Release The Inner Sleuth: Investigating Retina

21 11 2012


Sir Arthur Conan Doyle’s fictional detective Sherlock Holmes used an investigational technique known as deductive reasoning to solve his cases.  Through a series of inferences based on limited information present, Holmes could distil the evidence down to tell the finest of details of a crime – or at least so Doyle had crafted his character to do.  This approach of deductive reasoning is in fact a fundamental part of what health care providers do in history taking; asking probing questions about a particular chief complaint and using that information to direct the examination.  On occasion clinicians are faced with very limited historical information and are left with the objective findings alone to decipher what is actually going on with a particular patient.  Language and cultural differences are just a few examples of barriers that can exacerbate miscommunication.  However under this circumstance, clinical skills can become the water in the desert that the practitioner needs to make the right clinical judgement. This case exemplifies how using technology, with a limited history and subjective findings, can lead one to the correct diagnosis


A 60 year old female of Egyptian heritage reported for a routine assessment.  She spoke her native language, Arabic, and had very limited verbal and written English proficiency.  Her pertinent medical history was difficult to obtain as she came alone and did not bring a list of medications or allergies.  The ophthalmic technician was able to obtain a partial history, whereby the patient had previously been to an eye doctor in the United States 3 times within the last 3 months.  She was not specific as to what procedures, if any, had been performed or for what reason she had assessed.  Her chief complaint was “foggy” vision over the left eye with a vague onset of 6 months.  This was obtained by having the patient flip through a calendar in her personal diary to show when she started having problems.    She gestured with her hands that she had “pressure” for which she was taking a pill.  This was assumed to be systemic hypertension under some sort of medical management.

Initial testing demonstrated visual acuities with habitual correction was OD 20/20-1  OS 20/40+1.   Pupils were equal and reactive with no APD noted.  EOMS were full and binocularity was unremarkable.  Amsler grid was unreliable due to communicative barriers.  Anterior segments were deep and quiet OU.  Corneas showed trace arcus OU and mild conjunctival injection OU.  Mild anterior blepharitis was present associated with meibomian gland dysfunction

Final refraction was pl -0.50 x 180 OD yielding 20/20-1 and +0.50 DS OS yielding 20/30-1.

Fluorocaine eye drops were administered OU followed by IOP measurements with Goldmann applanation.  OD and OS were equal at 12 mmHg and pachymetry readings were 556 and 560 microns OD/OS respectively.  One drop each of Mydriacyl 1% and Phenylepherine 2.5% was instilled OU.

Dilated ophthalmoscopy was completed using 90D lens and peripheral ophthalmoscopy with 28 D lens.  Optic nerves were both pink and healthy with healthy rim tissue OU. CD ratio of 0.20 OD/OS was measured.  Artery/venous ratio was observed OU to be 2/3.  Peripheral retina revealed no holes, breaks or tears OU.  Macula OS showed no reflex with 20 vague pale lesions extending superior to the macula  that were less than 125 microns in size (see Figure 1).  There was a resolving nerve fibre haemorrhage in the superior temporal quadrant as well.  There didn’t appear to be any findings consistent with edema, however additional imaging was ordered to rule this out.  OD retina was unremarkable.

Figure 1. OS fundus image.

To refine and extract more clinical information, the patient underwent fundus autofluorescence (FAF) as well as spectral domain OCT imaging to further investigate the metabolic state as well as the in vivo anatomical state of the macula

Figure2. FAF image OS. Note pattern of hypofluorescent signal

Figure 3. SD-OCT OS macula. Intraretinal fluid confirms edema

Based on the above imaging, the clinical picture became clearer.  FAF, demonstrated an evenly distributed pattern of over thirty scattered hypofluorescent circular areas that were concentric around a branch arteriole/venule.  Additionally, these areas were noted to be crossing superior to and encroaching on the superior macular region.  This decreased signal indicated a diminished presence and, in fact, an absence of lipofuscin in the area due to dead or atrophic RPE.   The even spacing and ‘intentional’ pattern suggested this was not physiological but likely induced.  OCT demonstrated a small pocket of fluid in the supramacular region at the inferior border of the FAF hypofluorescent spots.  This fluid explained the decreased vision noted and added to the sequence of events that preceded this visit.

A clinical hypothesis was reduced to the following:  The induced local areas of atrophic RPE were as a result of grid argon or krypton laser photocoagulation to treat a BRVO which was located superior to the macular region resulting in macular edema.  The superior occlusion likely resulted in local edema which was noted in the gravity dependent macula.  According to the Branch Retinal Vein Occlusion Study (BRVOS) grid laser was indicated in patients whose vision was reduced to at least 20/40 or worse secondary to edema within 3 to 18 months post-occlusion (1).  The OCT in this case demonstrated residual edema present which coincided well with the expected time frame of the patient’s first reported symptoms (6 months previous).  This time frame was also consistent with the last eye exam in the US from her previous physician.  Closer examination of the FAF pattern revealed a non-uniform pattern of hypofluorescent between laser scars.  This suggested that there were likely multiple laser treatments done at different times, resulting in chronological stages of atrophy between treatment zones.  Going back to our patient’s history, she reported 3 visits with her previous eye physician which corresponds to the multiple treatment theory.  Once vision was restored to the clinical endpoint above 20/40, laser treatments were no longer indicated and the patient was likely advised to return to follow up with routine care.

Using Multispectral Imaging (MSI), remnant nerve fibre hemorrhages were apparent in the area associated which are indicated by the arrows in figure 4.  All the clues had added to the clinical diagnosis of BRVO with macular edema.

Figure 4. MSI OS. Note resolving NFL haemorrhages

The clinical decision at this point was made to have the patient return with a family member who could confirm the hypothesis to then determine a course of action.  The patient and daughter returned 3 days later and confirmed the BRVO and laser treatments performed in the US.  The daughter produced a report describing the satisfactory result of reduced edema and improved BCVA to an ‘acceptable’ level.  Fluorescein Angiography was conducted at the time of initial diagnosis which confirmed capillary perfusion to the area.  Instructions were to follow the edema monthly until resolution or otherwise, which time may call for further grid laser.  The physician had considered a final treatment prior to discharge with subthreshold micropulse diode (SMD) laser photocoagulation.  This was not done however, given that the endpoint acuity was achieved.

In follow up, this patient’s residual edema had resolved evenly over the following 2 months and BCVA improved to a final 20/25.


There are multiple areas of discussion that arise out of this case.   The two most obvious of which are: 1) The pathology and management of BRVO and 2) The method of deductive reasoning and its role in diagnoses where limited pre-visit information is available.

BRVOs are the most common type of retinal occlusive events as noted in the Beaver Dam Eye Study (2).   The arterial vascular supply to the retina drains into the venous system which carries back to the central retinal vein.  In a BRVO, a blockage at the venous level results in a backup into the capillary and arterioles that feed the drainage system.  This back up results in a leakage of blood and fluid into the intraretinal space and the site of occlusion determines the extent of the bleeding and edema.  Smaller veins result in quadrantal occlusions with larger veins resulting in hemispheric.  The site of occlusion generally occurs at the most proximal and central area of an artery crossing a vein.  Depending on the relative location of the BRVO to the macula, the risk of macular edema increases.  Superior BRVO’s are subject to the effects of gravity drawing the intraretinal fluid downward into the macular space (3).

The natural history of BRVO can be self-limiting, however risk of neovascularization and edema determine the need for intervention (3).  The likelihood of visual recovery without intervention to better then 20/40 was low according to the Center of Eye Research in Melbourne Australia (3).  Most predictive of a good recovery is the more distal the location of occlusion to the disc (BRVOS) in addition to the lack of non-perfusion on angiography studies (1).  If the area involved was shown to be ischemic, then the effect of intervention was limited with a guarded prognosis (1).

The Branch Retinal Vein Occlusion Study is the only multicenter randomized prospective trial from which treatment guidelines were derived.  The criteria included, but not limited to, vision below 20/40, capillary perfusion to the affected area, sufficient clearing of haemorrhage and angiography confirming leakage involving the fovea.  Eyes were randomized to argon grid laser vs. a control group and were followed to completion at 3 years.  The concluding findings of the study demonstrated that intervention with grid laser resulted in improved vision above threshold (20/40) and reduced risk of neovascularization (1).

The standard used in the BRVOS was the argon laser which causes photocoagulation to the retina by absorbing radiant energy causing protein denaturation in the region (4).  Laser energy initially is converted into heat mainly in the melanin of the RPE cells and choroidal melanocytes. Traditional laser burns create a radial wave of heat from the origin of the burn site within the RPE and/or choroid.   The discoloured grayish endpoint in conventional threshold photocoagulation signals that overlying neurosensory retina has been reached by the heat wave at a temperature high enough to damage the natural transparency of the retina (5).

The biological effect of the laser is unlikely in the cauterization of microaneurysmal changes, but rather the upregulation of biochemical mediators with antiangiogenic activity, such as pigment epithelium derived growth factor (PEDF) (6).  Additionally, the laser burns stimulate factors that activate inhibitors of vascular endothelial growth factor-angiogenesis and reduce VEGF inducers thereby reducing vascular permeability (7).

Subthreshold micropulse diode laser photocoagulation (SMD) is designed to target the RPE melanocytes while avoiding photoreceptor damage.  The term ‘subthreshold’ denotes the energy level of the laser being below which visible damage to neurosensory retina would occur. This results in no visible damage to retina either ophthalmoscopically or by FAF or angiography.  In these instances, history would be the only means to determine if SMD was used to treat (8).  One study compared the effect of SMD grid photocoagulation to conventional threshold grid photocoagulation in 36 eyes with macular edema secondary to BRVO. The number of SMD laser spots required to achieve endpoint was higher than threshold laser.   However at 2 years post treatment,  the SMD group had a 3 line or more gain in acuity (ETDRS) in 59% of eyes vs. 26% in the threshold group (9).  SMD, by having a reduced collateral effect, may be indicated for longer term stability and improved efficacy in certain cases and likely the rationale for the treating physician’s recommendation for a final treatment using SMD in his report.

Intravitreal injection of triamcinolone has been used to treat macular edema of different etiologies because of its potent anti-permeability and anti-inflammatory properties.   A few cases of macular edema secondary to BRVO treated with an intravitreal triamcinolone injection have been reported. The exact dose remains unclear however doses ranging from 4 mg to 25 mg have been reported to be effective (10).

AvastinTM (Bevacizumab) has been involved in several small retrospective and uncontrolled case series which suggest that intravitreal injections at doses up to 2.5 mg are effective in improving visual acuity and reducing macular edema secondary to BRVO. These results are often seen within 1 month of injection; however, most of the eyes required additional injections to maintain the effects of bevacizumab (11) (12).

From the above example, a case can certainly be made for the use of thorough testing to unveil a diagnosis, but what is likely more crucial are the small pieces of history that were obtained.   Combining this information and correlating it with the evidence presented by clinical exploration allows the full history to unfold.  Deductive reasoning in this examplewas the final diagnostic tool to give the most appropriate course of action for this patient.  It is possible that, without the historical information and deduction, this patient may have been referred for intravenous fluorescein angiography (IVFA) for further invasive scrutiny of the retina.  IVFA of course has known side effects that range from nausea to cardiac arrest.  By working through the case backwards, this unnecessary step was avoided and appropriate observation was indicated.


Current discussions in all clinical practices revolve around standards of care and how clinicians can rise to that standard.  One question illustrated by this case is, ‘is a standard enough?’   Is common ground the best way to drive health care decisions?  Establishing a standard requires common agreement of the majority of a spectrum of clinicians based on current evidence and available tools.   However in this scenario where the common denominator dictates what practitioners should and should not do, this actually reduces the standard to, arguably, a lower quality of care.   Individual standards give the practitioner the opportunity to think outside the box and truly reach a higher calibre of care.  In that context, using an intuitive tool like deductive reasoning, which, according to Piaget’s theory of cognitive development is established as early as shortly after birth, can turn a lack of communication from a patient into an opportunity to solve a mystery (13).  This can turn the average eye care provider into a sleuth with seemingly extraordinary powers; a superhero among all.


1. Argon laser photocoagulation for macular edema in branch vein occlusion. Group, The Branch Vein Occlusion Study. 3, 1984, Am J Ophthalmol, Vol. 98, pp. 271-282.

2. The epidemiology of retinal vein occlusion: the Beaver Dam Eye Study. Klein R, Klein BE, Moss SE, Meuer SM. 2000, Trans Am Ophthalmol Soc, Vol. 98, pp. 133-143.

3. Natural history of branch retinal vein occlusion: an evidence-based systematic review. Rogers SL, McIntosh RL, Lim L, Mitchell P, Cheung N, Kowalski JW, Ngueyn HP, Wang JJ, Wong TY. 6, June : s.n., 2010, Ophthalmology, Vol. 117, pp. 1094-1101.

4. Laser-tissue interaction studes for medicine. GR, Kulkarni. 1988, Bulletin Mat Sci, Vol. 11, pp. 239-244.

5. Micropusled diode laser therapy: evolution and clinical application. Sivaprasad S, Elagouz M, McHugh D et al. 6, Nov 2010, Surv Ophthalmol, Vol. 55, p. 516.

6. Upregulation of pigment epithelium-derived factor after laser photocoagulation. Ogata N, Tobran-Tink J, Jo N, et al. 3, Mar 2001, Am J Ophthalmol, Vol. 132, pp. 427-429.

7. Effect of pan retinal photocoagulation on the serum levels of vascular endothelial growth factor in diabetic patients. Manaviat MR, Rashidi M, Afkhami-Ardenkani M, et al. 4, Aug 2011, Int Ophthalmol, Vol. 31, pp. 271-275.

8. Short-pulse laser treatment: redefining retinal therapy minimizing side effects without compromising care. Paulus YM, Palanker D, Blumenkranz MS. Jan-Feb 2010, Retinal Physician, pp. 54-59.

9. Subthreshold grid laser treatment of macular edema secondary to branch retinal vein occlusion with micropulse ingrared (810 nanometer). Parodi MB, Spasse S, Iacono P, et al. 12, Dec 2006, Ophthalmology, Vol. 113, pp. 2237-2242.

10. Intravitreal triamcinolone acetonide injections in the treatment of retinal vein occlusions. Roth, DB, Cukras C, Radhakrishnan R, Feuer WK, Yarian DL, Green SN. 6, Nov-Dec 2008, Ophthalmic Surg Lasers Imaging, Vol. 39, pp. 446-454.

11. One-year results after intravitreal bevacizumab therapy for macular edema secondary to branch retinal vein occlusion. Jaissle GB, Leitritz M, Gelisken F, Ziemssen F, Bartz-Schmidt KU, Szurman P. 1, Jan 2009, Graefes Arch Clin Exp Ophthalmol, Vol. 247, pp. 27-33.

12. Intravitreal bevacizumab (Avastin) for macular oedema secondary to retinal vein occlusion: 12-month results of a prospective clinical trial. Prager F, Michels S, Kriechbaum K, Georgopoulos M, Funk M, Geitzenauer W. 4, Apr 2009, Br J Ophthalmol, Vol. 93, pp. 452-456.

13. JW, Santrock. A Topical Approach to Life Span Development. New York : McGraw-Hill, 2008. pp. 221-223.