear.1 For example, tonometry may be a useful measure for and intracranial pressure. The pattern of neurotrophic factor deprivation, hypoperfu- identifying changes in intracranial pres- axonal abnormality within individual fibre sion or ischaemia, glial cell activation, gluta- sure.10 Notwithstanding a highly significant bundles at the optic nerve head (ONH) mate excitotoxicity and abnormal immune correlation between IOP and intracranial provides support for mechanical compres- response may all contribute to the path- pressure within patients, a significant variabil- sion as a more likely cause of induced neural ogenesis of primary open angle glaucoma ity in the value of this relationship between damage.14 For all finite element models of (POAG).2 A role for adverse biomechanical patients has been demonstrated.11 For glaucoma, the largest strain magnitudes were responses is suggested with elevated intraocu- example, normal IOP was recorded in two found to occur in compression, followed by lar pressure (IOP) being identified as a signif- case series of patients with a diagnosis of shear and then by extension.15 The promi- icant stress factor in the eyes of patients with idiopathic intracranial hypertension.12,13 nence of compressive responses appears, in – glaucoma.3 5 However, the optic nerve is ex- For the purposes of this review and unless part, to be a consequence of IOP and intra- posed to not only IOP but also to intracranial otherwise indicated, any distinction between cranial pressure acting in opposite directions pressure (ICP), as it is surrounded by cerebro- cerebrospinal fluid pressure and intracranial on the lamina cribrosa (LC). It may be possi- spinal fluid in the subarachnoid space.6 The pressure is disregarded and the two terms ble for both IOP and intracranial pressure cerebrospinal fluid pressure (CSFP) is a good are used as specified in the sources cited. to be elevated with associated increased com- surrogate for the retrolaminar tissue intracra- In addition, this discussion is concerned in pression of the lamina cribrosa but without nial pressure,5 which can be a major determi- part with conditions under which changes significant extension and shear responses. nant of the biomechanical significance of in and differences between IOP and intra- Compression of the lamina cribrosa may variations in IOP varies with body position7,8 cranial pressure (the trans-lamina cribrosa damage the retinal ganglion cell axons, astro- as does intracranial pressure,9 with both pressure difference, TLCPD) can be relevant cyte and glial cells attached to the matrix of

the lamina cribrosa as well as result in hypo- lamina cribrosa and suggests an explanation may occur sporadically or routinely from day perfusion or ischaemia, with associated for increasing glaucoma prevalence with to day (Table 18). Significant differences in increased risks of glaucomatous progression. age, which can be exacerbated by associated intracranial pressure between patients with The aim of this review is to examine some of age-related IOP increases.1 glaucoma and non-glaucomatous controls the biomechanical features associated with The trans-lamina cribrosa pressure differ- suggest that fluctuations in the intracranial the trans-lamina cribrosa pressure difference ence is not the same as the trans-lamina pressure and the trans-lamina cribrosa pres- with particular consideration of compression cribrosa pressure gradient (TLCPG) because sure gradient may also be important factors of the lamina cribrosa, damage and thinning, the latter is partly determined by the thick- in the pathogenesis of glaucoma.21 as contributors to glaucomatous pathology. ness of the lamina cribrosa (the trans-lamina Whether lamina cribrosal thinning in ad- PubMed searches for ‘intraocular pressure cribrosa pressure gradient is equal to IOP- vanced glaucoma is cause or effect is unclear and intracranial pressure’ and for ‘lamina ICP divided by the thickness of the lamina but the thinning acts to increase the magni- cribrosal compression’ yielded 320 and 68 cribrosa).24 Risk for glaucoma appears likely tude of the trans-lamina cribrosa pressure publications respectively. A representative to increase in association with an increased gradient.47 For example, it is possible that sample of these and related publications trans-lamina cribrosa pressure gradient reduced thickness of the lamina cribrosa is a were used as the basis for this review accord- resulting from a reduced thickness of the consequence of compressive stress due to ing to their relevance to the biomechanical lamina cribrosa and/or an increased trans- opposing intracranial pressure and IOP characteristics of the lamina cribrosa and lamina cribrosa pressure difference.24 Nor- loading. Consequently, a lamina cribrosa the significance of the forces to which it is mal thickness of the lamina cribrosa is which becomes thinner due to glaucomatous exposed. around 458 μm16 and normal trans-lamina changes might progressively become more cribrosa pressure difference around 5.4 susceptible to IOP-related mechanical dam- 22 TRANS-LAMINA CRIBROSA PRESSURE mmHg, so that the normal trans-lamina age because of increasing compliance and DIFFERENCE AND GRADIENT cribrosa pressure gradient is about 1.0 reduced resistance to IOP and intracranial mmHg per 85 μm of lamina cribrosal thick- pressure due to associated reduced stiffness Intraocular pressure appears to be a misno- ness. The trans-lamina cribrosa pressure of the lamina cribrosa.5 Neither IOP nor mer for what really is a trans-corneal pressure gradient is higher in POAG than in normal cerebrospinal fluid pressure alone and only difference16,17 between atmospheric and in- tension glaucoma.22 The trans-lamina the trans-lamina cribrosa pressure gradient traocular pressures. In a similar fashion to cribrosa pressure gradient increases as the is significantly associated with perimetric the cornea, the lamina cribrosa functions as lamina cribrosa thins in glaucoma, as well loss.48 For example, the lack of glaucomatous a barrier between the posterior force of IOP as when the trans-lamina cribrosa pressure damage in some ocular hypertensive patients and the anterior force of intracranial pres- gradient increases due to an IOP elevation might be explained by higher IOP being sure,1 resulting in the trans-lamina cribrosa and/or a lowering of intracranial pressure.6 associated with elevated intracranial pressure, pressure difference. Sustained elevation of Compared with a normal value of 458 μm,16 so that the trans-lamina cribrosa pressure intracranial pressure can develop with an in- a mean thickness of the lamina cribrosa of gradient is within normal limits.6 In contrast, crease in cerebrospinal fluid formation, an 175 μm found in normal tension glaucoma patients with POAG have been found to have increase in cerebrospinal fluid outflow resis- and 235 μmfoundinPOAG25 would more a mean cerebrospinal fluid pressure, which is tance or an increase in the venous pressure than double the trans-lamina cribrosa pres- 33 per cent lower than healthy controls6 and at the site of cerebrospinal fluid absorption.18 sure gradient in normal tension glaucoma an associated higher trans-lamina cribrosa IOP elevation is a function of similar mecha- and almost double the trans-lamina pressure gradient. nisms.19 Morgan, Yu and Balaratnasingham20 cribrosa pressure gradient in POAG. Thin found that intracranial pressure and IOP corneas are associated with increased risk RESPONSES OF THE LAMINA CRIBROSA have opposite but equivalent effects on the of glaucoma, which may be explained by TO BIOMECHANICAL STRESS trans-lamina cribrosa pressure difference an associated thinner sclera and lamina and lamina cribrosal displacement. There cribrosa.6 Thinning of the lamina cribrosa The key biomechanical effects on the optic are normally significant differences between due to elevated compressive loading could nerve in glaucoma include lateral deforma- intracranial pressure and IOP, which can be facilitate the development and progression tion associated with canal expansion and an- greater in some types of glaucoma21 such as of glaucoma by increasing the trans-lamina terior-posterior deformation (displacement POAG and especially normal tension glau- cribrosa pressure gradient. and/or thinning) of the lamina cribrosa.49 coma (NTG).22 Physiologically IOP is slightly Although multiple factors, such as in- Apart from thinning, compressive stress may higher than intracranial pressure, resulting creased age, ethnicity and family history also also cause tissue damage with axonal trans- in a mean trans-lamina cribrosa pressure dif- contribute to glaucoma risk,21 it is well port being compromised by both acute and ference of around 5.4 mmHg22 and an associ- established that IOP is the main and only chronic IOP elevations.5 Permanent defor- ated physiological posterior displacement modifiable risk factor.22 IOP is modifiable by mation and hypercompliance of the lamina loading of the lamina cribrosa. It has been medical and surgical interventions,26 as well cribrosa can occur following mechanical found that cerebrospinal fluid pressure as by reducing exposure to activities which failure.5 Increased compliance of the lamina declines after 49 years of age and by a mean are known to elevate IOP.8,27 Multiple studies cribrosa may facilitate subsequent strain of 27 per cent for those over age 90.23 This have identified IOP fluctuation as an indepen- responses (such as astrocyte and glial cell acti- age-related change significantly increases the dent risk factor for the progression of glau- vation) with associated disease progression.5 trans-lamina cribrosa pressure difference23 coma21 and apart from diurnal fluctuations, The ease of deformation of the lamina and posterior displacement loading of the activities which also cause IOP fluctuation cribrosa, in response to an applied IOP

Light touch through adnexal skin or lids (e.g. gentle eye wiping) Approximately doubles baseline IOP28 Voluntary squeezing of lids (e.g. squinting) Elevations up to 90 mmHg.29 Eye compression, (e.g. massaging, rubbing, wiping, drying) Up to 400 mmHg.30 Short duration (30 minute) supine positions A mean elevation of 4.4 mmHg.31 The dependent (lower) eye during side sleeping A mean of 2 mmHg above supine IOP.32 Long duration prone sleeping A mean elevation of 40 mmHg.33 Contact between the eye and bedding surfaces A mean of 22 ± 5 mmHg (peak 40 ± 11 mmHg)34 Inverted body position A mean elevation of 36 mmHg.35 Wearing swimming goggles Elevations up to 48 mmHg.36 Astrenuousﬂexed muscle posture involving facial congestion Elevations of 10 to 25 mmHg.37 Playing loud, high pitch notes on a trumpet Elevations up to 44 mmHg.38 Wearing a tight necktie Elevations of 2 to 4 mmHg.39 Coughing or sneezing cause increased IOP,40–43 very high IOP,44,45 Have been associated with, an attack of acute glaucoma.46

Table 1. An indication of the intraocular pressure (IOP) elevation levels which have been recorded during activities known to cause such responses and which may contribute to glaucoma development or progression. (This is a supplemented version of a table8 which is reproduced here with the kind permission of The Spanish General Council of Optometry, Elsevier and the Journal of Optometry). load, will determine the extent to which it associated with eye massaging and rubbing POTENTIALLY IMPORTANT ROLE OF displaces posteriorly or anteriorly and/or is (Table 18); however, a key mechanism for INTRACRANIAL PRESSURE VARIATION compressed according to changes in the many of these elevations is a Valsalva ma- trans-lamina cribrosa pressure gradient.5 A noeuvre (closed glottis) or a quasi-Valsalva Unlike the eye, the brain is enclosed in the reduced trans-lamina cribrosa pressure gra- manoeuvre associated with increased ex- rigid osseous skull and surrounded by non- dient associated with a rise in intracranial piratory effort and elevated intra-thoracic compressible fluid.55 As a consequence, pressure means a lower posterior displace- pressure,40 which raises both intracranial increased intra-thoracic pressure causes an ment loading of the lamina cribrosa but pressure and IOP.8 Apart from increased increase in venous pressure, which is freely an increased compressive loading.47 intra-thoracic pressure, increased expiratory and almost instantly transmitted to the in- A mathematical model was found to pre- effort and associated acutely increased tracranial pressure 55 as a consequence of in- dict greater lamina cribrosal deformation intra-abdominal pressure also causes an increased volume of the choroidal plexuses of and higher shear stress and strain for a thin- crease in both intracranial pressure and the ventricles. IOPs and intracranial pres- ner lamina cribrosa as well as for a lamina IOP due to a functional obstruction of cere- sures are relatively independent pressure sys- cribrosa of larger radius.50 The resilience bral venous outflow via the jugular venous tems, although they are interrelated, with of the lamina cribrosa was found to de- system.52,53 Increased thoracic pressures both responding similarly to changes in crease with age, suggesting an increased caused by normal and abnormal respiration, posture and in response to changes in intra- susceptibility to plastic flow and permanent during exercise for example, frequently alter abdominal and intra-thoracic pressures.22 A deformation.51 The high correlation be- the central venous pressure by 4 to 5 mmHg higher body mass index, which is reportedly tween IOP and intracranial pressure11 ap- anduptoasmuchas20to30mmHg.54 IOP a risk factor for glaucoma, is positively and pears to be at least partly due to their and intracranial pressure are elevated by independently associated with cerebrospinal similar responses to changes in body posi- associated reduced outflow. fluid pressure.23 Abdominal (central) obesity tion and activities involving Valsalva ma- For example, due to the absence of valves in particular increases intra-abdominal pres- noeuvres (VMs). in the venous system, elevated intra-abdomi- sure with a corresponding increase in intracra- nal and intra-thoracic pressures are trans- nial pressure.23 Acute elevation of intracranial mitted to the eye.53 Elevation in venous pressure was associated with a 56 per cent aver- POTENTIALLY IMPORTANT ROLE OF 56 IOP pressure communicates through to the age increase in IOP in rhesus monkeys. choroid and therefore, can increase the Wostyn and colleagues57 hypothesised that, Glaucomatous eyes can undergo pulsatile IOP in two different ways.54 The elevated similar to IOP fluctuations, fluctuations in stretching due to greater ocular pulse ampli- pressure in the orbital veins interferes with intracranial pressure would result in changes tude and larger diurnal variation in IOP.47 outflow of aqueous from the anterior cham- in trans-lamina cribrosa pressure difference In addition to diurnal variations, reviews ber and increases IOP.48 In addition, the and concordant variations in stress in the have indicated a wide range of sporadic elevated pressure can cause venous stasis, retinal ganglion cell axons, ultimately lead- and routine activities which are known to with vascular engorgement and increase in ing to retinal ganglion cell glaucomatous in- elevate IOP.8,27 These activities range from the volume of the choroidal veins.54 As a jury. There is convincing evidence that minor elevations associated with supine consequence of increased choroidal plexus elevated IOP reduces axonal transport at body positions, normal blinking and wearing volume, intraocular fluid is displaced and the lamina cribrosa.6 Displacement or in- a tight necktie, to very large elevations IOP is elevated. creased compression of the lamina cribrosa

due to increases in intracranial pressure and/ trans-lamina cribrosa pressure difference supply to the laminar segments of the or IOP may contribute to this reduction. and greater risk of posterior displacement of axons through deformation of the capillary- The trans-lamina cribrosa pressure differ- the lamina cribrosa, which may be more sig- containing laminar beams. ence increases with IOP elevation and/or nificant if the lamina cribrosa is or becomes Obstructive sleep apnoea syndrome can with intracranial pressure lowering.6 During thinner than normal,19 due to an associated also cause damage to the vascular endothe- a sustained Valsalva manoeuvre, the short- increase in the trans-lamina cribrosa pressure lium through elevated blood pressure and term mean increase in intracranial pressure gradient. sympathetic tone.61 Endothelial dysregula- (10.5 ± 2.7 mmHg) was significantly higher tion can alter blood flow at and around the than the mean short-term increase in IOP VARIATIONS IN OCULAR PERFUSION optic nerve head, potentially lowering ocular 58 fi (1.9 ± 2.4 mmHg). These ndings indicate PRESSURE AT THE OPTIC NERVE HEAD perfusion and increasing the risk of glau- that a Valsalva manoeuvre caused a reversal coma.61 Chronic age-related changes as well of the trans-lamina cribrosa pressure differ- Evidence has accumulated that vascular as IOP-induced changes in the laminar extra- ence, at least in the short term.58 Inward bow- insufficiency at the optic nerve head plays cellular matrix and astrocyte basement mem- ing (anterior displacement) of the lamina an important role in the pathogenesis of branes may diminish nutrient diffusion to the cribrosa during a Valsalva manoeuvre indi- glaucomatous pathology.59 The main blood axons.65 In both normal patients and those cates a reversal of the trans-lamina cribrosa supply to the optic nerve head is from the with glaucoma, IOP tends to peak nocturnally pressure difference and contrasts with out- posterior ciliary artery via the peripapillary in the supine position.61 The mechanical ward bowing observed with increased IOP, choroid and the short posterior ciliary arter- environment in the optic nerve head appears such as in glaucoma or during experimental ies or the circle of Zinn-Haller.60 It is the qual- likely to mediate reductions in blood flow elevation of IOP.58 The reduction or reversal ity of blood flow from these vessels that may with mechanical and vascular mechanisms of the trans-lamina cribrosa pressure differ- be particularly affected, rather than the of glaucomatous injury being inseparably ence appears to be due to the brain being blood flow from the central retinal artery, entwined.66 That glaucoma may progress enclosed in the rigid osseous skull and but there are several other risk factors which despite pharmacological control of IOP, when surrounded by non-compressible fluid 55 so can contribute to oligaemic reduced blood obstructive sleep apnoea syndrome is present that increased venous pressure has a more volume and hypoxic optic nerve head in- but may be found to stabilise, when obstructive immediate influence on intracranial pressure sult.60 At night, blood pressure normally dips sleep apnoea syndrome is treated,66 suggests a compared with a slower influence on IOP. and dipping can be associated with glaucoma role for mechanical strain in glaucomatous Longer Valsalva manoeuvres might eventu- progression, although not always.60 Ocular neuropathy.65 ally result in further elevation of IOP and a perfusion pressure will be reduced by sleep- better correlation between intracranial pres- related IOP elevation and blood pressure COMPRESSION OF THE LAMINA 58 61 fl sure and IOP responses. It appears that, (BP) lowering and may also be in uenced CRIBROSA instead of intracranial pressure and IOP by sleep-related elevation of the intracranial changing equally in tandem, they will change pressure. Insult within the optic nerve head may be, for to different degrees and on different period- Alveolar hypoventilation, which occurs in example, ischaemic, physical compression of icities, which could cause the trans-lamina normal sleeping individuals, is thought to the axons secondary to deformation of the cribrosa pressure difference to fluctuate over be a major mechanism causing arterial oxy- lamina cribrosa or spontaneous axonal com- time, as would the responses to it.57 In addi- gen desaturation,61 which occurs in all sleep pression secondary to tissue pressure differ- tion, the compressive stress on the lamina stages but maximum desaturation usually ences across the intact lamina cribrosa.24 cribrosa can be greatly increased by a occurs during rapid eye movement sleep,62 Mechanical forces such as tension, compres- sustained Valsalva manoeuvre.58 As described which is also the period of most sleep sion, shear stress and associated strains, which earlier, the most important mechanical apnoea episodes.61 About half of all normal are due to the IOP and intracranial pressure, influences loading the lamina cribrosa are tension glaucoma patients and about one- as well as the interaction between them, may compressive forces.15 Even if the trans-lamina third of all primary open-angle glaucoma cause changes in the cells within the lamina cribrosa pressure difference is zero during a patients have obstructive sleep apnoea syn- cribrosa, which contribute to the develop- Valsalva manoeuvre, the lamina cribrosa is drome (OSAS).63 The relationship between ment of glaucomatous optic atrophy.50 The nevertheless exposed to increased compres- nocturnal blood pressure, glaucoma and ob- complex geometry of the laminar trabeculae sive forces due to the increased loading from structive sleep apnoea syndrome is complex has been hypothesised to amplify the levels both directions. and incompletely understood.61 Episodic of strain, so that the cells attached to the Higher intracranial pressure and associ- marked elevations of cerebrospinal fluid matrix of the lamina cribrosa could be sub- ated lower trans-lamina cribrosa pressure pressure measured at the lumbar level in su- jected to stresses, which are several orders of difference in ocular hypertensive patients pine patients were found to occur frequently magnitude larger than those of the larger- may explain why so few of them develop during sleep preceded and accompanied by scale structure.5 For example, hoop or in- glaucomatous pathology.6 However, increased an episode of sleep apnoea or hypopnoea.64 wall circumferential stress dominates lamina compression of the lamina cribrosa associated Episodes of elevated cerebrospinal fluid cribrosa biomechanics.65 It is approximately with higher intracranial pressure might help pressure and/or IOP occurring during sleep 15 times greater than the stress generated by explain why some ocular hypertensives would expose the lamina cribrosa to in- the trans-lamina cribrosa pressure gradient.65 develop neuropathy. Lower intracranial pres- creased compressive forces. Downs, Roberts Nevertheless, collapse of the lamina cribrosa sure in patients with normal tension glau- and Burgoyne65 indicate that mechanical due to compressive loading may contribute coma and POAG is consistent with a higher stress could detrimentally affect blood to reduced blood supply in the optic nerve

head.60 The lack of deformation in the lam- activities included Valsalva manoeuvre-re- inhalation of fluff can also lead to extended ina cribrosa does not mean that the lamina lated activities such as weight lifting, playing paroxysms of coughing,72 which typically in- cribrosa is not strained.65 Quigley and col- high wind-resistance instruments, coughing volve a series of 15 to 20 short coughs of in- leagues67 have shown that damage to axons associated with chronic asthma, straining at creasing intensity, associated with increasing occurred in eyes in which there was signifi- stool associated with constipation, and ob- venous pressure.72 Transient pressures of up cant compression of the lamina cribrosa struction of the urinary system.27 Conditions to 40 kPa (300 mmHg) may occur in the tho- before it was bowed by displacement loading. and participation in activities causing intra- rax, arterial blood and the cerebrospinal Astrocytes in the optic nerve head and abdominal and intra-thoracic pressure eleva- fluid during the act of coughing with large cells in the lamina cribrosa can sense their tion were reported by 45 per cent of normal increases in both intracranial pressure and mechanical environment and respond to tension glaucoma and 11 per cent of POAG IOP.72 Patients with chronic coughing- mechanical stimuli by remodelling the patients.27 Males with normal tension glau- related diseases, who have susceptibility for extracellular matrix in the progression of coma showed the highest frequency for these glaucoma may be at higher risk for glaucoma lamina cribrosal morphology to a cupped, factors.27 As discussed above, these activities onset or progression. Treatment for chronic excavated glaucomatous state.68 In vitro, can be associated with Valsalva manoeuvres cough hypersensitivity with new drugs, such retinal astrocytes have been observed to and quasi-Valsalva manoeuvres and eleva- as theobromine,73 neuromodulating medica- release nitric oxide and glutamate and tions in IOP and intracranial pressure. Glau- tions such as gabapentin or with new behav- undergo cytoskeletal rearrangement after coma suspects reported a great variety of ioural approaches such as speech therapy,74 small deformations resulting from exposure types and prevalence of exposures to IOP could help reduce exposure to cough-related to elevated hydrostatic pressure.50 Cells of elevating activities, which were not greatly dif- IOP and intracranial pressure elevation. the lamina cribrosa in vitro respond to me- ferent from the broad range and prevalence Similarly, respiratory distress syndromes and chanical stimuli by transcription of several of those reported by normal subjects.8 It was prolonged expiratory apnoea are associated extracellular matrix components.69 In stud- suggested that the prognosis for glaucoma with high intra-thoracic and hence intra- ies unrelated to glaucoma, acute strain in suspects might be improved by their avoid- cranial venous and capillary pressure72 as well neurons and neuron-like cells can lead to ance of or reduction in exposures to these as with a high prevalence of glaucoma.75 cellular injury.53 Changes to intracellular sources of IOP and intracranial pressure ele- Rapid cycles of high expiratory effort during Ca2+ functions in response to cell compres- vation. Those activities which elevate both in- vigorous exercise and associated cyclic eleva- sion, can also cause necrosis and apopto- tracranial pressure and IOP will induce tions of IOP and intracranial pressure may sis.70 Although the relationship of glial greater compression of the lamina cribrosa also involve a pumping action aggregation reactivation to neurodegeneration in glau- and risk of mechanical trauma. Fluctuation of IOP and intracranial pressure. coma has not been established, increased in IOP and intracranial pressure with these Episodic marked elevations of cerebrospi- production of some neurotoxic substances activities throughout a 24-hour period nal fluid pressure measured at the lumbar by astrocytes of the optic nerve head has may be significant. Pulsatile and repeated level in supine patients occurred frequently been identified in glaucomatous eyes.71 Af- mechanical loadings have a more dramatic during sleep preceding and/or accompanied ter focal ischaemia or during mechanical effect on cell physiology than steady me- by episodes of sleep apnoea or hypopnea.64 trauma, reactive astrocytes as well as microg- chanical load.57 IOP is also elevated during sleep31 so that lia within the central nervous system pro- lamina cribrosa compression and any duce cytokines, reactive oxygen species and COUGHING AND OTHER associated pathological changes may be ex- nitric oxide, all of which are implicated as INVOLUNTARY ACTIVITIES acerbated during episodic elevations of ce- 71 fl mediators of tissue injury. One theory is ASSOCIATED WITH INTRACRANIAL rebrospinal uid pressure in patients with that elevated IOP induces compression of PRESSURE AND IOP ELEVATION obstructive sleep apnoea syndrome. Un- retinal ganglion cell axons and blockage of treated obstructive sleep apnoea syndrome axoplasmic flow, as well as causing interfer- Increases in IOP and intracranial pressure was associated with an increased hazard of ence in retrograde neurotrophin transport with quasi-Valsalva manoeuvre-related phe- developing non-arteritic ischaemic optic to retinal ganglion cells, which leads to reti- nomena may occur with coughing, sneezing neuropathy and idiopathic intracranial nal ganglion cell death.71 Elevated intracra- or pathological states like asthma or chronic hypertension.76 Treatment of respiratory nial pressure could contribute to similar obstructive pulmonary disease in which acute distress syndromes may improve the progno- outcomes by increasing the compressive or chronic increases in intra-thoracic pres- sis for glaucoma suspects or patients with loading on the lamina cribrosa. sure occur.58 A single ‘ahem’ vocalisation glaucoma. and spontaneous coughing raise intra-thoracic pressure to about 20 mmHg and 100 ACTIVITIES INVOLVING EPISODES OF 40 DISCUSSION IOP AND INTRACRANIAL PRESSURE mmHg, respectively. Following a single ELEVATION cough, about 15 seconds is required to re-es- Adverse biomechanical responses in re- tablish normal vascular pressure.72 If another sponse to elevated IOP and/or intracranial Histories of conditions and participation in cough occurs within 15 seconds, the increases pressure appear to be significant factors in – activities which are known to be associated in venous pressure aggregate so that a parox- the eyes of glaucoma patients.2 4,47,68 The with intra-thoracic and abdominal pressure ysm of coughing and the resulting pumping trans-lamina cribrosa pressure difference elevation and related IOP elevation were action cause very high venous pressure.72 between IOP and intracranial pressure is a recorded for normal tension glaucoma Apart from whooping cough, bronchial/ measure of the tendency for the lamina and POAG patients.27 These conditions and laryngeal infection, milk in the trachea and cribrosa to displace. Posterior displacement

forces can result in non-reversible scleral pathological cupping also appears to be of progression of glaucoma.83 Lee and col- canal expansion and the formation of patho- greater, if the lamina cribrosa becomes more leagues84 found that a thinner lamina logical cupping.68 Apart from IOP elevation, compliant due to mechanical damage which cribrosa and a larger displacement of the the trans-lamina cribrosa pressure difference, occurs in response to non-physiological dis- lamina cribrosa had a significant influence trans-lamina cribrosa pressure gradient and placement and compressive loading. For on the rate of progressive thinning of the risk of pathological cupping can also be example, focal defects of the lamina cribrosa retinal nerve fibre layer. Thinning of the greater, if intracranial pressure is low; and loss of laminar beams detected using lamina cribrosa may not be the only re- however, in the absence of displacement, enhanced depth imaging optical coherence sponse to increased compression. For exam- compressive loading of the lamina cribrosa tomography were found to occur in tandem ple, Faridi and colleagues85 found that focal may also cause pathological changes in and with glaucomatous neuroretinal rim and defects of the lamina cribrosa are strongly to the lamina cribrosa. Even a physiological visual field loss.80 associated with more rapid glaucomatous trans-lamina cribrosa pressure gradient Compressive stress on the lamina cribrosa visual field progression. places the lamina cribrosa under compressive can be greatly increased by Valsalva manoeu- Reducing participation in activities which el- stress due to the opposing IOP and intracra- vres, which have been shown to elevate both evate IOP and/or intracranial pressure may nial pressure compressive loadings. Although IOP and intracranial pressure.58 Pulsatile support glaucoma treatment27 and/or may an elevation of intracranial pressure will and repeated mechanical loading might have help prevent progression to glaucomatous reduce or even reverse the trans-lamina a more dramatic effect on cell physiology pathology in glaucoma suspects.8 The poten- cribrosa pressure difference, there appears than a steady mechanical load.57 The re- tial for pathological significance of par- to be a related increased risk of irreversible sponse of cells to deformation is known to ticipation in IOP and intracranial pressure thinning of the lamina cribrosa and/or dam- be dependent on both the magnitude and elevating activities will depend on the degree, age in response to the increased compressive rate of mechanical strain.57 Consequently, duration and frequency of such elevations, stress associated with the elevation of intracra- fluctuating variations in the trans-lamina the length of the period over which they nial pressure. In addition to the associated re- cribrosa pressure gradient and compressive occur, as well as individual susceptibility to duction in the trans-lamina cribrosa pressure forces loading the lamina cribrosa may develop glaucomatous pathology. Consider- difference and trans-lamina cribrosa pressure increase the risk of non-reversible strain, per- ation of how reducing involvement in IOP gradient, another beneficial consequence of haps especially during activities, which in- and intracranial pressure elevating activities lowered IOP in patients with glaucoma may volve cyclic quasi-Valsalva manoeuvres such could negatively influence health or quality be the resulting reduced compression load- as vigorous aerobic respiration and particu- of life needs to be weighed against the poten- ing of the lamina cribrosa. Similar levels of larly in the case of deeper anaerobic respira- tial for negative influence on quality of life elevation in both intracranial pressure and tion. 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