normal tension glaucoma ( ntg ) is an optic neuropathy associated with glaucomatous optic nerve head damage , progressive retinal nerve fiber layer thinning , characteristic visual field defects , open anterior chamber angles on gonioscopy and maximum intraocular pressure ( iop ) below 21 mmhg .
glaucoma is a major optic neuropathy characterized by significant death of retinal ganglion cells . according to global surveys , the second leading cause of blindness after cataracts is glaucoma .
glaucoma affects more than 66 million people and is the second leading cause of visual loss worldwide .
ntg accounted for 92% of primary open - angle glaucoma ( poag ) in a japanese population .

 patients with ntg tend to be older than those with primary open angle glaucoma ( poag)female subjects have a higher prevalence of the disease than male counterpartsntg is more frequent among japanese peoplethe most important risk factor for glaucoma is elevated iop .
it has been established that high iop is a part of the pathogenic process of ntg ; however , the pressure theory can not sufficiently explain how ntg causes loss of vision .
multicenter clinical trials have confirmed the value of reducing iop both in poag and ntg .
there is yet to be a consensus regarding the specific relationship between iop and ntg .
however , in many cases the progression of gon has been observed even after lowering iop .
patients with ntg have wider diurnal fluctuations of iop as compared to the healthy population .
iop spikes may occur at night , and thus iops measured during office hours may miss nocturnal spikes in many patients .
associated changes in nocturnal orbital blood pressure and iop may affect optic nerve head blood perfusion differently in glaucomatous eyes as compared to healthy eyes , and this issue may also influence the susceptibility of the optic nerve to damagecentral corneal thickness ( cct ) in patients with ntg is lower than poag subjectsvascular dysfunction and ischemia have been considered as important factors in the progression of ntg . however , the ischemia in glaucoma is not simply insufficiency of blood flow , but also due to improper vascular autoregulation , and hypothetically episodes of transient ischemia and re - perfusion injury occurcold hands and feet , as an over - reaction to cold or stress , are suggestive of defective vasoregulation .
abnormal vasoregulation such as raynaud 's phenomenon and migraine are more associated with ntg than poag .
a study of peripheral vascular endothelial function in patients with ntg found impaired acetylcholine - induced peripheral endothelium - mediated vasodilation in comparison to healthy age- and sex - matched control subjects , and polymorphisms of the endothelin receptor type a gene have been associated with ntgpatients with ntg have an increased frequency of headaches with or without migraine featuresnon - iop - related cardiovascular dysregulation factors , such as systemic hypertension , systemic hypotension , nocturnal hypotension , and cardiac arrhythmia are implicated in ntgthere are reports suggesting that signs of glaucoma in certain eyes may be related to an acute ischemic episode ( shock - induced neuropathy ) , or chronic obstructive arterial disease , which may be non - progressivemojon et al suggested that patients with sleep apnea syndrome are at high risk for glaucoma .
the prevalence of obstructive sleep apnea syndrome ( osas ) was higher in patients with ntg .
osas may cause optic nerve head hypoperfusion and glaucomatous optic neuropathy by creating transient hypoxemia and increasing vascular resistanceabnormally low diastolic double product ( ddp = diastolic blood pressure  heart rate ) may represent a state of cardiovascular autonomic dysregulation , resulting in low ocular perfusion in certain ntg patientsntg patients with lower heart - rate variability , which reflects autonomic dysfunction with sympathetic predominance , manifested a faster rate of central visual field progression as compared to patients with higher heart - rate variabilityglaucoma patients have a decrease in central retinal vein ( crv ) blood velocities .
this is particularly important in ntg patientsduplication of the tank - binding kinase 1 ( tbk1 ) gene can be a rare cause of ntglifestyle factors such as smoking and high body mass index can cause progression of glaucomatous visual field defect . in the blue mountain eye study , smokers were found to have higher iop than non - smoker counterpartsout of the metabolic syndrome components , hypertension and impaired glucose tolerance ( igt ) may contribute to an increased risk of ntg . 
 
patients with ntg tend to be older than those with primary open angle glaucoma ( poag ) female subjects have a higher prevalence of the disease than male counterparts ntg is more frequent among japanese people the most important risk factor for glaucoma is elevated iop .
it has been established that high iop is a part of the pathogenic process of ntg ; however , the pressure theory can not sufficiently explain how ntg causes loss of vision .
multicenter clinical trials have confirmed the value of reducing iop both in poag and ntg .
there is yet to be a consensus regarding the specific relationship between iop and ntg .
however , in many cases the progression of gon has been observed even after lowering iop .
patients with ntg have wider diurnal fluctuations of iop as compared to the healthy population .
iop spikes may occur at night , and thus iops measured during office hours may miss nocturnal spikes in many patients .
associated changes in nocturnal orbital blood pressure and iop may affect optic nerve head blood perfusion differently in glaucomatous eyes as compared to healthy eyes , and this issue may also influence the susceptibility of the optic nerve to damage central corneal thickness ( cct ) in patients with ntg is lower than poag subjects vascular dysfunction and ischemia have been considered as important factors in the progression of ntg .
however , the ischemia in glaucoma is not simply insufficiency of blood flow , but also due to improper vascular autoregulation , and hypothetically episodes of transient ischemia and re - perfusion injury occur cold hands and feet , as an over - reaction to cold or stress , are suggestive of defective vasoregulation .
abnormal vasoregulation such as raynaud 's phenomenon and migraine are more associated with ntg than poag .
a study of peripheral vascular endothelial function in patients with ntg found impaired acetylcholine - induced peripheral endothelium - mediated vasodilation in comparison to healthy age- and sex - matched control subjects , and polymorphisms of the endothelin receptor type a gene have been associated with ntg patients with ntg have an increased frequency of headaches with or without migraine features non - iop - related cardiovascular dysregulation factors , such as systemic hypertension , systemic hypotension , nocturnal hypotension , and cardiac arrhythmia are implicated in ntg there are reports suggesting that signs of glaucoma in certain eyes may be related to an acute ischemic episode ( shock - induced neuropathy ) , or chronic obstructive arterial disease , which may be non - progressive mojon et al suggested that patients with sleep apnea syndrome are at high risk for glaucoma .
the prevalence of obstructive sleep apnea syndrome ( osas ) was higher in patients with ntg .
osas may cause optic nerve head hypoperfusion and glaucomatous optic neuropathy by creating transient hypoxemia and increasing vascular resistance abnormally low diastolic double product ( ddp = diastolic blood pressure  heart rate ) may represent a state of cardiovascular autonomic dysregulation , resulting in low ocular perfusion in certain ntg patients ntg patients with lower heart - rate variability , which reflects autonomic dysfunction with sympathetic predominance , manifested a faster rate of central visual field progression as compared to patients with higher heart - rate variability glaucoma patients have a decrease in central retinal vein ( crv ) blood velocities .
this is particularly important in ntg patients duplication of the tank - binding kinase 1 ( tbk1 ) gene can be a rare cause of ntg lifestyle factors such as smoking and high body mass index can cause progression of glaucomatous visual field defect . in the blue mountain eye study , smokers were found to have higher iop than non - smoker counterparts out of the metabolic syndrome components , hypertension and impaired glucose tolerance ( igt ) may contribute to an increased risk of ntg .
history has to be taken regarding migraine , raynaud 's phenomenon , episodes of shock , head injury , headache and other neurological symptoms .
use of medications including systemic steroids and antihypertensive agents such as beta blockers should also be taken into account .
goldmann applanation tonometry , gonioscopy , stereoscopic biomicroscopy of the optic nerve head , optical coherence tomography and humphrey field analyser are the main tools of investigation for diagnosis of ntg .
increased cup to disc ratio or asymmetry of cupping between the two eyes ( difference more than 0.2 ) is significant [ figure 1 ] .
a region of absent retinal pigment epithelium ( rpe ) is more often seen as a crescent or halo at the disc border in ntg .
the cupping is often worse in the region of absent rpe , with field loss more marked in the corresponding region .
occasionally , there is a notch due to thin or absent neuro - retinal rim , referred as a 
this is associated with a highly localized dense arcuate field defect or even a dense hemifield defect .
other discs have diffuse shallow cupping and pallor , leading to the designation  senile sclerotic  disc .
patients with high myopia may be particularly susceptible to ntg . with a frequent temporal crescent ,
scotomas tend to be closer to fixation than the paracentral scotomas of non - myope cases .
splinter hemorrhages are seen more commonly in ntg , but may also be found in poag .
hemorrhages may simply indicate poor control . although the optic nerve head may be larger in ntg than in poag , glaucomatous cupping is comparable .
normal - tension glaucoma eyes can have greater optic nerve head ( onh ) torsion as compared to poag eyes with matched axial length .
the direction of the onh tilt and torsion can be related to the location of the visual field defect only in ntg eyes .
as compared to normal subjects , peripapillary choroidal thickness was significantly thinner in ntg patients , at least in some locations .
another revealed a difference in the progression pattern as compared to poag patients ; in poag eyes , field defects initially increased in area and later in depth , whereas in patients with ntg , the increases in area and depth remained in constant proportion .
other investigations include 24-hour blood pressure monitoring to exclude nocturnal systemic hypotension ; blood tests to rule out other causes of glaucomatous optic neuropathy such as vitamin b12 and folate levels , esr / crp and serum ace .
cranial mri may be necessary to rule out intracranial space occupying lesions ( sols ) ; and nail fold capillaroscopy with cold provocation may detect blood flow abnormalities .
a number of congenital disorders may be confused with ntg ; these include optic nerve anomalies including coloboma , pits , oblique insertion of the optic nerve , in addition to autosomal dominant optic atrophy ( kjer type )
. acquired disorders which need to be considered in the differential diagnosis of ntg include history of steroid use by any route which may have led to prior elevated iop , prior trauma or surgery which may have caused elevated iop , hemodynamic crisis , methyl alcohol poisoning , optic neuritis , ischemic optic neuropathy ( both arteritic and non - arteritic ) , compressive lesions of the optic nerve and tract ( e.g. , meningioma , vascular lesion ) ; and wide diurnal fluctuation in iop .
the early manifest glaucoma trial showed that glaucoma progression was decreased by 10% with reduction of each mmhg of iop . according to the collaborative normal tension glaucoma study group ,
choices for medical treatment in progressive cases include betaxolol eye drops which have a beneficial effect on optic nerve blood flow in addition to iop reduction . other beta blockers and adrenergic drugs ( such as dipivefrine )
should better be avoided because of the probability of nocturnal systemic hypotension and optic nerve hypoperfusion .
. dorzolamide - timolol fixed combination ( dtfc ) is a safe and effective iop - lowering agent in patients with ntg .
brimonidine significantly improved retinal vascular autoregulation in ntg patients ; however , short - term alterations in visual function could not be demonstrated . in the collaborative normal tension glaucoma study ( cntgs ) ,
57% of the patients achieved 30% iop reduction with topical medications , laser trabeculoplasty or both .
the remaining 43% required filtering surgery which may prevent progressive damage . a single session of selective laser trabeculoplasty ( slt ) for ntg achieved iop reduction of 20% from pre - study iop and 30% reduction from baseline iop at 6 months .
deep sclerectomy seems to be effective and safe in reducing iop in patients with ntg .
intraoperative use of mmc results in lower postoperative iop after 12 months without an increased rate of complications
. an additional part of managing ntg is treatment of any cardiovascular abnormality such as anemia , hypotension , congestive heart failure ( chf ) , transient ischemic attacks and cardiac arrhythmias to increase optic nerve head perfusion .
if significant nocturnal dips in blood pressure are detected , it may be necessary to reduce the antihypertensive medication especially at bedtime .
finally treatment is aimed at neuroprotection to improve the retinal ganglion cell or optic nerve head function .
nilvadipine , a calcium channel blocker , increases blood flow to the optic nerve head and fovea .
there was a significant reduction in the rate of disc and field damage in ntg patients who received calcium channel blockers .
 normal tension glaucoma ( ntg ) is labelled when typical glaucomatous disc changes , visual field defects and open anterior chamber angles are associated with intraocular pressure ( iop ) constantly below 21 mmhg . 
 chronic low vascular perfusion , raynaud 's phenomenon , migraine , nocturnal systemic hypotension and over - treated systemic hypertension are the main causes of normal tension glaucoma 
 . goldmann applanation tonometry , gonioscopy , slit lamp biomicroscopy , optical coherence tomography and visual field analysis are the main tools of investigation for the diagnosis of ntg . 
 management follows the same principles of treatment for other chronic glaucomas : to reduce iop by a substantial amount , sufficient to prevent disabling visual loss . 
 treatment is generally aimed to lower iop by 30% from pre - existing levels to 12 - 14 mmhg . 
 betaxolol , brimonidine , prostaglandin analogues , trabeculectomy ( in refractory cases ) , systemic calcium channel blockers ( such as nifedipine ) and 24-hour monitoring of blood pressure are considered in the management of ntg . 
 the present review summarises risk factors , causes , pathogenesis , diagnosis and management of ntg . 
INTRODUCTION
RISK FACTORS
DIAGNOSIS
DIFFERENTIAL DIAGNOSIS
TREATMENT
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Conflicts of Interest