Saturday, August 31, 2019





Wednesday, August 28, 2019



For generations of ophthalmologists, glaucoma was simply defined as a disease characterized by high intraocular pressure (IOP). It was almost forgotten that the eminent German ophthalmologist Albrecht von Graefe (1828-1870) already in 1857 - and thus just seven years after the invention of the ophthalmoscope which made the hallmarks of the disease like the optic nerve head (ONH) excavation finally visible to physicians - encountered a patient with that characteristic damage but with an IOP that did not seem to be increased at all.

Today, normal tension glaucoma (NTG) is a widely recognized disease though there are still ongoing discussions on whether it is just a special form of primary open-angle glaucoma (POAG) or whether it is a distinct clinical entity with its very own pathogenetic risk factors and with clinical features different from POAG. Professor Josef Flammer has over the years in his many contributions to science strenghtened the latter point of view. No doubt: the observation of patients suffering from glaucomatous optic neuropathy (GON) with an IOP within the normal range challenges the traditional pathophysiological concept of glaucoma solely based on  elevated IOP.

A number of studies have evaluated the prevalence of normal tension glaucoma - formerly sometimes described by the term "low tension glaucoma" - among the overall glaucoma population.There are marked epidemiological differences between different ethnicities. NTG seems to be much more frequent among Asians than among a European population or one of European heritage. In the Beaver Dam Eye Study, for instance, the prevalence of NTG among glaucoma patients (predominantly white individuals) was 32%, in the Rotterdam Study it was 39%. It was higher among people of African heritage (who are more susceptible to glaucoma in general than other groups) as demonstrated in a study from Zululand where 57% of glaucoma patients had NTG. In Asia, however, it dominates the POAG population: a study from Guangzhou, China, showed an NTG prevalence of 85%; the highest NTG proportion ever reported was from Japan: 92% of POAG patients.

Pathogenesis and Risk Factors

Professor Josef Flammer remembers quite well an experience he had as a young physician who was doing a year-long residency at the eye clinic of the University of British Columbia in Vancouver which at that time was the leading center worldwide when it came to the management of glaucoma and research about its causes. Not only did Flammer encounter patients with characteristic glaucomatous damage at the ONH and the retinal nerve fibre layer (RNFL) while having IOP within the normal range. His mentor and teacher, Professor Stephen Drance, pointed to something that was peculiar about these patients: they often had small hemorrhages at the rim of the optic disc. Drance was convinced that this feature that today is widely regarded as a hallmark of NTG points to an issue of the ocular perfusion - to be sure, POAG patients may have these hemorrhages as well but they are about five times more frequent in individuals suffering from normal tension glaucoma. Drance therefore ordered a routine cardiovascular check-up for patients with NTG.

Professor Flammer's research has established that the risk factors that lead to IOP increase and thus to the "classical" version of glaucoma and those that initiate GON are not identical but tend to be widely different. Risk factors that lead to artherosclerosis are also risk factors that predispose to elevated IOP like age, smoking, obesity, male gender, dislipidemia, diabetes mellitus, systemic hypertension. NTG patients who show GON have, however, a very different risk profile than "ocular hypertensives". Risk factors for NTG include female gender, race (i.e. Asian heritage, see above) primary vascular dysregulations (PVD) and low blood pressure. On average, NTG patients tend to be younger than glaucoma patients with an elevated IOP.

Ocular blood flow (OBF) tends to be reduced in glaucoma patients and particularly so in NTG patients. An unstable OBF is supposed to be a major cause of glaucomatous damage; OBF is also significantly more reduced in glaucoma patients showing progression than in patients who do noz progress. Normal tension glaucoma patients have a reduced autoregulation: these eyes lack the capacity to properly ensure a stable blood supply which becomes critical when PVD and low blood pressure lead to a diminished blood flow towards the ocular structures.

It has been demonstrated that even more damaging than a continuously low blood pressure are irregularities in blood pressure, excessive "spikes" and equally excessive drops. Sharp decreases - particularly at night - play a pathogenetic role in many NTG patients. The same can unfortunately been said sometimes about medical therapy to lower an increased blood pressure, therapy usually initiated by a general practitioner or specialist in internal medicine. These medications can lead to blood pressure reductions - again, particularly during sleeping hours - that prove to be dangerous to an already compromised OBF in an NTG patient. Some sleeping pills have also the unwanted effect of lowering the blood pressure during sleep in susceptible patients.

Professor Flammer and his co-workers have over the years developed a pathogenetic concept of glaucoma based on the role of OBF and led to the discovery of Flammer syndrome which supports the hypothesis of "glaucoma as a sick eye in a sick [from a vascular point of view] body". Both OBF and Flammer syndrome have been discussed earlier in this series. Suffice it here to say that vascular factors like recurrent hypoxia due to increased vascular resistance or PVD as well as the so called reperfusion injury (the damage done to cells that have for some time been deprived of adequate blood flow and than sometimes virtually "drown" in re-established OBF and in oxygen) lead to oxidative stress and inflammation, resulting in damage to the retinal ganglion cells, the astrocytes and other layers at the ONH and the RNFL.

A possible link between NTG and general disease has been the focus of a number of studies. There is so far no established significant association between NTG and diabetes mellitus. There are indications of a link between NTG and obstructive sleep apnea (OSA), both having a multifactorial pathogenesis in which recurrent hypoxia obviously plays a major role.


The basic diagnostics in glaucoma management apply also for NTG patients - with one probable exception: IOP readings are no reliable predictors of progression. For diagnosis and to draw a line versus POAG, IOP should always be below 21 mm Hg before we speak of normal tension glaucoma. It has to be kept in mind, though, that this is a rather arbitrary boundary - we are dealing with a continuum, not with a clear distinction between NTG and POAG. The lower the IOP value that is associated with glaucomatous damage and/or with progression, the higher is the likelihood of vascular factors as a primary pathogenetic mechanism.

Structural and functional measurements are valuable in establishing the diagnosis and performing controls. Like in other fields of ophthalmology, the advent and incresing sophistication of OCT has improved the diagnosis of glaucoma in general and of NTG in perticular. Dynamic retinal vessel analysis (DVA) may add further valuable information on the status of the patient's ocular vasculature.

Measuring retinal venous pressure (RVP) can point to NTG: it is more frequently increased in these eyes than in POAG.


In general, therapy of NTG has much in common with therapy of POAG: ophthalmologists try to lower the patient's IOP as good as they can. IOP reduction improves the prognosis in all types of glaucoma. This can be done pharmacologically, by laser treatment or with a surgical intervention. Nevertheless, some patients are known to progress despite an IOP level regarded as appropriate ("target pressure") has been reached.

In NTG patients in which OBF seems to be a major factor, other treatment options in addition to IOP lowering have been tried to achieve functional stability and to prevent further progression. Since low blood pressure is common among NTG patients, further reductions should be prevented or, in some cases, even raising the blood pressure moderately will be tried. This requires a close cooperation between ophthalmologist and general practitioner or internal medicine specialist or cardiologist - the latter disciplines are traditionally concerned with lowering blood pressure, not elevating it. In daily practice, informing these colleagues about the dangers of low blood pressure in NTG patients and convincing them to stabilize blood pressure at a somewhat higher level as well as avoiding fluctuations has often proven to be quite a challenge for ophthalmologists.

In Basel, Professor Flammer and his team have been able to improve vascular regulation locally by carbonic anhydrase inhibitors and systemically with low dose magnesium and low dose calcium channel blockers. Evening eals with a higher-than-average dose of salt can be helpful in preventing nighttime blood pressure dips. Oxidative stress can potentially be reduced by gingko biloba. The elucidation of IOP-independent risk factors will most likely add therapeutic options in the future - and will challenge the in many places still-dominant concept of glaucoma therapy: IOP reduction alone.


Ronald D. Gerste, born in Magdeburg, Germany, grew up and studied medicine (M.D.) and history (Ph.D.) at the University of Düsseldorf, Germany. He has worked as an ophthalmologist, but over the years moved to the field of medical publishing. Work for a number of journals and publishers, based since 2001 near Washington DC where he is acting as a science correspondent. Have the privilege of being associated with and a friend of Prof. Flammer for more than 20 years; was part of the team that translated his great book "Glaucoma" into the English language. He has written repeatedly on Flammer Syndrome in German-language journals. Also the publicist for the Swiss Academy of Ophthalmology (SAoO), the German Society for Cataract and Refractive Surgery (DGII) and the German Glaucoma Awareness Association (Initiativkreis Glaukom).

Thursday, August 22, 2019





Glaucoma has no characteristic features. It is an amalgamation of signs and symptoms which form the basis for diagnosis of glaucoma in one individual but may be regarded as some other condition or even as normal in others. Richard Bannister (1622 AD) described the “glaucoma triad” of raised intra-ocular pressure (IOP), optic disc cupping and visual field (VF) changes as diagnostic of glaucoma. 

However, IOP now has been thrown entirely out of the equation. Ostensibly, high IOP is just a statistical figure. It can occur in an entirely harmless way in certain individuals. It is also surprising that nearly half of all glaucoma patients who have been on apparently well controlled IOP end up with glaucomatous optic atrophy (GOA) in atleast one eye during their lifetime. Thus, IOP has become much of an enigma in the development of GOA.

Structural changes in glaucoma probably occur late. So, GOA may not be seen until significant amount of damage has already been done. What causes GOA? Is it mechanical, vascular, biochemical molecules, translaminar pressure difference or genetic factors which make the optic nerve head vulnerable? Moreover, optic atrophy may also occur in a diverse range of other conditions such as ischemic, compressive and hereditary optic neuropathies, pointing to a possible common thread running through some of these optic nerve degenerations. 

What about VF changes? Why are there just a handful of techniques available to record the VF? Then too, a Humphrey VF chart may not resemble a printout from an Octopus perimeter for the same patient. Dr Hasnain mentions that glaucomatous field loss correlates fully with the arrangement of nerve fibers while in the retina, but DOES NOT correlate at all with the arrangement of nerve fibers after they have made their 900 turn into the prelaminar region. The characteristic glaucomatous field loss such as arcuate scotoma and Ronnie’s nasal step cannot be produced if the primary site of injury is in the prelaminar area or lamina cribrosa and beyond, according to Dr Hasnain.  

DARC (Detection of Apoptosing Retinal Cells) technology, a technique which can identify retinal ganglion cell (RGC) damage at a very early stage, has shown random damage to RGCs which cannot explain the classical VF defects on a Humphrey Visual Field Analyzer.

How can apoptosis like this produce visual field changes seen on perimeters ?

This brings me to the current topic. Prof Flammer has published a great deal on the vascular aspects of glaucoma. However, an article co-authored by him sheds some light on the role of cerebro-spinal-fluid (CSF) pressure (intracranial pressure or ICP) in the pathogenesis of glaucoma. 

The optic nerve is regarded as an extension of the brain. Like other parts of the CNS, the optic nerve (ON) is covered by the dura, arachnoid and pia mater. The optic nerve is exposed to IOP within the eye and to ICP due the presence of CSF in the sub-arachnoid space (SAS). The lamina cribrosa demarcates these two pressurized zones (eye vs. SAS) and the pressure difference between them is called “translaminar pressure difference” (TPD) (IOP-ICP=TDP). There is increasing evidence that TDP could play an important role in the pathophysiology of glaucoma.

Disc cupping is assumed to represent a typical morphological pattern of anterograde atrophy of axons on their way from the intraocular to the retrolaminar portion of the ON. However, there is a possibility that in some cases the primary damage occurs in the ON and then a retrograde process leads to the destruction of RGCs. This direct damage to the ON is attributed to the environment of the nerve especially to the surrounding CSF.

The ON is distinct from other cranial nerves in that it is surrounded by CSF throughout its entire length. The subarachnoid space (SAS) enveloping the ON may become or act as a separate CSF compartment in patients with normal-tension-glaucoma (NTG). CSF-cisternography, using an iodinated contrast agent (Lopamidol), has demonstrated blockage (stasis) and impaired influx of CSF from the chiasmal cistern into the SAS of the ON in normal-tension-glaucoma.

The ON compartment syndrome (and impaired CSF turnover) develops through postulated mechanisms such as inflammatory changes and mechanical stress on the arachnoid and it’s trabeculae as well as glial cells in the ON. This leads to increased expression of MHC II cells, tumor necrosis factor-alpha (TNF-α) and endothelin.

The apices of the meningoepithelial cells (MECs) lining the arachnoid layer face the SAS. These cells are highly reactive to various stimuli such as increased ICP and inflammation due to meningitis and arachnoiditis, as well as mechanical stress.

MECs also produce a rather unique factor called L-PGDS (Lipocalin-type Prostaglandin D Synthase). Upregulation of L-PGDS is demonstrated in αβ-crystalline positive oligodendrocytes and astrocytes in chronic multiple sclerosis. Elevated L-PGDS contributes to apoptosis of PC12 neuronal cells. Conversely, L-PGDS appears to protect the perineuronal oligodendrocytes from apoptosis. Studies have shown that when high concentration of L-PGDS is added to neuronal cultures the proliferation of astrocytes can be markedly inhibited in vitro.

L-PGDS could also act through the synthesis of prostaglandins which regulate vascular tone. ON compartmentalization leads to reduced CSF turnover; accumulation of substances such as L-PGDS, beta-amyloid, peroxinitrates and TNF-α; as well as possibly an effect on mitochondrial function. These are detrimental to the health of the ON.

The concept of an ON compartment syndrome offers an entirely new approach to the understanding of the pathophysiology of visual loss in patients with NTG. A disturbance of CSF components following compartmentation would cause damage to axons, astrocytes and mitochondria. It would also severely affect the blood vessel tone of the pial plexus supplying the ON in the SAS, leading to cupping of the optic disc and retrograde atrophy with loss of VF and ultimately involve the central visual acuity.

Physiologically, the difference between IOP (avg. 14.3 mmHg) and ICP (avg. 12.9 mmHg) in the supine position is small. A higher TPD may lead to abnormal function and damage of the ON due to changes in axonal transportation, deformation of the lamina cribrosa, altered blood flow or a combination thereof, leading to GON.

A meta-analysis of TPD published in “Nature” found that ICP was significantly lower in patients with primary open angle glaucoma, particularly NTG, than in healthy subjects. TPD was almost two times higher in patients with NTG and nearly five times higher in patients with high-tension-glaucoma (HTG), compared to healthy controls.

As the optic nerve head is exposed to both IOP and ICP, the TPD becomes an important parameter and its reduction might assist in halting the progression of glaucoma.

It is easy to define glaucoma as a “multifactorial” neurodegenerative disorder. These factors unfortunately, are multiplying by each passing day. Instead of presenting a clearer picture they are muddying the waters. The only hope is that out of chaos order will come and one day a better understanding of these factors will help us in determining the pathogenesis of glaucoma and thereby lead us to more positive treatment outcomes.


Dr Syed Shoeb Ahmad is just a "regular guy" with an interest in glaucoma.

Monday, August 19, 2019




The term “iridotomy” refers to the creation of a hole in the iris. Through common usage the laser procedure for doing this has become known as “laser iridotomy” or less commonly “laser iridectomy” and the incisional technique as “surgical iridectomy”.


  • Primary angle closure.
  • Pupillary block associated with uveitis.
  • Plateau iris configuration.
  • Nanophthalmos.
  • Ciliary block glaucoma.


Informed signed consent from the patient should be taken.

Pilocarpine eye-drops maybe instilled twice at 15 minute intervals, if the patient was previously not on these drops. By inducing miosis, pilocarpine unfolds the iris, reducing the thickness of the iris and improving the surgeon’s ability to create a full thickness hole with less amount of energy.

These advantages must be weighed against a possible increase in inflammation and development of posterior synechiae, which are enhanced by the miotic.

To blunt post-laser increase in intraocular pressure (IOP), 1% Apraclonidine can be instilled an hour prior to the procedure and immediately following the laser.

In case Apraclonidine is not available, Tab Acetazolamide 500mg before and after the procedure can be given.

Anesthesia is achieved by topical anesthetic drops.

Patients presenting during an acute attack of pupillary block glaucoma may require special measures to prepare the eye for the laser iridotomy.

In such cases the cornea may be cloudy from acutely elevated IOP and intravenous acetazolamide can be given to reduce the IOP to reduce the corneal edema sufficiently for better visualization of the anterior segment structures and accurate laser application.

Topical hypertonic saline may also be instilled to reduce corneal edema.

In extreme cases peribulbar or sub-tenon anesthesia can be given to reduce the pain.

If argon laser is not possible due to cloudy cornea, Nd:YAG laser alone can be attempted.

In the patient who is unresponsive to medical therapy or a poor surgical candidate, then a laser pupilloplasty or peripheral iridoplasty with argon laser can be used to break the pupillary block and relieve the attack.


The patient is seated at the laser instrument (Slit-lamp delivery system) and the iris viewed through the slit-lamp magnification.

A special contact lens such as the Abraham iridotomy lens is used to stabilize the eye, provide additional magnification and to keep the eyelids open.

The Abraham lens has a +66 diopter plano-convex lens button affixed to its anterior surface. This lens adds increased convergence to the laser beam, reducing its diameter and thus increasing the power density at the iris and decreasing it at the cornea. This facilitates creation of an iridotomy and reduces the risk of producing a corneal burn.

Following the same principles, the Wise lens, which uses a 103 diopter optical button, increases the energy density at the iris surface 2.92 times greater than the Abraham lens and further enhances the efficiency of the laser energy.


It is advisable to perform the iridotomy in the superior quadrant of the iris so that it is covered by the upper eyelid (thus avoiding uniocular diplopia in the patient). It is probably preferable to avoid the 12 o’clock area as gas bubbles formed during argon laser application tend to rise up and obscure the surgeon’s view of the iridotomy site.

The iridotomy is easier to achieve where the iris is thinnest. Relatively thin areas are found at the base of the iris crypts.


Various combinations of laser parameters have been described in order to perform an iridotomy.


Spot size: 200-500 microns
Spot size: 50 microns.
Duration: 0.1-0.5 seconds.
Duration: 0.2 seconds.
Energy level: 200-600 mW.
Energy: 800-1000 mW.
The thermal energy contracts the underlying iris and increases the tension on adjacent iris tissue. Contraction burns can be placed on either side of the intended site. A single broad laser burn will create an elevated area or “hump” nearby. Placing the iridotomy at the top of the hump may facilitate the penetration of the iris. In the “drumhead technique”, three to six such contraction burns are placed in a ring around the intended iridotomy site.
Some surgeons do not use preparatory burns as exposing the iris to additional laser energy releases more pigments which may block the trabecular meshwork.
These settings are usually effective in dark-medium brown eyes. However, in pale irides (with little pigment to absorb) and in dark irides (thick), difficulty may be encountered.


Usually laser settings of 6-8 mJ are sufficient in most cases.

Bursts of 5-6 pulses have been associated with damage to the lens.

Higher energy burns may also cause bleeding into the anterior chamber. Application of pressure by the iridotomy contact lens for sometime may stop the bleeding.


The end point of treatment is observation of a gush of aqueous through the patent iridotomy and visualization of the anterior lens capsule through the iridotomy.


  • Transient and occasionally, chronic uveitis.
  • Acute or chronic IOP elevation.
  • Late closure of iridotomy.
  • Localized corneal and lens damage.
  • Hemorrhage from iris vessels.
  • Laser burns to the peripheral retina.
  • Laser burns to the fovea causing profound visual loss.
  • Glare and diplopia through the iridotomy.
  • Pupillary distortion and formation of posterior synechiae.


The patient's anti-glaucoma treatment is not stopped immediately after the laser procedure. The patient is followed up periodically over a month to assess the IOP and the anti-glaucoma medications tailored to the need.
The patient is also put on topical steroid eye-drops (usually 4 times a day for a week). the frequency and duration can be tailored according to the inflammation.