- Email: [email protected]
Does the treatment of normal pressure hydrocephalus put the retinal ganglion cells at risk? A brief literature review and novel hypothesis
Medical Hypotheses 81 (2013) 686–689
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Does the treatment of normal pressure hydrocephalus put the retinal ganglion cells at risk? A brief literature review and novel hypothesis Rakan F. Bokhari, Saleh S. Baeesa ⇑ Division of Neurosurgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
a r t i c l e
i n f o
Article history: Received 12 March 2013 Accepted 12 July 2013
a b s t r a c t Normal pressure hydrocephalus (NPH) is a poorly understood entity as well as a source of continuous controversy in the neuroscientific community. The surgical management of this disease requires that intracranial pressure (ICP), also referred to as the cerebrospinal fluid pressure (CSFP), be lowered using a cerebrospinal fluid (CSF) diversion procedure. Numerous complications are linked with this procedure; we believe that new evidence suggests that the induction or acceleration of glaucomatous optic neuropathy are possible sequelae that warrant further investigation. We also suggest potential solutions derived from the increased understanding of the disease’s pathophysiology and new advances in imaging of the optic nerve head complex. The recent inclusion of the translaminar gradient (TLG) (the difference between the intraocular pressure (IOP) and the ICP/CSFP across the thickness of the lamina cribrosa in the optic nerve head complex) in the pathogenesis of normal tension glaucoma (NTG) suggests that the disease may be a complication encountered during the treatment of NPH with CSF diversion procedures. The significant decrease in CSFP required to treat NPH increases this gradient. In addition, there have been recent observations of an increased prevalence of NTG, as well as other forms of glaucoma, among patients with NPH, thought to be due to inherently fragile neurons in these patients. This new data suggest that patients who undergo ICP lowering therapy for their NPH may be at a higher risk of developing or accelerating already present NTG. We present the clinical and theoretical basis for our hypothesis after reviewing the relevant literature linking the two entities. We also propose a possible solution, as we believe that treatment guidelines for NPH should take the TLG into account. Indeed, recent advances in the imaging of the optic nerve head complex may provide an opportunity to detect the mechanical sequelae of an increased TLG in the preclinical stage, i.e., prior to optic nerve damage. If we are able to determine safe parameters for the TLG in this population, we may be able to recommend the initiation of prophylactic glaucoma therapy for selected patients. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction The role of decreased intracranial pressure (ICP) in the pathogenesis of open angle glaucoma has recently been an area of active research [1]. The lack of a cure for glaucoma or a method that consistently halts its progression indicates that our current understanding of the pathophysiology of this disease is incomplete. As a result, there have been many investigations of possible non-IOP causes of optic nerve damage [2] that may explain the oftentimes observed dissociation between the intraocular pressure (IOP) and disease progression. One attractive target for research is cerebrospinal fluid pressure (CSFP), which offers the advantage of being readily manipulated should the need arise.
⇑ Corresponding author. Address: Division of Neurosurgery, King Abdulaziz University Hospital, PO Box 80215, Jeddah 21589, Saudi Arabia. Tel.: +966 2 6408207, mobile: +966 555690832; fax: +966 2 6408469. E-mail address: [email protected] (S.S. Baeesa). 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.07.027
CSFP is now believed to play a role in glaucoma as a mechanical stressor on the optic nerve head; this is based on anatomic studies that demonstrated the cerebrospinal fluid (CSF)-containing subarachnoid space of the optic nerve to be intimately related to the intra-ocular compartment, being separated mainly by a thin diaphragm of scleral tissue, the lamina cribrosa (LC) [3]. This rigid, mesh-like collagenous barrier contains many pores through which the retinal ganglion cells and retinal vessels are transmitted between the bulbar and retrobulbar compartments. IOP or CSFP changes alter the absolute intercompartmental pressure difference, affecting the extent of the (normally) posteriorly directed pressure differential from the usually higher IOP to the lower ICP. It is this vector of trans-laminar pressure difference that is believed to mechanically deform the LC. When taking the thickness of the LC into account, it is referred to as the translaminar gradient (TLG), with decreased thickness being associated with a higher, more disruptive gradient, and larger TLG values [3]. This mechanical deformation adversely affects the traversing retinal ganglion cells (RGC), and central retinal
R.F. Bokhari, S.S. Baeesa / Medical Hypotheses 81 (2013) 686–689
vessels with resultant shearing and deformation forces causing neuronal dysfunction, ischemia and damage [3]. The inclusion of TLG in the pathogenesis of glaucoma potentially implicates the shunting procedures used to treat NPH as a cause of the observed visual morbidity in this population by possibly inducing or accelerating glaucoma; as they act to steepen the gradient. Our theory does not only have the possibility of impacting the management guidelines for normal pressure hydrocephalus (NPH) but may also provide the foundation for a better understanding of glaucoma and provide us with the opportunity to discover those at risk of progressing to overt disease. If proven to be authentic, this theory may also have implications relevant to all hydrocephalic patients undergoing CSFP lowering treatment. We initially review the pertinent literature linking the two entities then present our theory. Normal pressure hydrocephalus Hydrocephalus refers to ventricular dilation secondary to a rise in CSFP. A particular subset of patients present with symptomatic ventriculomegaly with normal opening pressures during lumbar. Hakim and Adams first described this phenomenon in 1965, and the entity of ‘‘NPH’’ was subsequently introduced to the medical community [4]. NPH has since been the source of constant controversy among medical practitioners, as its diagnosis is seldom clear. There are often other differential diagnoses that co-exist, and the response of NPH to treatment tends to be unpredictable and fraught with complications [5]. Consequently, there has been a continued pursuit of the disease’s pathophysiology with the goal of improving diagnostic accuracy and identifying predictors of responsiveness to therapy. Many theories have attempted to explain the underlying pathophysiology of this disease but no consensus has been reached. One theory relevant to our discussion implies that an inherent neuronal susceptibility to degeneration plays some role in the pathogenesis of NPH. This theory is supported by the observation of familial variants of isolated idiopathic NPH, suggesting at least some role for neurons made intrinsically vulnerable by an abnormal genotype [6]. This may explain the appearance of intolerance to pressures that fall within the normal range. The controversies surrounding this entity are significant, with some calling into question its very existence [7,8]. The argument that is often made is that a single normal CSFP measurement is not sufficient to rule out the presence of intermittently elevated ICP, as studies have shown that normal opening pressures can occur both in patients with normal average CSFP and a clinical diagnosis of NPH, but the latter may show episodic fluctuations outside the normal range [7,8]. Our theory is not rendered obsolete by this paradigm shift in the understanding of NPH, from a disease of normal pressure to that of episodically elevated pressure, especially given the discovery of NPH’s association with other degenerative diseases and its recognised genetic component [6]. Normal tension glaucoma The understanding of the pathophysiology underlying normal tension glaucoma (NTG) is similarly lacking. Although intraocular pressure was originally considered the cornerstone of a glaucoma diagnosis, increased intraocular pressure is now regarded as merely one of the disease’s contributing factors. Its solitary presence does not establish the diagnosis of glaucoma but rather demonstrates the presence of ocular hypertension [9]. In addition, its absence in a patient with typical fundoscopic and visual field changes does not rule out the disease but rather suggests a normal
687
tension variant. Much to the frustration of the ophthalmologist, normalisation of intraocular pressure in patients with increased tension glaucoma does not necessarily arrest disease progression [10]. The recent data suggesting that glaucoma may not be strictly associated with increased IOP have caused a shift in the perception of glaucoma as being a purely pressure-driven optic neuropathy to a perception that it is a multi-factorial disease [2]. Factors proposed to have a role in this pathophysiology include ischemic and vascular insults, degeneration of neurons, accumulation of toxins, and inflammatory and immune aetiologies [2]. These non-IOP related factors are believed to play a prominent role in NTG. However, the effects of IOP in the development of NTG should not be disregarded as it is still considered a treatment target with proven efficacy [11,12]. This has led to the belief that the problem lies partially within the RGC, whose susceptibility to IOP and nonIOP stressors is increased, i.e., NTG may be a neurodegenerative disease [13]. An emerging association between NTG & NPH Because both diseases include a role for abnormally fragile neurons in their pathogenesis, a hypothesis has been made that the presence of degeneration-susceptible neurons in one compartment (the brain) would increase the risk of neuronal degeneration in another (the eye), i.e. patients with NPH are more likely to develop NTG than the general population. A recent study has lent support to this hypothesis [14]. A substantial increase in glaucoma prevalence (including NTG) was found among patients with NPH [14]. Although a similar trend has been also observed in some cohorts with Alzheimer’s disease, which is another degenerative cause of dementia, the association is still controversial, with conflicting results [15,16]. This weaker association between NTG and Alzheimer’s disease may be a reflection of the lack of a role for increased neuronal pressure susceptibility in the pathophysiology of Alzheimer’s disease, despite a shared degenerative aetiology. The interplay between intracranial and intraocular pressures on the optic nerve head Papilledema is a manifestation of both increased ICP and of decreased IOP [17]. This was an early indicator of the interplay between these two compartmental pressures on the optic disc appearance and provides evidence that the gradient between these two compartments may play an equally important role as the absolute pressure values. What would later be hypothesised is a logical consequence of the aforementioned observation: that optic disc changes classically attributed to increased IOP (i.e., optic nerve cupping) may be facilitated by a decreased ICP in addition to the increased IOP [18–21]. Case series have shown that reversal of optic nerve cupping may occur in some glaucoma patients after filtration surgery as their IOP normalises [18]. Recent literature also describes patients with NTG who have also been found to have an ICP that is approximately 33% lower than that of the controls, which further supports the role of ICP in optic nerve cupping [19]. While in those patients with an isolated elevation of their IOP and no optic neuropathy (ocular hypertension), the ICP is found to be significantly higher than in matched controls who go onto develop glaucoma [20]. An antagonistic effect may exist between the IOP and ICP on the progression of the optic neuropathy and that the elevation in one may be attenuated by an elevation in the other. This theory has resulted in the hypothesis that the pressure gradient across these two
688
R.F. Bokhari, S.S. Baeesa / Medical Hypotheses 81 (2013) 686–689
compartments may play a role in the pathogenesis of glaucoma, heralding a new frontier for treatment targets in glaucoma [1,21]. This intercompartmental relationship may also explain the inconsistent association between Alzheimer’s disease and NTG [16]. It has been shown that there is considerable variability in CSFP among patients with Alzheimer’s disease [22], with studies showing that the ICP range in this population is much more variable with values ranging from significantly higher than normal to values that are much lower; the latter being more common. It is this heterogeneity that may cause one cohort to have significantly different TLG from another, with a resultant discrepancy in glaucoma risk. The anatomic basis for this association The rigid LC forms the bottom-most part of the optic cup. It is, therefore, a barrier between the anterior intraocular compartment and the posterior retrolaminar compartment that contains the subarachnoid space (SAS) surrounding the optic nerve as it attaches to the eye globe. The SAS of the optic nerve contains CSF continuous with that of the SAS surrounding the brain and spinal cord. The LC thereby functions to stabilize the intraocular contents (preventing their leakage and maintaining turgor) while supporting and allowing the transmission of the RGC axons and central retinal artery and vein between the compartments through its many pores [3,23]. Its anterior surface is exposed to the IOP, while the posterior surface faces the retrolaminar compartment pressure (of which CSFP is a major contributor) [3]. Alterations in the pressures of either compartment have been observed to result in mechanical deformation of this barrier in the form of bowing, which corresponds to the direction of the pressure gradient across the LC [24,25]. This gradient across the thickness of the LC is referred to as the translaminar gradient (TLG) and is dependent on the difference between IOP and ICP, in addition to the thickness of the LC [21,25], with thinner LC associated with larger TLG values and more severe glaucomatous damage [3,21,25]. The resultant bowing of the LC is thought to contribute to the pressure-induced changes in optic nerve head morphology. This bowing of the lamina may stress the blood vessels that perforate it to supply RGC axons, with resultant ischaemia and neuronal loss evident at the optic nerve head [26]. Ischaemia has a well-established role in glaucoma, thus; the hypothesis appears to be biologically sound [27]. This deformation of the lamina and the resulting change in the structure of the pores that transmit the RGC axons [24] may also result in disruption of axoplasmic flow by direct mechanical deformation, thereby representing another method of TLG-induced cell dysfunction [28]. Can the treatment of NPH cause NTG? Because the pathophysiology of NPH attributes neuronal dysfunction to intolerance for the existing CSFP (normal or otherwise), the treatment of this condition is to decrease the ICP using a CSF diversion procedure that lowers pressures to a more tolerable, less symptomatic level [4,29,30]. This is usually achieved using a programmable, ventriculoperitoneal shunt. The treatment is guided by improvements in patient symptoms, with no safe lower limit identified prior to the occurrence of complications. In fact, lower pressures are advocated despite the common complications of overshunting, which include the formation of slit ventricles and subdural bleeds [29]. With the emerging evidence that NPH patients are at an increased risk of developing NTG and that an increased TLG is important in the pathogenesis of NTG, we believe that shunting procedures may tip the balance towards RGC degeneration or has-
ten its progression in these patients by increasing the TLG. The observed increase in the incidence of NTG and open angle glaucoma may in fact be caused by the shunting surgery itself with its effect on the TLG and not the underlying NPH alone. Suggestive evidence can also be found in a sample of paediatric patients who underwent shunting operations for a variety of indications. In that cohort, a very high prevalence (52%) of visual field deficits was noted [30], with concentric constriction of vision being the most common pattern with no clear causes identified by the authors or in the literature. This leads us to believe that perhaps the TLG exaggeration by CSF shunting may play a role in the development of these deficits compatible with injury of the optic nerve. The effect of shunting may be another reason for the stronger association between glaucoma and NPH, as opposed to that with Alzheimer’s disease, which is a disease without a role for CSFP manipulation in its management.
Possible implications on the management of NPH and future directions in research A possible solution to resolve this dilemma is to measure the patient’s IOP and use it to identify a range of acceptable ICP values that would result in a TLG for which there is limited damage to the optic nerve. This may be achieved by determining what constitutes a safe TLG, a parameter that is not included in the current practice guidelines. Should the case arise where we need to exceed these safe confines, this would provide grounds to initiate prophylactic IOP-lowering therapy with close ophthalmologic follow up. Advanced imaging modalities are now able to visualise and track changes in the configuration of the LC, its attachments and surrounding structures of the optic nerve head [31]. Park et al. [31] describe in great detail visualisation of the LC and perforating vessels. Even newer studies have correlated the morphology of the LC with the observed visual field deficits [32], we may be able to use this technology to develop surrogate markers of impending optic nerve damage, and potential candidates include changes in the configuration of the lamina or optic nerve vessel blood flow and calibre. To date, the literature has not clearly linked variations in bowing of the LC to specific changes in the visual field nor has it described studies that evaluate the effect of blood flow changes in vessels of the optic nerve head. The literature has also yet to establish a timeline between pressure changes, lamina deformation and onset of visual deficits. These limitations in the literature could be addressed by a prospective clinical trial in a cohort of NPH patients that compares visual outcomes and changes in the optic nerve head complex after shunting. Modern programmable valves allow for alterations in valve pressures providing insight into the temporal relationship between known ICP changes and imaging outcomes in vivo, thereby providing a human research model. It is also worth mentioning that we chose to evaluate the effect of shunting on NPH patients because of the theoretic susceptibility of their RGC, making even relatively small increases in the TLG clinically significant. Should our hypothesis be proven, the next step would be to implement this study in patients undergoing shunting for other indications, as they are also susceptible to RGC damage, although at a theoretically higher gradient given the presence of neurons not deemed at higher risk of degenerating.
Conflicts of interest statement None.
R.F. Bokhari, S.S. Baeesa / Medical Hypotheses 81 (2013) 686–689
Acknowledgement The authors would like to thank Dr. Omar Ayoub (Department of Medicine) and Dr. Ahmed Bawazeer (Department of Ophthalmology) for their valuable input and review of the manuscript. References [1] Berdahl JP, Allingham RR. Intracranial pressure and glaucoma. Curr Opin Ophthalmol 2010;21:106–11. [2] Vasudevan SK, Gupta V, Crowston JG. Neuroprotection in glaucoma. Indian J Ophthalmol 2011;59(Suppl):S102–13. [3] Jonas JB. Role of cerebrospinal fluid pressure in the pathogenesis of glaucoma. Acta Ophthalmol 2011;89:505–14. [4] Adams RD, Fisher CM, Hakim S, Ojemann RG, Sweet WH. Symptomatic occult hydrocephalus with ‘‘normal’’ cerebrospinal-fluid pressure. A treatable syndrome. N Engl J Med 1965;273:117–26. [5] Krauss JK, Halve B. Normal pressure hydrocephalus: survey on contemporary diagnostic algorithms and therapeutic decision-making in clinical practice. Acta Neurochir (Wien) 2004;146:379–88. [6] Takahashi Y, Kawanami T, Nagasawa H, Iseki C, Hanyu H, Kato T. Familial normal pressure hydrocephalus (NPH) with an autosomal-dominant inheritance: a novel subgroup of NPH. J Neurol Sci 2011;308(1–2):149–51. [7] Dunn L. ‘Normal pressure hydrocephalus’: what’s in a name? J Neurol Neurosurg Psychiatry 2002;73:8. [8] Klassen BT, Ahlskog JE. Normal pressure hydrocephalus: how often does the diagnosis hold water? Neurology 2011;77(12):1119–25. [9] Gordon MO, Beiser JA, Brandt JD, et al. The ocular hypertension treatment study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120:714–20. [10] Parrish 2nd RK, Feuer WJ, Schiffman JC, Lichter PR, Musch DC. Five-year follow-up optic disc findings of the collaborative initial glaucoma treatment study. Am J Ophthalmol 2009;147:717–24. [11] CNTGS group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Collaborative normal-tension glaucoma study group. Am J Ophthalmol 1998;126:498–505. [12] Anderson DR, Drance SM, Schulzer M, Collaborative Normal-Tension Glaucoma Study Group. Factors that predict the benefit of lowering intraocular pressure in normal tension glaucoma. Am J Ophthalmol 2003;136:820–9. [13] Gupta N, Yucel YH. Glaucoma as a neurodegenerative disease. Curr Opin Ophthalmol 2007;18:110–4. [14] Chang TC, Singh K. Glaucomatous disease in patients with normal pressure hydrocephalus. J Glaucoma 2009;18(3):243–6. [15] Kessing LV, Lopez AG, Andersen PK, Kessing SV. No increased risk of developing Alzheimer disease in patients with glaucoma. J Glaucoma 2007;16(1):47–51.
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[16] Tsolaki F, Gogaki E, Tiganita S, et al. Alzheimer’s disease and primary openangle glaucoma: is there a connection? Clin Ophthalmol 2011;5:887–90. [17] Dellaporta A. Creasing of retina in hypotonia. Klin Monbl Augenheilkd Augenarztl Fortbild 1954;125(6):672–8. [18] Levy NS, Crapps EE. Displacement of optic nerve head in response to shortterm intraocular pressure elevation in human eyes. Arch Ophthalmol 1984;102(5):782–6. [19] Berdahl JP, Allingham RR, Johnson DH. Cerebrospinal fluid pressure is decreased in primary open-angle glaucoma. Ophthalmology 2008;115:763–8. [20] Berdahl JP, Fautsch MP, Stinnett SS, Allingham RR. Intracranial pressure in primary open angle glaucoma, normal tension glaucoma, and ocular hypertension: a case-control study. Invest Ophthalmol Vis Sci 2008;49(12):5412–8. [21] Morgan WH, Yu DY, Balaratnasingam C. The role of cerebrospinal fluid pressure in glaucoma pathophysiology: the dark side of the optic disc. J Glaucoma 2008;17(5):408–13. [22] Silverberg G, Mayo M, Saul T, Fellmann J, McGuire D. Elevated cerebrospinal fluid pressure in patients with Alzheimer’s disease. Cerebrospinal Fluid Res 2006;3:7. [23] Jonas JB, Berenshtein E, Holbach L. Anatomic relationship between lamina cribrosa, intraocular space, and cerebrospinal fluid space. Invest Ophthalmol Vis Sci 2003;44:5189–95. [24] Burgoyne CF, Downs JC, Bellezza AJ, Suh JK, Hart RT. The optic nerve head as a biomechanical structure: a new paradigm for understanding the role of IOPrelated stress and strain in the pathophysiology of glaucomatous optic nerve head damage. Prog Retin Eye Res 2005;24:39–73. [25] Morgan WH, Chauhan BC, Yu DY, Cringle SJ, Alder VA, House PH. Optic disc movement with variations in intraocular and cerebrospinal fluid pressure. Invest Ophthalmol Vis Sci 2002;43:3236–42. [26] Downs JC, Roberts MD, Burgoyne CF. Mechanical environment of the optic nerve head in glaucoma. Optom Vis Sci 2008;85(6):425–35. [27] Yanagi M, Kawasaki R, Wang JJ, Wong TY, Crowston J, Kiuchi Y. Vascular risk factors in glaucoma: a review. Clin Exp Ophthalmol 2011;39(3):252–8. [28] Quigley HA, Anderson DR. Distribution of axonal transport blockade by acute intraocular pressure elevation in the primate optic nerve head. Invest Ophthalmol Vis Sci 1977;16:640–4. [29] Boon AJ, Tans JT, Delwel EJ, et al. Dutch normal-pressure hydrocephalus study: randomized comparison of low- and medium-pressure shunts. J Neurosurg 1998;88(3):490–5. [30] Rudolph D, Sterker I, Graefe G, Till H, Ulrich A, Geyer C. Visual field constriction in children with shunt-treated hydrocephalus. J Neurosurg Pediatr 2010;6(5):481–5. [31] Park SC, De Moraes CG, Teng CC, Tello C, Liebmann JM, Ritch R. Enhanced depth imaging optical coherence tomography of deep optic nerve complex structures in glaucoma. Ophthalmology 2012;119(1):3–9. [32] Kiumehr S, Park SC, Syril D, Teng CC, Tello C, Liebmann JM, et al. In vivo evaluation of focal lamina cribrosa defects in glaucoma. Arch Ophthalmol 2012;130(5):552–9.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Does the treatment of normal pressure hydrocephalus put the retinal ganglion cells at risk? A brief literature review and novel hypothesis Rakan F. Bokhari, Saleh S. Baeesa ⇑ Division of Neurosurgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
a r t i c l e
i n f o
Article history: Received 12 March 2013 Accepted 12 July 2013
a b s t r a c t Normal pressure hydrocephalus (NPH) is a poorly understood entity as well as a source of continuous controversy in the neuroscientific community. The surgical management of this disease requires that intracranial pressure (ICP), also referred to as the cerebrospinal fluid pressure (CSFP), be lowered using a cerebrospinal fluid (CSF) diversion procedure. Numerous complications are linked with this procedure; we believe that new evidence suggests that the induction or acceleration of glaucomatous optic neuropathy are possible sequelae that warrant further investigation. We also suggest potential solutions derived from the increased understanding of the disease’s pathophysiology and new advances in imaging of the optic nerve head complex. The recent inclusion of the translaminar gradient (TLG) (the difference between the intraocular pressure (IOP) and the ICP/CSFP across the thickness of the lamina cribrosa in the optic nerve head complex) in the pathogenesis of normal tension glaucoma (NTG) suggests that the disease may be a complication encountered during the treatment of NPH with CSF diversion procedures. The significant decrease in CSFP required to treat NPH increases this gradient. In addition, there have been recent observations of an increased prevalence of NTG, as well as other forms of glaucoma, among patients with NPH, thought to be due to inherently fragile neurons in these patients. This new data suggest that patients who undergo ICP lowering therapy for their NPH may be at a higher risk of developing or accelerating already present NTG. We present the clinical and theoretical basis for our hypothesis after reviewing the relevant literature linking the two entities. We also propose a possible solution, as we believe that treatment guidelines for NPH should take the TLG into account. Indeed, recent advances in the imaging of the optic nerve head complex may provide an opportunity to detect the mechanical sequelae of an increased TLG in the preclinical stage, i.e., prior to optic nerve damage. If we are able to determine safe parameters for the TLG in this population, we may be able to recommend the initiation of prophylactic glaucoma therapy for selected patients. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction The role of decreased intracranial pressure (ICP) in the pathogenesis of open angle glaucoma has recently been an area of active research [1]. The lack of a cure for glaucoma or a method that consistently halts its progression indicates that our current understanding of the pathophysiology of this disease is incomplete. As a result, there have been many investigations of possible non-IOP causes of optic nerve damage [2] that may explain the oftentimes observed dissociation between the intraocular pressure (IOP) and disease progression. One attractive target for research is cerebrospinal fluid pressure (CSFP), which offers the advantage of being readily manipulated should the need arise.
⇑ Corresponding author. Address: Division of Neurosurgery, King Abdulaziz University Hospital, PO Box 80215, Jeddah 21589, Saudi Arabia. Tel.: +966 2 6408207, mobile: +966 555690832; fax: +966 2 6408469. E-mail address: [email protected] (S.S. Baeesa). 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.07.027
CSFP is now believed to play a role in glaucoma as a mechanical stressor on the optic nerve head; this is based on anatomic studies that demonstrated the cerebrospinal fluid (CSF)-containing subarachnoid space of the optic nerve to be intimately related to the intra-ocular compartment, being separated mainly by a thin diaphragm of scleral tissue, the lamina cribrosa (LC) [3]. This rigid, mesh-like collagenous barrier contains many pores through which the retinal ganglion cells and retinal vessels are transmitted between the bulbar and retrobulbar compartments. IOP or CSFP changes alter the absolute intercompartmental pressure difference, affecting the extent of the (normally) posteriorly directed pressure differential from the usually higher IOP to the lower ICP. It is this vector of trans-laminar pressure difference that is believed to mechanically deform the LC. When taking the thickness of the LC into account, it is referred to as the translaminar gradient (TLG), with decreased thickness being associated with a higher, more disruptive gradient, and larger TLG values [3]. This mechanical deformation adversely affects the traversing retinal ganglion cells (RGC), and central retinal
R.F. Bokhari, S.S. Baeesa / Medical Hypotheses 81 (2013) 686–689
vessels with resultant shearing and deformation forces causing neuronal dysfunction, ischemia and damage [3]. The inclusion of TLG in the pathogenesis of glaucoma potentially implicates the shunting procedures used to treat NPH as a cause of the observed visual morbidity in this population by possibly inducing or accelerating glaucoma; as they act to steepen the gradient. Our theory does not only have the possibility of impacting the management guidelines for normal pressure hydrocephalus (NPH) but may also provide the foundation for a better understanding of glaucoma and provide us with the opportunity to discover those at risk of progressing to overt disease. If proven to be authentic, this theory may also have implications relevant to all hydrocephalic patients undergoing CSFP lowering treatment. We initially review the pertinent literature linking the two entities then present our theory. Normal pressure hydrocephalus Hydrocephalus refers to ventricular dilation secondary to a rise in CSFP. A particular subset of patients present with symptomatic ventriculomegaly with normal opening pressures during lumbar. Hakim and Adams first described this phenomenon in 1965, and the entity of ‘‘NPH’’ was subsequently introduced to the medical community [4]. NPH has since been the source of constant controversy among medical practitioners, as its diagnosis is seldom clear. There are often other differential diagnoses that co-exist, and the response of NPH to treatment tends to be unpredictable and fraught with complications [5]. Consequently, there has been a continued pursuit of the disease’s pathophysiology with the goal of improving diagnostic accuracy and identifying predictors of responsiveness to therapy. Many theories have attempted to explain the underlying pathophysiology of this disease but no consensus has been reached. One theory relevant to our discussion implies that an inherent neuronal susceptibility to degeneration plays some role in the pathogenesis of NPH. This theory is supported by the observation of familial variants of isolated idiopathic NPH, suggesting at least some role for neurons made intrinsically vulnerable by an abnormal genotype [6]. This may explain the appearance of intolerance to pressures that fall within the normal range. The controversies surrounding this entity are significant, with some calling into question its very existence [7,8]. The argument that is often made is that a single normal CSFP measurement is not sufficient to rule out the presence of intermittently elevated ICP, as studies have shown that normal opening pressures can occur both in patients with normal average CSFP and a clinical diagnosis of NPH, but the latter may show episodic fluctuations outside the normal range [7,8]. Our theory is not rendered obsolete by this paradigm shift in the understanding of NPH, from a disease of normal pressure to that of episodically elevated pressure, especially given the discovery of NPH’s association with other degenerative diseases and its recognised genetic component [6]. Normal tension glaucoma The understanding of the pathophysiology underlying normal tension glaucoma (NTG) is similarly lacking. Although intraocular pressure was originally considered the cornerstone of a glaucoma diagnosis, increased intraocular pressure is now regarded as merely one of the disease’s contributing factors. Its solitary presence does not establish the diagnosis of glaucoma but rather demonstrates the presence of ocular hypertension [9]. In addition, its absence in a patient with typical fundoscopic and visual field changes does not rule out the disease but rather suggests a normal
687
tension variant. Much to the frustration of the ophthalmologist, normalisation of intraocular pressure in patients with increased tension glaucoma does not necessarily arrest disease progression [10]. The recent data suggesting that glaucoma may not be strictly associated with increased IOP have caused a shift in the perception of glaucoma as being a purely pressure-driven optic neuropathy to a perception that it is a multi-factorial disease [2]. Factors proposed to have a role in this pathophysiology include ischemic and vascular insults, degeneration of neurons, accumulation of toxins, and inflammatory and immune aetiologies [2]. These non-IOP related factors are believed to play a prominent role in NTG. However, the effects of IOP in the development of NTG should not be disregarded as it is still considered a treatment target with proven efficacy [11,12]. This has led to the belief that the problem lies partially within the RGC, whose susceptibility to IOP and nonIOP stressors is increased, i.e., NTG may be a neurodegenerative disease [13]. An emerging association between NTG & NPH Because both diseases include a role for abnormally fragile neurons in their pathogenesis, a hypothesis has been made that the presence of degeneration-susceptible neurons in one compartment (the brain) would increase the risk of neuronal degeneration in another (the eye), i.e. patients with NPH are more likely to develop NTG than the general population. A recent study has lent support to this hypothesis [14]. A substantial increase in glaucoma prevalence (including NTG) was found among patients with NPH [14]. Although a similar trend has been also observed in some cohorts with Alzheimer’s disease, which is another degenerative cause of dementia, the association is still controversial, with conflicting results [15,16]. This weaker association between NTG and Alzheimer’s disease may be a reflection of the lack of a role for increased neuronal pressure susceptibility in the pathophysiology of Alzheimer’s disease, despite a shared degenerative aetiology. The interplay between intracranial and intraocular pressures on the optic nerve head Papilledema is a manifestation of both increased ICP and of decreased IOP [17]. This was an early indicator of the interplay between these two compartmental pressures on the optic disc appearance and provides evidence that the gradient between these two compartments may play an equally important role as the absolute pressure values. What would later be hypothesised is a logical consequence of the aforementioned observation: that optic disc changes classically attributed to increased IOP (i.e., optic nerve cupping) may be facilitated by a decreased ICP in addition to the increased IOP [18–21]. Case series have shown that reversal of optic nerve cupping may occur in some glaucoma patients after filtration surgery as their IOP normalises [18]. Recent literature also describes patients with NTG who have also been found to have an ICP that is approximately 33% lower than that of the controls, which further supports the role of ICP in optic nerve cupping [19]. While in those patients with an isolated elevation of their IOP and no optic neuropathy (ocular hypertension), the ICP is found to be significantly higher than in matched controls who go onto develop glaucoma [20]. An antagonistic effect may exist between the IOP and ICP on the progression of the optic neuropathy and that the elevation in one may be attenuated by an elevation in the other. This theory has resulted in the hypothesis that the pressure gradient across these two
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R.F. Bokhari, S.S. Baeesa / Medical Hypotheses 81 (2013) 686–689
compartments may play a role in the pathogenesis of glaucoma, heralding a new frontier for treatment targets in glaucoma [1,21]. This intercompartmental relationship may also explain the inconsistent association between Alzheimer’s disease and NTG [16]. It has been shown that there is considerable variability in CSFP among patients with Alzheimer’s disease [22], with studies showing that the ICP range in this population is much more variable with values ranging from significantly higher than normal to values that are much lower; the latter being more common. It is this heterogeneity that may cause one cohort to have significantly different TLG from another, with a resultant discrepancy in glaucoma risk. The anatomic basis for this association The rigid LC forms the bottom-most part of the optic cup. It is, therefore, a barrier between the anterior intraocular compartment and the posterior retrolaminar compartment that contains the subarachnoid space (SAS) surrounding the optic nerve as it attaches to the eye globe. The SAS of the optic nerve contains CSF continuous with that of the SAS surrounding the brain and spinal cord. The LC thereby functions to stabilize the intraocular contents (preventing their leakage and maintaining turgor) while supporting and allowing the transmission of the RGC axons and central retinal artery and vein between the compartments through its many pores [3,23]. Its anterior surface is exposed to the IOP, while the posterior surface faces the retrolaminar compartment pressure (of which CSFP is a major contributor) [3]. Alterations in the pressures of either compartment have been observed to result in mechanical deformation of this barrier in the form of bowing, which corresponds to the direction of the pressure gradient across the LC [24,25]. This gradient across the thickness of the LC is referred to as the translaminar gradient (TLG) and is dependent on the difference between IOP and ICP, in addition to the thickness of the LC [21,25], with thinner LC associated with larger TLG values and more severe glaucomatous damage [3,21,25]. The resultant bowing of the LC is thought to contribute to the pressure-induced changes in optic nerve head morphology. This bowing of the lamina may stress the blood vessels that perforate it to supply RGC axons, with resultant ischaemia and neuronal loss evident at the optic nerve head [26]. Ischaemia has a well-established role in glaucoma, thus; the hypothesis appears to be biologically sound [27]. This deformation of the lamina and the resulting change in the structure of the pores that transmit the RGC axons [24] may also result in disruption of axoplasmic flow by direct mechanical deformation, thereby representing another method of TLG-induced cell dysfunction [28]. Can the treatment of NPH cause NTG? Because the pathophysiology of NPH attributes neuronal dysfunction to intolerance for the existing CSFP (normal or otherwise), the treatment of this condition is to decrease the ICP using a CSF diversion procedure that lowers pressures to a more tolerable, less symptomatic level [4,29,30]. This is usually achieved using a programmable, ventriculoperitoneal shunt. The treatment is guided by improvements in patient symptoms, with no safe lower limit identified prior to the occurrence of complications. In fact, lower pressures are advocated despite the common complications of overshunting, which include the formation of slit ventricles and subdural bleeds [29]. With the emerging evidence that NPH patients are at an increased risk of developing NTG and that an increased TLG is important in the pathogenesis of NTG, we believe that shunting procedures may tip the balance towards RGC degeneration or has-
ten its progression in these patients by increasing the TLG. The observed increase in the incidence of NTG and open angle glaucoma may in fact be caused by the shunting surgery itself with its effect on the TLG and not the underlying NPH alone. Suggestive evidence can also be found in a sample of paediatric patients who underwent shunting operations for a variety of indications. In that cohort, a very high prevalence (52%) of visual field deficits was noted [30], with concentric constriction of vision being the most common pattern with no clear causes identified by the authors or in the literature. This leads us to believe that perhaps the TLG exaggeration by CSF shunting may play a role in the development of these deficits compatible with injury of the optic nerve. The effect of shunting may be another reason for the stronger association between glaucoma and NPH, as opposed to that with Alzheimer’s disease, which is a disease without a role for CSFP manipulation in its management.
Possible implications on the management of NPH and future directions in research A possible solution to resolve this dilemma is to measure the patient’s IOP and use it to identify a range of acceptable ICP values that would result in a TLG for which there is limited damage to the optic nerve. This may be achieved by determining what constitutes a safe TLG, a parameter that is not included in the current practice guidelines. Should the case arise where we need to exceed these safe confines, this would provide grounds to initiate prophylactic IOP-lowering therapy with close ophthalmologic follow up. Advanced imaging modalities are now able to visualise and track changes in the configuration of the LC, its attachments and surrounding structures of the optic nerve head [31]. Park et al. [31] describe in great detail visualisation of the LC and perforating vessels. Even newer studies have correlated the morphology of the LC with the observed visual field deficits [32], we may be able to use this technology to develop surrogate markers of impending optic nerve damage, and potential candidates include changes in the configuration of the lamina or optic nerve vessel blood flow and calibre. To date, the literature has not clearly linked variations in bowing of the LC to specific changes in the visual field nor has it described studies that evaluate the effect of blood flow changes in vessels of the optic nerve head. The literature has also yet to establish a timeline between pressure changes, lamina deformation and onset of visual deficits. These limitations in the literature could be addressed by a prospective clinical trial in a cohort of NPH patients that compares visual outcomes and changes in the optic nerve head complex after shunting. Modern programmable valves allow for alterations in valve pressures providing insight into the temporal relationship between known ICP changes and imaging outcomes in vivo, thereby providing a human research model. It is also worth mentioning that we chose to evaluate the effect of shunting on NPH patients because of the theoretic susceptibility of their RGC, making even relatively small increases in the TLG clinically significant. Should our hypothesis be proven, the next step would be to implement this study in patients undergoing shunting for other indications, as they are also susceptible to RGC damage, although at a theoretically higher gradient given the presence of neurons not deemed at higher risk of degenerating.
Conflicts of interest statement None.
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