TREATMENT TRIALS FOR AGE RELATED MACULAR DEGENERATIONS

TRIALS FOR PHOTODYNAMIC THERAPY (PDT)

TAP STUDY ( P for PDT & Predominantly classic CNVM) : 

• PDT vs Sham group in Predominantly classic CNVM.
• Showed statistically significant benefit in predominantly classic CNVM.

VIP STUDY ( P for PDT; VIPs are Occult)

• PDT vs placebo
• Included patients with Occult CNVM without classic component.
• No significant benefit in visual acuity.

Conclusion :  PDT is effective only in Predominantly Classic CNVM. 

TRIALS FOR PEGAPTANIB (MACUGEN)

• Pegaptanib is VEGF-165 inhibitor.
• First FDA approved drug for treatment of AMD in 2004.
• Got approval on the basis of VISION( VEGF inhibitor study in ocular neovascularisation) trial. 
• KEY : VISION = MACULA (macugen).

VISION TRIAL:

• Intravitreal Macugen (0.3 mg, 1mg & 3mg)  vs sham injection at 6 weekly interval.
• 0.3 mg dose proved to be more effective than 1mg and 3mg injections and sham injections with statistically significant reduction in moderate to severe visual acuity loss over 2 years of follow up.

TRIALS FOR RANIBIZUMAB (LUCENTIS)

• FDA approved in 2006 on the basis of the results of MARINA & ANCHOR TRIALS.
• First FDA approved anti VEGF agent that has shown improvement in visual acuity in all isoforms of CNVM and prevented leakage and further growth of the lesion.

MARINA TRIAL ( Minimally classic/Occult CNVM anti VEGF Ranibizumab in Neovascular AMD).

• Intravitreal Ranibizumab (0.3 & 0.5 mg) monthly injection in minimally classic or occult CNVM vs sham group.
• Statistically significant reduction in visual acuity loss along with improvement in visual acuity over 1 year of follow up.
• Clinical improvement was associated with improved angiographic and OCT picture.

ANCHOR STUDY ( Anti VEGF Ranibizumab for the treatment of predominantly Classic CNVM in neovascular AMD ).

• PDT controlled trial
• 0.3 & 0.5 mg intravitreal Ranibizumab monthly injection vs 3 monthly PDT in Classical CNVM.
• Statistically significant reduction in visual acuity loss along with improvement in visual acuity with 0.5 mg Ranibizumab over 2 year of follow up as compared to PDT.

PIER STUDY ( R for Ranibizumab)

• 3 consecutive monthly injections of Ranibizumab followed by 3 monthly injection.
• Improvement in visual acuity observed during first 3 months which was not sustained after discontinuance of monthly injections over 1 year of follow up.

PRONTO TRIAL ( Prospective OCT imaging of patient with Neovascular AMD treated with intraocular Ranibizumab )

• 3 consecutive monthly injections of Ranibizumab followed by monthly OCT evaluation.
• Injections repeated only when OCT showed progression.
• Comparable visual acuity outcomes with ANCHOR & MARINA trials.

TRIALS FOR BEVACIZUMAB (AVASTIN)

• FDA approved in 2004 for systemic use in colorectal cancer.
• 5mg/kg intravenous also tried in AMD cases, 3 injections @ 2 weekly interval, later injections were OCT guided.                                                                                                                         

SANA TRIAL ( Systemic Avastin for Neovascular AMD) 

• 5mg/kg I.V dose.
• Advantage of systemic  Avastin - bilateral disease can be treated.
• Increased B.P controllable with medication was the only reported adverse effect.
• First intravitreal Avastin was given in May 2005, has shown comparable results with systemic Avastin and intravitreal Ranibizumab.

CATT TRIAL ( Comparison of ARMD treatment trial ) 

• Comparison between intravitreal Avastin and Lucentis in all isoforms of neovascular AMD.
• Both came out to be equally effective in the treatment of all isoforms of neovascular AMD.

OCULAR MYASTHENIA GRAVIS : DIAGNOSTIC PEARLS

OCULAR MYASTHENIA GRAVIS: DIAGNOSTIC PEARLS

CLINICAL TESTS

• SLEEP TEST :  Improvement in muscle activity after 30 minutes of rest with closed eyes.
• ICE PACK TEST : Improvement in ptosis (after 2 minutes) and extraocular muscle activity (after 5 minutes) after placing ice pack over closed eyelids. improvement of atleast 2 mm in ptosis is required to consider the test as positive.

PHARMACOLOGICAL TESTS 

•  EDROPHONIUM TEST :  DOSE - I.V edrophonium 0.10mg/kg in children and upto 10mg in adults.

           Initially 2mg of dose is given to look for any adverse effect, if not 3-4 mg is injected further                upto maximum dose of 10 mg. 

           Onset of action : within 60 seconds.

            Effect lasts for 5-10 minutes.

           Improvement in ptosis or muscle activity suggests positive test.

           Contraindicated in bronchial asthama and cardiac patients.

• NEOSTIGMINE TEST : DOSE - 1.5 mg in adults, injected intramuscularly in deltoid region.

          Onset of action: 15-30 minutes. Effect lasts for several hours (longer duration of action).

          Contraindications : Same as Edrophonium.

LABORATORY INVESTIGATIONS

• Positive anticholine-esterase receptor antibody (AChR-Ab) titres confirm the diagnosis.
• Repeatative nerve fiber stimulation & single fiber electromyography.

IMAGING may reveal thymic hyperplasia (70%) or thymoma (10-15%) in some cases.

4-5% patients may have concurrent autoimmune thyroid disease.

THE RISE OF AN OBLIVION MONSTER: NON TUBERCULAR MYCOBACTERIAL KERATITIS

NON TUBERCULAR MYCOBACTERIAL KERATITIS : A BRIEF NOTE

• Aerobic, acid fast bacilli.
• Causes delayed onset keratitis with indolent course.
• Increased incidence after LASIK.
• Other causes include trauma, cataract surgery, penetrating keratoplasty or contact lens use.

• Fast growing Non Tubercular Mycobacteria : M. chelonae, M. abscessus, M. fortuitum, M. mucogenicum. Onset after 3-4 weeks of procedure. 

• Slow growing Non Tubercular Mycobacteria : M. szulgai. Onset after 6-24 weeks of procedure.

• Symptoms & Signs :  * mild foreign body sensation, pain, photophobia, reduced visual acuity.                                      * Non suppurative corneal involvement.                                                                                        * Multifocal lesions.                                                                                                                        * CRACKED WIND SHIELD APPEARANCE. 

• Diagnostic Stains and Culture media : STAINS- Gram stain, Giemsa stain, Ziehl Neilson stain.
• CULTURE MEDIA- Lowenstein-Jensen Media, Middlebrook 7H9 or 7H12.                         Fast growing NTMB are culture positive within 7 days while slow growing NTMB takes few weeks to be culture positive.
• Flap elevation in post LASIK cases for corneal swabs facilitates easy microbial recovery.

• Treatment : Fortified Amikacin (6-7 mg/ml) + 1% azithromycin or Clarithromycin eye drops half hourly are antibacterials of choice along with adjuvent therapy. Flap amputation in post LASIK cases facilitates drug penetration and early response.

corneal preservation medium

CORNEAL  PRESERVATION MEDIA

For short term storage (upto 96 hours at 4 degree   celsius)

MOIST CHAMBER

For maximum 1 day. Whole globe is kept in moist chamber. 

MODIFIED McCarey Kaufman (MK) MEDIUM :

Constituents:

*Tissue culture 199

*5% dextran

*N'-2 hydroxy ethyl piperazine Nethane sulfonic acid (HEPES) 15-20mmol/L.

*Penicillin G

*Gentamicin 200 microgms/ml

*Polymyxin B 50 micrograms/ml

*Phenol red as an indicator

*pH 7-7.5

*Osmolality 295-355 

For intermediate term storage (upto 15 days at 4 degree celcius)

LIKEROL

Constituents:

*Sodium pyruvate

*Glucose

*Vitamins

*Na, K, Cl and other electrolytes

* 2% chondritin sulfate

*HEPES

*Gentamicin, Penicillin, Streptomycin

*Phenol red as an indicator

OPTISOL GS

Constituents:

*TC199 + Minimum essential medium (base medium)

*Chondroitin sulfate 2.5%

*Dextran 40

*HEPES

*Gentamicin

*Streptomycin

*Cholesterol

*ATP

*Iron

*Sodium bicarbonate

*Sodium pyruvate

*Antioxidants

*Non easential amino acids

*Na+ 181mEq/L

Eusol C, Dexol, Procell are other examples

For long term storage(months)

ORGAN CULTURE

* Room temperature storage

* Upto 4 weeks

Constituents:

*Eagles MEM (Minimum essential medium)

*2% Fetal bovine serum

*Penicillin, Streptomycin, Amphotericin B

*HEPES

*Sodium bicarbonate

*L-glutamine

** European organ culture supports endothelium upto 120 days.

EUROSOL TISSUE CULTURE

Storage at 31 degree celcius for upto 1 month.

CRYOPRESERVATION

Corneas are stored at -80 degree celcius in liquid nitrpgen with dimethyl superoxide (DMSO) for indefinite period of time.

**  Grafts for lamellar keratoplasty, corneoscleral buttons are stored in 100% glycerine. Endothelium is non viable and they can be used upto 1 year.

ANTI FUNGAL DRUGS: MUST KNOW POINTS

* Most antifungal agents interfere with fungal cell wall synthesis and are fungistatic.

Here are few important points and dosages of important antifungal agents classwise:

1. Polyenes

NATAMYCIN

• Broad spectrum
• 5% topical suspension

AMPHOTERICIN B

• Highly effective against yeast.
• Topical 0.15%
• Subconjunctival 0.5-1 mg
• Intracameral 7.5 -10 micrograms/0.1 ml
• Intravitreal 5 micrograms/0.1 ml

Natamycin and Amphotericin B are not preferred for subconjunctival administration baecause of significant toxicity.

2. Triazoles

FLUCONAZOLE

• Most effective against Yeast.
• oral dose 400mg/day upto 4-6 weeks
• Topical 0.2%
• Subconjunctival 1-2mg. 

ITRACONAZOLE

• Supposed to have good corneal permeability and aqueous levels.
• Oral 200 mg/day.
• Topical 1%
• Subconjuntival 100mg twicw daily injection.

VORICONAZOLE

• Broad spectrum
• Topical 1%
• Subconjunctival 10 mg.
• Oral 100mg/day. 98% bioavailability with peak action in 2-3 hours.

3. Imidazoles

• This group of drugs have poor corneal penetration.
• Useful in superficial infections.

 KETOCONAZOLE

• Oral 200-400mg/day.
• topical 5% (oil based).

MICONAZOLE

• Topical 1% suspension
• Subconjunctival 5-10 mg.

CLOTRIMAZOLE

• Topical 1%.

4. Pyrimidines

FLUCYTOSINE

• Rapid resistance.
• Effective against Candida sp.
• Oral 50-150 mg/kg/day.
• Topical 2%. 

NEWER ANTIFUNGAL AGENTS

• Ravuconazole : Triazole, oral, effective against Candida and Aspergillus.
• Posaconazole: Triazole, oral, effective against Candida and Aspergillus.
• Caspofungin: Echinocandin group. Effective against Candida (fungicidal) with some activity against Aspergillus.
• Micofungin: Echinocandin group. Effective against Candida (fungicidal). Available for oral and subconjunctival administration.
• Echinocandins are the safest antifungals available with lowest hepatic and renal toxicity profiles.

INDICATIONS OF ORAL ANTIFUNGAL THERAPY:

• Large ulcer >6mm.
• Severe deep keratitis (endothelial plaque, AC penetration)
• Scleritis
• Post penetrating keratoplasty
• Endophthalmitis
• Diabetes Mellitus
• Immunocompromised

Liver function profiles should be repeated every 15 days in patients taking oral antifungals.

Signs in thyroid ophthalmopathy

DALRYMPLE  SIGN. Stairing and frightend appearance. Most common sign(95%).

VON GRAEFE'S SIGN. Lid lag in downgae (50%).

ENROTH'S SIGN. Fullness of eyelids.

GIFFORD'S SIGN. Difficulty in eversion of upperlid.

STELLWAG'S SIGN. Infrequent blinking.

MOBIUS'S SIGN. Convergence weakness.

KOCHER SIGN. Eyelid-  globe lag on supradduction.

ROSENBACH SIGN. Tremors of eye lids on gentle closure.

POCHIN SIGN. Reduced amplitude of blinking.

BOSTON SIGN. Jerky movements of upper eyelids in downgaze.

GELLINEK SIGN. Abnormal pigmentation of upper eyelids.

REISMAN SIGN. Bruit over eyelids

Congestion over insertion of horizontal recti.

Cornea in numbers

Vertical diameter (anterior surface) :10.6 - 11.7 mm 

Horizontal diameter (anterior surface) : 11.6-12.6 mm

Avg. posterior surface diameter : 11.6-12 mm

Avg. corneal diameter at birth :  9.8 mm

Maximum increase in corneal diameter occurs during 6 to 12 months of age.

Megalocornea :
* Horizontal diameter >= 12 mm in newborns and >= 13 mm in adults.

Microcornea :
* Horizontal diameter < 10 mm (down upto 4 mm)

Horizontal corneal diameter more than 12mm in the first year of life is highly suspicious for congenital glaucoma.

Refractive power of anterior central cornea : 48-48.8 D.

Approx. refractive power of central posterior corneal surface : -5.8 D.

Net corneal refractive power : 43 D (70% of total refractive power of eye).

Refractive power of a full term new born cornea : 51D.

Minimum 13% oxygen is required at the anterior corneal surface for normal corneal metabolism and to prevent lactate accumulation in aqueous.

Thickness of cornea : * periphery : 0.65-1mm
                                       * centre : 0.47 - 0.62 mm
                                            (0.5mm).
* epithelium : 50 - 100 microns.
*  bowman's membrane : 8-13 microns.
* stroma forms 90% of total corneal thickness.
* thickness of descemet's membrane: 2-3 microns at birth. 20-30 microns in old age.

Avg. life cycle of a new epithelial cell is 3-7 days.    

Corneal endothelial cell density:
* Highest at birth - 4000 cells/sq mm.
* 5 yrs of age- 3600+/- 400 cells/sq mm .
* adult - 2000 cells/sq mm.

After 2 years of age endothelial cell loss occurs at the rate of 0.56% approx. per annum.

Critical cell density to prevent corneal decompensation is 300-400 cells / sq mm.

Desirable endothelial cell density in donor tissue is atleast 2000 cells / sq mm.

Grading of corneal haze :
0   - clear cornea.
0.5- barely detectable or trace haze.
1   - mild haze not interfering with refraction.
2   - moderate haze interfering with refraction.
3   - marked haze that obscure iris details.
4   - severe haze that preclude iris details.
         

IRON DEPOSITION LINES ASSOCIATED WITH VARIOUS DISEASES

Fleischer ring : seen in keratoconus. At the base of cone.

Hudson Stahli line : seen at the junction of middle and lower 1/3rd of cornea of aged persons (>50 years). Yellowish brown in colour, curves downward. Appears black in blue light.

Ferry line : seen around filtering bleb.

Stocker's line : seen in the body of pterygium.

Coat's white ring : subepithelial in location. Forms long after resolution of corneal iron ring due to corneal iron foreign body.

Iron deposition also occur around Salzmann nodules.

Uveitis and its associations

Uveitis with internuclear ophthalmoplegia : Multiple sclerosis, sarcoidosis, non Hodgkins lymphoma.

Uveitis with erythema nodosum:
Sarcoidosis, Behcet's disease

Uveitis more common in females:
VKH, Juvenile Idiopathic arthritis, chronic anterior uveitis

Uveitis with headache:
VKH,  Sympathetic ophthalmitis, sarcoidosis

Uveitis with deafness:
VKH, Sarcoidosis

Uveitis with paraesthesia:
Multiple sclerosis (MS),  Behcet's disease

Uveitis with psychosis:
MS, VKH, Behcet's disease

Uveitis with oral ulcer:
Behcet's disease, inflammatory bowel disease (IBD)

Uveitis with genital ulcer:
Behcet's disease, Reiter's syndrome

Uveitis with arthritis:
HLA B27 associated arthritis, Juvenile Idiopathic Arthritis (JIA) , SLE, Behcet's disease, sarcoidosis in children

Uveitis with sacroileitis:
Ankylosing spondylitis, IBD, Reiter's syndrome.

New revised criteria for diagnosis of Vogt Koyanagi Harada Syndrome

5 crieterias :

1. No history of penetrating trauma or surgery.
2. No evidence of any ocular disease.
3.  (a) Early stage characterized by
             * diffuse choroiditis seen with or    
               without optic nerve involvement and
               vitritis.
              *presenceof bullous RD.
      (b) Chronic or late stage characterized by
             * Siguira sign
             * Sunset glow fundus
             * Dalen Fuch nodules
4. Neurological and auditory symptoms
5. Integumentary symptoms

Based on these crieteria VKH has been described in 3 subtypes :
Complete VKH : all 5 criterias present
Incomplete VKH : crieteria 1 to 3 with either
                                crieteria 4 or 5
Probable disease : criteria 1 to 3