Introduction and aims
The of primary open-angle glaucoma (POAG) are still unclear. The recent discovery of a lymphatic system in the brain and eye (1–5), called the glymphatic system, appears to shed new light on the etiopathogenic causes of this disease, bringing together various different hypotheses: vascular, biomechanical, and biochemical (6).
Intraocular pressure (IOP) is the principal risk factor for glaucoma and the main factor that can be rectified by therapy (7). According to Flammer (8, 9), vascular dysregulation is in reality a rectifiable factor, but one which is difficult to identify on the spot.
In normal-tension glaucoma (NTG), damage to the visual field occurs while damage to the visual field may be absent in cases of high ocular pressure (10). In patients with NTG, the cerebrospinal fluid (CSF) pressure, which is equivalent to the intracranial pressure, appears to be lower (10–13), while in patients with high IOP who present no functional damage, the CSF pressure is higher (14, 15). Other studies substantiate the preceding hypotheses explaining how the influence of translaminar pressure has a determining role in POAG (16–18). Conversely, a retrospective study of CSF pressure in NTG puts the preceding hypotheses in doubt, suggesting changes in the investigative methodology, with the aim of proving the validity of the new theories concerning translaminar pressure (19).
Recent systematic studies have shown that blood flow may be lower in other parts of the body and that this reduction in blood flow to the eye is a precursor to glaucomatous damage. This presupposes that hemodynamic changes can be, at least in part, a primary factor in patients with glaucoma (8, 9). This further explains the effect of osteopathic manipulative treatment (OMT) in areas, such as cervical-cranial, aiming at an overall improvement in lymphatic drainage and vascular perfusion inside the cranium (20–26).
In the osteopathy literature, it is found that several techniques have been proposed for the eyes and orbital areas and demonstrated the influence of OMT on IOP (27–35).
The aim of this work is to identify the effect and duration of osteopathic treatment on ocular pressure, in patients with POAG, who were stable and under medication.
Materials and methods
In this study, 40 patients (80 eyes), all of the Caucasian descent, were examined for 13 months. The patients were randomized into two groups: TG and CG (20 per group), with Excel 2010. As glaucomatous disease often strikes where the damage and progression do not manifest symmetrically, we chose to evaluate the effect of OMT on both eyes to determine the effect of OMT in either of the eyes.
The average mean age of patients was 71.2 years (range 34–83), all diagnosed with stable and medicated POAG. Patients with increased eye pressure, reduction in the visual field or visual acuity, undergoing topical treatment temporarily, or those requiring an anti-glaucoma operation or extraction of a cataract were excluded from this study.
The average age of the patients in TG was 70.5 years (range 34–87), while that in CG was 71.8 years (range 51–95).
In the TG patients, the average defect (AD) was −5.55 dB in the right eye (RE) and −7.06 dB in the left eye (LE), while in the CG patients, the AD was −6.51 dB in RE and −4.65 dB in LE.
The inclusion and exclusion criteria are given in Table 1.
Table 1. Inclusion and exclusion criteria.
Every patient had a preceding follow-up of a minimum of 3 years and a maximum of 10, with at least three visual field tests, at least one for each year. Four osteopathic treatments were performed at regular intervals for all patients, from 1 week to 5 months (see Table 2). The CG was checked at the same interval to measure the ocular pressure.
Table 2. Methods and timescales for the osteopathic treatment and tonometry testing.
Informed consent was obtained for all patients, as set out in the Helsinki Declaration. Every member of the TG provided a detailed personal medical history and underwent a general health check to exclude local or general pathologies that could falsify or compromise the OMT (following the inclusion and exclusion criteria). From the second examination onward, they completed a quality survey questionnaire in order to suspend the OMT in case of the appearance of eventual side effects due to the treatment (Table 3) (36).
Table 3. Questionnaire on the appreciation of the treatment.
In the TG, the ocular pressure was measured immediately before and after the OMT to detect any variation. Ocular pressure was measured for all 40 patients in a seated position, using a Goldmann pressure apparatus. Ocular pressure was measured in the CG (one single measurement) with no osteopathic treatment, at the same interval as the TG patients.
The visual field test was carried out with a Humphrey apparatus, program 30\2, threshold test, not earlier than 3 months from the beginning of the study and not later than 3 months from the end.
The OMT was not directed exclusively at the cranial-cervical area; rather it had the aim of favoring the systemic and local circulation and of acting on the somatic dysfunction (SD). SD is defined as an expression of a compromised or altered function of somatic structures – skeletal, arthrodial, and myofascial structures – and their related vascular, lymphatic, and neural components. It is considered a principal reversible and functional factor that influences homeostasis and can be the cause of many pathologies even in areas well away from where the dysfunction is located and whose normalization is considered essential to restore normal mobility and functioning of the entire somatic system (body).
Somatic dysfunction is identified through palpation of various structures where the compromised functionality of the tissues has its origin. Connective tissue alterations bring about an individual reaction manifested in changes in T.A.R.T. – the texture of the tissue (T), structural asymmetry (A), restricted motion (R), and tenderness (T) (37).
The OMT process is divided into four phases:
• Recording of patients’ medical history
• Osteopathic examination
• OMT
• Exit test
Patients’ medical history
Patients are invited to sit at a desk where their personal medical history is recorded. Furthermore, a carefully cataloged record is made of any eventual pain, previous health conditions, previous operations, any serious accidents, current medication regimes, and any irregular bodily function parameters regarding fatigue, sleep patterns, digestion, bowel movement, and urination (38).
Osteopathic examination
The patients in the TG underwent the following osteopathic examinations for the initial evaluation (entry test) and after the OMT (exit test).
Diaphragm mobility test
All the patients underwent the diaphragm breathing test to determine any breathing imbalances in the diaphragm movement or any mechanical restrictions which could influence the correct exchange of the fluids (blood and lymph) (39, 40) or the circulation of the CSF (41). The tests were carried out by palpation and manual examination of the following musculoskeletal structures: rib margins, costoxifoid angle, sternum, ribs, and clavicles. A manual examination of thoracic expansion was also performed to determine the range of diaphragm breathing movement (38).
Spinal column and ribcage mobility test
These tests are carried out with the patient seated and prone and are used to identify the SD. Any eventual SD detected in the spinal column or the ribcage was identified by mobilization and palpation of the vertebral segments (38).
Abdominal palpation
Abdominal palpation is carried out to identify any eventual correspondence between the autonomous nervous system, a dysfunctional vertebral tract known as a “facilitated segment” and the viscera that are innervated from this region. A facilitated segment is diagnosed using the T.A.R.T. model and by vertebral mobilization, which shows a regular and rhythmic lateral inclination of the vertebral transverse processes, on the side of the body where the organ is located (38, 42, 43).
Craniosacral test
These tests are carried out with the patient in the supine position and are aimed at evaluating the craniosacral system and any eventual alterations in the expression of this movement. The approach to the cranium was analogous to the evaluation of the other areas of the body, such as testing the mobility and asymmetry of the cranial and sacral bones.
By means of palpation, the tension vector is identified and traced to its origin, distinguishing the skin, fascial tissue, bone, and pachymeninges (dura mater) layers.
In one of these layers, the origin of the tension vector can be found, at which point the evaluation of the SD through the mobility of the revealed structure can proceed (38, 42).
Once the SD is identified on the three levels – musculoskeletal, visceral, or craniosacral – the OMT begins. The treatment carried out at every session did not represent a series of previously chosen techniques, but it was based exclusively on the clinical evidence gathered in the initial tests by means of osteopathic palpation. This practice is known as “blackbox” (44). At the end of the treatment, exit tests were performed (equivalent to the entry tests), particularly in the area where any eventual SD was discovered. On average, the osteopathic manipulation lasted for 50 min and was carried out with patients either lying on their sides or in supine or prone positions.
Results and statistical analysis
The appreciation survey questionnaire and the recording of the side effects, particularly in relation to the OMT, revealed a unanimously favorable reaction in the treated patients. None of the patients reported side effects or negative reactions from the manipulation throughout the entire period of the treatment, nor for months afterward.
The statistical tests performed include the following:
The Mann-Whitney test, which involves a comparison between treated and non-treated patients.
The Wilcoxon test, which involves the comparison in a longitudinal sense.
A comparison test from a group of three individual treatments, before the osteopathic manipulation, at a distance of 5 months and a distance of 13 months.
The mean ocular pressure in both TG and CG was compared throughout the treatment cycle and showed a statistically significant lowering in both eyes (RE: p < 0.0561, LE: p < 0.0073). The reduction of the ocular pressure in the TG compared to the CG was maintained at 10 months from the first treatment or rather after 5 months from the last, and was shown to be present even at checkup after 13 months from the beginning of the study or rather 8 months in the absence of treatment (p < 0.000434).
The fluctuations in pressure in CG maintained a random evolution while still remaining within the normal range.
The visual field tests, carried out over 14 months, showed up neither significant differences between the two groups nor significant differences in the AD.
Discussion
The inspiration for this pilot study of integrated medicine arose from the growing interest primarily on the part of neurobiologists and secondarily ophthalmologists, in the circulation of the CSF in connection with eye fluids. Recent studies have shown how the CSF enters the optic nerve of rodents by way of the glymphatic system and suggested that further research on humans could take us to the same conclusion (4, 5).
Wostyn et al. explained how the stasis of the glymphatic system, in the region of the lamina cribrosa of the optic nerve, could influence the structure of the axons of the ganglion cells developing glaucoma (45).
According to these new models, the CSF is secreted not only from the choroid plexus located inside the cerebral ventricles but also inside the arterial paravascular spaces that are made up of glia cells, called Virchow and Robin Spaces (VRS) (46). VRS are made up of astrocyte pedicels that are wrapped around the capillaries of the cerebral parenchyma, and these astrocyte sheaths present numerous acquaporine-4 canals, thus facilitating the passage of the CSF into the interstices and its intermixing with the interstitial fluid (IF) (46–48).
Cerebrospinal fluid and interstitial fluid seem to mingle in the interstitial spaces, which then drain off interstitial solutes and catabolytes through lymphatic ducts present in the dura mater located in correspondence with cranial sinuses. This system of ducts flows together in the cervical lymph ducts and exits through the right lymph duct and the thoracic duct into the subclavian veins (1–3, 47, 48). The fluids inside this system of perivascular canals are driven by arterial pulsation and diaphragmatic breathing (39–41, 48, 49).
Various studies carried out in vivo on rodents and recently on humans show that the function of catabolyte clearance attributed to the glymphatic system takes place mainly during deep sleep and is almost absent during waking hours (2, 50–53). This function takes place via an expansion of the interstitial space, facilitating the ingress of CSF to the brain and its interchange with the IF. An eventual malfunction of the glymphatic system and the consequent deficit in the elimination of catabolytes can influence the homeostasis of the CNS, favoring the development of central neurodegenerative disease due to a buildup of neurotoxins (54–58).
In 2006, Flammer and Pache attempted to bring glaucoma into a wider medical discussion and debated the systemic peculiarities revealed in POAG. These systemic alterations include cardiovascular system, autonomous nervous system, and immune system, as well as endocrinological, psychological, and sleep disturbances (59).
Every patient at every osteopathy session was treated according to whatever clinical evidence was discovered during the osteopathic evaluation test and ascertained from their relative medical histories.
This “blackbox” practice can be described as an individually tailored treatment for every patient and is performed based on the problems and medical conditions of each individual (37, 60).
The results are obtained from the analysis of the initial tests and a comparison with the final tests.
In the TG, the osteopathic tests showed frequent SD of the diaphragm and those organs below the diaphragm, the ribcage, the occipital area, and the cervical tract C1–C2. At the end of the session, exercises were recommended (60) to encourage correct diaphragmatic breathing, especially in sedentary patients who had restricted ribcage mobility, often associated with shallow and irregular breathing.
Current knowledge in the medical field identifies the thoracic diaphragm as a principal factor for lymphatic and CSF circulation (39–41). A diaphragm is a transverse membrane which creates two distinct zones, whose correct functioning depends on the maintenance and balancing of the pressures within the two zones it divides.
Osteopathy recognizes other structures as diaphragm, including the pelvic floor, the thoracic outlet, the buccal floor, the diaphragm of the hypophysis, and the tentorium cerebelli. These structures are considered to be general-purpose pumps which permit the expansion, distribution, transmission, and regulation of the fluids (blood, CSF, and lymph) to the peripheries (37, 60).
Recently, osteopathic medicine has proposed manipulations which seem to influence the flow of CSF for conditions such as chronic fatigue syndrome (61), where this flow appears to be reduced. OMT also appears to induce changes during sleep in healthy patients (62). With these considerations, the improvement or resolution of visceral or structural problems could be extended throughout the body in addition to the cranial and cervical regions to include functional areas of the lymphatic system (37, 60).
Support for the efficiency of osteopathic treatments in neurodegenerative pathologies, such as glaucoma, could be attributed to the positive influence that these treatments would have not only on the IOP but also on the cerebral vascular perfusion, also enabling to influencing venous, lymphatic, and CSF circulation by facilitating its drainage (20–35).
With regard to future projects, we have planned a follow-up of at least 3 years and the use of Angio-OCT for measuring eventual variations in the vascularization of the retina and the optic nerve subsequent to OMT.
Conclusion
A reduction in pressure after the first treatment, which was persistent and statistically significant at every manipulation session carried out, shows that in some selected cases, it is possible to influence ocular pressure by means of osteopathic treatments without interfering with in-place pharmacological regimes.
Therefore, this places before the panorama of scientific research a possible starting point for future research and investigation into POAG in both the ophthalmological and osteopathic spheres. However, the small sample and an insufficiently long follow-up do not permit us to evaluate the eventual progression and the stabilization of the disease (visual field) and cannot provide conclusive data on the duration of the pressure-reducing effects of OMT.
References
1. Louveau A, Smirnov I, Keyes T, Eccles J, Rouhani S, Peske J, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. (2015) 523:337–41.
2. Jessen NA, Munk A, Lundgaard I, Nedergaard M. The glymphatic system: a beginner’s guide. Neurochemical Res. (2015) 40:2583–99.
3. Aspelund A, Antila S, Proulx S, Karlsen T, Karaman S, Detmar M, et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. (2015) 212:991–9.
4. An D, Morgan WH, Yu DY. Glymphatics and lymphatics in the eye and central nervous system. Clin Exp Ophthalmol. (2017) 45:440–1.
5. Mathieu E, Gupta N, Ahari A, Zhou X, Hanna J, Yücel Y. Evidence for cerebrospinal fluid entry into the optic nerve via a glymphatic pathway. IOVS. (2017) 58:4785.
6. Wostyn P, De Groot V, Van Dam D, Audenaert K, Killer H, De Deyn P. The glymphatic hypothesis of glaucoma: a unifying concept incorporating vascular, biomechanical, and biochemical aspects of the disease. Biomed Res Int. (2017) 2017:5123148.
7. De Moraes C, Liebmann J, Levin L. Detection and measurement of clinically meaningful visual field progression in clinical trials for glaucoma. Prog Retin Eye Res. (2017) 56:107–47.
8. Grzybowski A, Och M, Kanclerz P, Leffler C, Moraes C. Primary open angle glaucoma and vascular risk factors: a review of population based studies from 1990 to 2019. J Clin Med. (2020) 9:761.
9. Flammer J, Orgül S, Costa V, Orzalesi N, Krieglstein G, Serra L, et al. The impact of ocular blood flow in glaucoma. Prog Retin Eye Res. (2002) 21:359–93.
10. Berdahl JP, Fautsch M, Stinnett S, Allingham R. Intracranial pressure in primary open angle glaucoma, normal tension glaucoma, and ocular hypertension: a case-control study. Invest Ophthalmol Vis Sci. (2008) 49:5412–8.
11. Berdahl J, Allingham R, Johnson D. Cerebrospinal fluid pressure is decreased in primary open-angle glaucoma. Ophthalmology. (2008) 115:763–8.
12. Ren R, Jonas J, Tian G, Zhen Y, Ma K, Li S, et al. Cerebrospinal fluid pressure in glaucoma: a prospective study. Ophthalmology. (2010) 117:259–66.
13. Killer H, Miller N, Flammer J, Meyer P, Weinreb R, Remonda L, et al. Cerebrospinal fluid exchange in the optic nerve in normal-tension glaucoma. Br J Ophthalmol. (2012) 96:544–8.
14. Ren R, Zhang X, Wang N, Li B, Tian G, Jonas J. Cerebrospinal fluid pressure in ocular hypertension. Acta Ophthalmol. (2011) 89:e142–8.
15. Xie X, Chen W, Li Z, Thomas R, Li Y, Xian J, et al. Non-invasive evaluation of cerebrospinal fluid pressure in ocular hypertension: a preliminary study. the Beijing Intraocular and Intracranial Study Group. Acta Ophthalmol. (2018) 96:e570–6.
16. Jonas J, Berenshtein E, Holbach L. Anatomic relationship between lamina cribrosa, intraocular space, and cerebrospinal fluid space. Invest Ophthalmol Vis Sci. (2003) 44:5189–95.
17. Jonas JB, Nangia V, Wang N, Bhate K, Nangia P, Nangia P, et al. Trans-lamina cribrosa pressure difference and open-angle glaucoma. the central India eye and medical study. PLoS One. (2013) 8:e82284. doi: 10.1371/journal.pone.0082284
18. Jonas J, Wang N, Yang D. Translamina cribrosa pressure difference as potential element in the pathogenesis of glaucomatous optic neuropathy. Asia Pac J Ophthalmol. (2016) 5:5–10.
19. Pircher A, Remonda L, Weinreb R, Killer H. Translaminar pressure in Caucasian normal tension glaucoma patients. Acta Ophthalmol. (2017) 95:e524–31.
20. Tamburella F, Piras F, Piras F, Spanò B, Tramontano M, Gili T. Cerebral perfusion changes after osteopathic manipulative treatment: a randomized manual placebo-controlled trial. Front Physiol. (2019) 10:403. doi: 10.3389/fphys.2019.00403
21. Franzini D, Cuny L, Pierce-Talsma S. Osteopathic lymphatic pump techniques. J Am Osteopath Assoc. (2018) 118:e43–4.
22. Hitscherich K, Smith K, Cuoco J, Ruvolo K, Mancini J, Leheste J, et al. The glymphatic-lymphatic continuum: opportunities for osteopathic manipulative medicine. J Am Osteopath Assoc. (2016) 116:170–7.
23. Seffinger MA, Rich J. Lymphatic pump OMT releases cytokines into central circulation. J Am Osteopath Assoc. (2014) 114:587–8.
24. Chikly B. Manual techniques adressing the lymphatic system: origins and development. J Am Osteopath Assoc. (2005) 105:457–64.
25. Prajapati P, Shah P, King H, Williams A Jr, Desai P, Downey H. Lymphatic pump treatment increases thoracic duct lymph flow in conscious dogs with edema due to constriction of the inferior vena cava. Lymphatic Res Biol. (2010) 8:149–54.
26. Seidel B, Desipio G. Use of osteopathic manipulative treatment to manage recurrent bouts of singultus. J Am Osteopath Assoc. (2014) 114:660–4.
27. Pandey R. Effect of MET & MFR on primary open angle glaucoma in adult aged between 15-30 years. Int J Adv Res Dev. (2017) 2:14–7.
28. Bach A, Qureshi Y. Osteopathic Manipulative Treatment of the Eye. Fort Lauderdale, FL: Nova Southeastern University (2017).
29. Kuhmann O. The Impact of Osteopathic Treatment on Intraocular Hypertension—An Experimental Study. Ph.D. thesis. Gochsheim: Danube University (2007).
30. Bilgeri S. The impact of Osteophatic Treatment on increased ocular Pressure in Primary Open-Angle Glaucoma. Ph.D. thesis. Vienna: Danube University (2006).
31. Esser T. Kann durch osteopathische Techniken eine Senkung des Augeninnedrucks beim primärchronischen Offenwinkelglaukom bewirkt werden – eine Pilotstudie. New Haven, CT: Neonatal intensive care unit (2005).
32. Fowler S, et al. The role of the sympathetic nervous system in ocular hypertension. J Am Osteopath Assoc. (1984) 84:72.
33. Feely R, Castillo T, Greiner J. Osteopathic manipulative treatment and intraocular pressure. J Am Osteopath Assoc. (1982) 82:60.
34. Misischia P. The evaluation of intraocular tension following osteopathic manipulation. J Am Osteopath Assoc. (1981) 80:750.
35. Cipolla VT, Dubrow C, Schuller E Jr. Preliminary study: an evaluation of the effects of osteopathic manipulative therapy on intraocular pressure. J. Am. Osteopath Assoc. (1975) 74:433–7.
36. Seffinger AM. The safety of Osteopathic Manipulative Treatment (OMT). J Am Osteopath Assoc. (2018) 118:137–8.
37. Patterson MM, Wurster RD. Somatic dysfunction, spinal facilitation, and viscerosomatic integration. 3rd Edn. In: A Chila editor. Foundations of osteopathic medicine. Philadelphia, PA: Lippincott William & Wilkins (2011). 118–33.
38. Mayer J, Standen C. Manuale di Medicina Osteopatica. Rozzano MI: Casa editrice Ambrosiana Pioltello (2019).
39. Kocjan J, Adamek M, Gzik-Zroska B, Czyżewski D, Rydel M. Network of breathing. Multifunctional role of the diaphragm: a review. Adv Respir Med. (2017) 85:224–32.
40. Kocjan J, Gzik-Zroska B, Nowakowska K, Burkacki M, Suchoń S, Michnik R, et al. Impact of diaphragm function parameters on balance maintenance. PLoS One. (2018) 13:e0208697. doi: 10.1371/journal.pone.0208697
41. Dreha-Kulaczewski S, Joseph A, Merboldt K, Ludwig H, Gärtner J, Frahm J. Inspiration is the major regulator of human CSF flow. J Neurosci. (2015) 35:2485–91.
43. Fossum C, Kuchera M, Devine W, Wilson K. Chapman’s approach. 3rd Edn. In: A Chila editor. Foundations of Osteopathic Medicine. Baltimore, MD: Lippincott Williams & Wilkins (2011).
45. Wostyn P, Killer HE, De Deyn PP. Glymphatic stasis at the site of the lamina cribrosa as a potential mechanism underlying open-angle glaucoma. Clin Exp Ophthalmol. (2017) 45:539–47.
46. Nakada T. Virchow-Robin space and aquaporin-4: new insight on an old friend. Croat Med J. (2014) 55:328–36.
47. Brinker T, Stopa E, Morrison J, Klinge P. A new look at cerebrospinal fluid circulation. Fluids Barriers CNS. (2014) 11:1–16. doi: 10.1186/2045-8118-11-10
48. Iliff JJ, Nedergaard M. Is there a cerebral lymphatic system? Stroke. (2013) 44(Suppl. 1):S93–5.
49. Wagshul EM, Eide PK, Madsen JR. The pulsating brain: a review of experimental and clinical studies of intracranial pulsatility. Fluids Barriers CNS. (2011) 8:5.
50. Xie L, Kang H, Xu Q, Chen M, Liao Y, Thiyagarajan M, et al. Sleep drives metabolite clearance from the adult brain. Science. (2013) 342:373–7.
51. Mendelsohn AR, Larrick J. Sleep facilitates clearance of metabolites from the brain: glymphatic function in aging and neurodegenerative disease. Rejuvenation Res. (2013) 16:518–23.
52. Achariyar TM, Li B, Peng W, Verghese P, Shi Y, McConnell E, et al. Glymphatic distribution of CSF-derived apoe into brain is isoform specific and suppressed during sleep deprivation. Mol Neurodegener. (2016) 11:74.
53. Demiral SB, Tomasi D, Sarlls J, Lee H, Wiers C, Zehra A, et al. Apparent diffusion coefficient changes in human brain during sleep-Does it inform on the existence of a glymphatic system? NeuroImage. (2019) 185:263–73.
54. Rasmussen MA, Mestre H, Nedergaard M. The glymphatic pathway in neurological disorders. Lancet Neurol. (2018) 17:1016–24.
55. Wostyn P, De Groot V, Van Dam D, Audenaert K, Killer H, De Deyn P, et al. Glaucoma considered as an imbalance between production and clearance of neurotoxins. Investig Ophthalmol Visual Sci. (2014) 55:5351–2.
56. Wostyn P, De Groot V, Van Dam D, Audenaert K, De Deyn P. Senescent changes in cerebrospinal fluid circulatory physiology and their role in the pathogenesis of normal-tension glaucoma. Am J Ophthalmol. (2013) 156:5–14.
57. Guo L, Salt T, Luong V, Wood N, Cheung W, Maass A, et al. Targeting amyloid-β in glaucoma treatment. Proc Natl Acad Sci U.S.A. (2007) 104:13444–9.
58. Wostyn P, Van Dam D, Audenaert K, Killer H, De Deyn P, De Groot V. A new glaucoma hypothesis: a role of glymphatic system dysfunction. Fluids Barriers CNS. (2015) 12:16.
59. Pache M, Flammer J. A sick Eye in a sick body? Systemic findigs in patients with Open-angle Glaucoma. J Survey Ophtalmol. (2006) 5:179–212.
60. Lunghi C, Baroni F, Alò M. Il ragionamento clinico osteopatico. Trattamento salutogenico e approccio progressivi individuali. Italiano: Edra (2017).
61. Perrin RN. Lymphatic Drainage of the Neuraxis in Chronic Fatigue Syndrome: A Hypothetical Model for the Cranial Rhythmic Impulse. J. Am Osteopath Assoc. (2007) 107:218–24.