Normal Tension Glaucoma
Joseph Sowka, OD, FAAO, Diplomate
Normal Tension Glaucoma (NTG)
 IOP is within the "statistically normal" range. IOP consistently under 21 mm hg.
 Sometimes referred to as “low tension glaucoma”, “low pressure glaucoma” and
“pressure independent” glaucoma
 Prevalence not truly known.
 Varies considerably - from 10% to > 50% (dependent upon study source).
 Prevalence is likely greatly over inflated
NTG: The 3 Questions
1. Is the cupping physiologic or pathologic?
 Accurate visual fields as well as other optic nerve function and structure studies should
identify truly diseased nerves.
 Misdiagnosis of megalopapillae
2. Is the cupping progressive?
 Serial or sequential optic nerve function and structure studies will identify progression.
There are a host of masquerading conditions that present with field defects (e.g., tilted
discs) that are non-progressive. You should not beat your head against a wall trying to
treat a non-progressive anomaly.
3. If the cupping is pathologic and progressive, what is the optimal treatment?
 Virtually every therapy has alternately been both advocated and vilified
NTG: Differential Diagnosis
 Congenital defects: optic nerve hypoplasia, tilted discs, optic pits and colobomas, large
physiologic cup (megalopapilla), optic nerve drusen.
 Burnt-out POAG
 Hypovolemic optic neuropathy
 Arteritic and non-arteritic AION
 Diurnal variations in POAG
 Chronic angle closure glaucoma
 Compressive lesions: the neuroradiological fishing trip
 Non-glaucomatous optic neuropathy
 Previously high IOP
 IOP lowering systemic medications
 Beta blockers for HTN
 Other types of glaucoma (secondary) – particularly those with intermittent IOP spikes or wide
diurnal IOP variations
 Pigmentary
 Exfoliative
 Glaucomatocyclitic crisis
 Steroid-induced
 “Masked POAG” - Abnormally thin cornea masking true ocular hypertension
1

70 um change in corneal thickness can approximate 5 mm Hg of IOP
Clinical Pearl: Normal tension glaucoma is a diagnosis of exclusion. If the doctor works
hard enough, most cases of “NTG” can be correctly ascribed to another disease.
NTG: Risk Factors and Associated Factors:
 Peripheral vascular disease: if glaucoma is truly a vascular disease which is affected by
elevated IOP to cause an optic neuropathy, then the patients who are severely vascularly
compromised can possibly develop glaucomatous changes at “normal” pressures
 Age – disease mostly of elderly
 Probably just increased susceptibility to IOP related damage due to aging
 Family history of glaucoma
 Myopia
 Disc hemorrhages
 Raynaud’s phenomenon
 Vasospastic neuropathy?
 Migraine HA
 Vasospastic neuropathy?
 Low blood pressure
 Low OPP
 Hemodynamic crisis
 Hypovolemic optic neuropathy
 Carotid insufficiency
 Empty sella syndrome:
 DM and hypercholesterolemia
 Cardiovascular disease
 Abnormal blood coagulation and platelets
 Abnormal antibodies and other immune factors
 Most of these risk factors have a positive correlation, but unknown role.
Collaborative Normal Tension Glaucoma Study (CNTGS) 1998
 Randomized, controlled 5 year clinical trial (144 eyes) of the effectiveness of IOP reduction
in slowing the progression of field loss in pts. with NTG.
 Inclusion criteria
 Showed documented progression, high risk field defects that threatened fixation, or
appearance of new disc hemorrhage
 Goal: 30% reduction from IOP baseline
 Due to potential (theoretical) impact to optic nerve perfusion, adrenergic drugs such as
beta blockers and epinephrine weren’t used. Alphagan and prostaglandins weren’t
invented yet. Essentially, the only way that IOP was reduced in this study was with
pilocarpine, laser trabeculoplasty, and trabeculectomy. Surprisingly, over half of the
treated patients achieved the goal IOP reduction without having to undergo
trabeculectomy.
 Results: 35% of control eyes (untreated) showed progression (glaucomatous optic disc
2
progression or visual field loss) whereas only 12% of treated eyes showed progression.
Conclusion: Intraocular pressure is part of the pathogenic process of NTG. Therapy that reduces
IOP and is free of side effects would be expected to be beneficial in patients who are at risk of
disease progression.
Problems: 1. Which patients are at risk for disease progression? 2. While 35% of untreated eyes
showed progression, 65% of untreated eyes did not progress.
Further Conclusions from CNTGS: Lowering IOP without producing cataracts is beneficial.
Because not all untreated patients progressed, the natural history of NTG must be considered
prior to embarking on IOP reduction with therapy apt to exacerbate cataract formation unless
NTG threatens serious visual loss.





According to the CNTGSG, those at risk of progression include:
 Females
 Those with history of migraines
 Those manifesting disc hemorrhage
Factors that were not associated with an increased risk of progression include:
 Older age
 Higher mean IOP
 Field defects threatening fixation
Factors associated with treatment benefit include:
 No disc hemorrhage
 Female gender
 Family history of glaucoma
 No family history of stroke
 No personal history of cardiovascular disease
 Less initial disc damage (C/D < 0.7/0.7)
Factors not associated with treatment benefit include:
 Male gender
 Disc hemorrhage
 Severely damaged discs
 Migraine
Clinical notes and curiosities:
 Asian patients have less severe disease than Caucasians
 Disc hemorrhage is strongly predictive of progression, yet doesn’t benefit from treatment
 Females gender is strong factor for having NTG, progression of disease, and benefit of
treatment
 Female gender does NOT show up as risk factor in Ocular hypertension
NTG: Pathophysiology
 Unknown
 Theories:
 Small vessel disease
3





Vasospasm
Hemodynamic crisis (single event theory)
Nocturnal hypotension
Structurally weak lamina (collagen vasculopathy)
New theory: autoimmunity
 30% prevalence of systemic autoimmune diseases in NTG vs POAG and controls
 Immuno-pathogens may damage optic nerve, vessels, or both
 Patients with “NTG” have increased prevalence of monoclonal paraproteinemias
 Paraproteinemias are seen in patients with peripheral neuropathies
 ”NTG” may be organ-specific autoimmune disease
 Patients with “NTG” have increased prevalence of monoclonal paraproteinemias
 Paraproteinemias are seen in patients with sensory peripheral neuropathies (Wax et al.
1994 Am J Ophthalmol)
 Immunoglobin IgG, IgA (and other retinal antibodies) deposition found in RGC layer
of patient with NTG and paraproteinemia (Wax et al. 1998 Arch Ophthalmol)
 Increased antiphospholipid antibodies (antiphosphatidylserine) in “NTG” vs POAG
vs controls
 IgG anticardiolipin antibodies greater in “NTG” than POAG and controls (Kremmer
et al. 2001 Clin Exp Immunol)
 Serum from NTG pts. contained high titres of antibodies against retinal proteins,
including rhodopsin and heat-shock protein (HSP)
 Immune responses to HSP implicated in human autoimmune diseases
 HSP are significant autoantigens
 Antibodies to HSP found in many autoimmune disease
NTG vs POAG
 Sharper field loss in NTG
 Shallower cupping in NTG
 Larger overall disc area in NTG
 Disc hemorrhages 5-fold more prevalent in NTG than POAG
 Higher and greater incidence of peripapillary atrophy and crescents in NTG than POAG
NTG: Diagnostic Evaluation
 Diagnosis of exclusion
 R/O impostors
 Complete eye exam and history
 Pachymetry and gonio especially important
 Multiple IOP readings at different times of day
 General medical exam and neuro-evaluation
 Serial fields and photos
 Medical evaluation
NTG: Medical Evaluation
 Vascular studies
4
















Blood glucose
CBC (Hyperviscosity/ anemia)
B12
ANA
ACE
CXR
FTA-ABS/ RPR
Lyme
Thyroid
Mitochondrial DNA
SPEP retinal antibodies
Serum chemistries (lipids)
ESR (erythrocyte sedimentation rate)
Carotid blood flow studies
Neuroimaging (if under age 65, rapidly progressing, unilateral, dyschromatopsia, acuity loss)
of the orbits and chiasm.
NTG may actually be a systemic disease with ocular manifestations
 Autoimmunity? This may be a self-limiting autoimmune disease that mimics glaucoma
NTG: Management
 Determine progressive nature. If non-progressive, monitor.
 If progressive, reduce IOP by 30% (per CNTGS results)
NTG: Management
 Prostaglandins are supported due to their ability to reduce IOP that is already within the
statistically normal range with minimal adverse effects
 Alpha-2 adrenergic agonists and beta blockers theoretically may affect OPP adversely
 CAIs often not advocated due to poor IOP lowering potential in statistical normal range
 Trabeculoplasty and trabeculectomy
Clinical Pearl: Do not rush to make this diagnosis. It should take at least 6-12 months in
order to make the diagnosis when you insist on determining progression.
Clinical Pearl: Glaucoma is glaucoma regardless of the pressure level. However, in the
“normotensive” range, there is a great difference between an IOP of 19 mm Hg and 12 mm
Hg in terms of management.
Conclusion: “NTG” is a diagnostic garbage can in which many things are thrown. There
may be a rare few patients who have true glaucoma at a statistically normal intraocular
pressure. However, most of the patients diagnosed as “NTG” likely have congenital
anomalies, other neuropathies, other types of undiscovered glaucoma, or a self-limiting
neuropathy that mimics glaucoma and may have an autoimmune etiology.
5