Thursday, June 27, 2019

NEUROPROTECTION


GUEST AUTHOR

ZEBA SALEEM

AJMAL KHAN TIBBIYA COLLEGE
ALIGARH





INTRODUCTION

  • Glaucoma is a multifactorial neurodegenerative disorder. There is chronic loss of retinal ganglion cells (RGCs) and their axons in this condition. It is hoped that interventions involving neuromodulation (preserving neuronal structure/function), neuroprotection (preventing further neuronal damage) and neuro-regeneration (re-growth of damaged cells/neurons) could be utilized to manage this fearfully blinding disease. 
  • Neuroprotection in glaucoma refers to any intervention intended to protect the optic nerve or prevent the death of RGCs, in addition to and as a separate effect from lowering of IOP. 
  • This blog post reviews the pharmacological basis of neuroprotection in glaucoma.



PHARMACOLOGICAL APPROACHES TO NEUROPROTECTION

NMDA receptor antagonists:

  • Excess glutamate leads to NMDA receptor overactivity and excitotoxicity.
  • Initial experiments involved MK-801 (Dizocilpine).
  • It completely blocks normal glutamatergic neurotransmission (required for normal CNS function).
  • Experiments have shown MK-801 to be neuroprotective by decreasing expression of Bad and transient deactivation of the pro-survival kinase Akt pathway.
  • However, since MK-801 is a non-specific blocker of glutamatergic neurotransmission it is not appropriate for clinical use. 
  • Memantine is a non-competitive, low-affinity open channel NMDA blocker.
  • It exhibits selective blockade of excessively open channels with a fast off-rate.
  • It inhibits excessive NMDA receptor activity, while maintaining neoronal cell function.
  • It does not accumulate significantly within the channel.
  • However, a phase 3 clinical trial on memantine in OAG did not meet its primary end point.



Neurotrophic factors:

  • Experimentally neurotrophic factors such as BDNF and CNTF have been reported to enhance survival of RGCs (in optic nerve crush injury models).
  • A combination of BDNF and LINGO-1 antagonist has been experimentally shown to enhance long term RGC viability.
  • In vitro application of BDNF to isolated RGCs prolongs their survival. In vivo RGC survival is also found to be prolonged by intravitreal injection of BDNF.



Anti-apoptotic agents:

  • Supplements of creatine, alpha-Lipoic acid, nicotinamide and epigallocatechin-gallate (EGCG) act by countering oxidative stress, promote mitochondrial function and confer neuroprotection.
  • Inhibition of apoptosis can be achieved by 2 mechanisms=


  1. Activation of anti-apoptotic extracellular signal regulated kinase (ERK) and Akt by Brimonidine. These enhance the production of Bcl-2 and Bcl-xL.
  2. Blocking of apoptotic machinery by the use of caspase inhibitors. Caspases are a family of aspartate-specific cysteine proteases. The term caspase denotes the Cysteine requiring ASPartate proteASE activity of these enzymes.


  • Calpeptin, a calpain-specific inhibitor, has been studied for its role in neuroprotection. It prevents Ca++ influx, proteolytic activities and apoptosis in RGC cells.



Nitric oxide synthase antagonists:

  • NOS inhibitors such as 2-aminoguanidine, I-NOS and L-N6-(1-iminoethyl) lysine 5-tetrazole amide have been studied for their neuroprotective role.
  • Nipradiol, a beta- and alpha1- antagonist was also found to be neuroprotective.
  • However, others have reported an absence of NOS release by astrocytes and did not find any neuroprotective effect of amino-guanidine.



Anti-oxidants:

  • Anti-oxidants and free radical scavengers reduce RGC death occurring from NMDA toxicity.
  • Vitamins C, E, superoxide dismutase, catalase, Ginkgo biloba (EGb 761) have been shown to have these properties.
  • Ginkgo biloba also preserves mitochondrial metabolism and enhances ATP production in various tissues.



Calcium channel blockers:

  • Nifedipine and Verapamil confer neuroprotection by enhancing OBF. They also improve glutamate metabolism and are responsible for homeostasis in the ONH.
  • On the downside, these Ca++ channel blockers cause systemic hypotension which may aggravate retinal ischemia.
  • In a rat model, continuous treatment with candesartan (angiotensin II type I receptor blocker) provided significant neuroprotection.



Gene therapy:

  • Deprenyl (a monoamine oxidase inhibitor) increases gene expression of factors that halt apoptosis.
  • Flunarizine and aurintricarboxylic acid were found to retard apoptosis following light-induced photoreceptor cell death.



Immunomodulators and vaccination:

  • Glaucoma can be regarded as an immunogenic mechanism with prominent activation of resident and systemic immune responses during the early course of the disease. 
  • Chronic glial activation is regarded as a hallmark of neuroinflammation in glaucoma.
  • Associated failure in regulation of immune response pathways may lead to a neurodegenerative state and promote injury to neurons.
  • Adaptive/protective responses of resident or systemic immune cells can support neurons and promote tissue repair mechanisms after injurious insults.
  • Glatiramer acetate= A non-biological complex heterogeneous mixture of synthetic polypeptides. Peptide epitopes in Glatiramer acetate compete with autoantigens for binding with major histocompatibility complex molecules or antigen-presenting cells, thereby altering the functional outcome of T-cells signaling from inflammatory to anti-inflammatory responses.
  • Pharmaceutical inhibition of TNF-a, a major pro-inflammatory and pro-apoptotic cytokine has provided protection against RGC and axonal degeneration in experimental models of glaucoma.
  • Selective inhibition of TLR4 signaling with  TAK-242 (resatorvid) has been found to reduce astrocyte activation and RGC death after ON crush injury in mice.
  • Inactivation of astroglial NF-kB the key transcriptional activator of inflammatory mediators downstream of TNF-a/TNFR and TLR signaling pathways has reduced the pro-inflammatory genes and promoted RGC survival after retinal ischemia.
  • Intraocular administration of cAMP phosphodiesterase inhibitor (Ibudilast) has resulted in decreased production of pro-Iflammatory mediators and increased survival of neurons in Ocular hypertensive rat eyes.



Geranylgeranylacetone (GGA):

  • GGA has been observed to evoke the synthesis of HDP70, this could have a neuroprotective role.



Stem cell therapies:

  • Stem cells are thought to exert neuroprotective effects by generating neurotrophic factors, modulating MMP and other aspects of the CNS environment that may promote endogenous healing.
  • Granulocyte-Colony stimulating factor (G-CSF) is greatly expressed by RGCs and may provide neuroprotection.
  • Oligodendrocyte precursor cells (OPCs), a type of neural stem cell, may provide protection to RGCs.
  • Mesenchymal stem-cell derived exosomes have been reported to deliver trophic and immunomodulatory factors, suppress the migration of inflammatory cells, attenuate pro-inflammatory cytokine secretion and promote RGC survival. 



Bioenergetics:

  • It is the study related to metabolic processes  leading to energy utilization in the form of ATP molecules.
  • Energy failure and mitochondrial dysfunction in the ONH may have a role in glaucoma due to reduced energy and increased free radical production.
  • Enhanced mitochondrial function or increasing energy supply of neurons may provide neuroprotection.



Sunday, June 16, 2019

MALIGNANT GLAUCOMA


Guest author
NAZMI USMANI
Ajmal Khan Tibbiya College
Aligarh
India




Introduction:

It is also known as:
Aqueous misdirection syndrome
Ciliary block glaucoma
Cilio-lenticular block
or Direct lens block glaucoma


The term “malignant glaucoma” was used by Von Graefe (1869) for a condition characterized by: “A shallow or flat anterior chamber with an inappropriately high intraocular pressure (IOP), despite a patent iridectomy”. 

As it was a violent form of secondary glaucoma (especially in the post-operative setting), that was resistant to treatment and often resulted in blindness (poor prognostic outlook), it was termed “malignant”.

It is regarded as a multifactorial condition that is thought to occur in anatomically predisposed eyes.

Etiology:
It may occur in phakic, pseudophakic or aphakic eyes.

It can occur following:
  • Glaucoma filtering surgery (GFS) [especially in angle closure eyes].
  • Other surgeries, such as: cataract surgery (with or without intra-ocular lens), scleral buckle, pars plana vitrectomy.
  • Laser procedures: Nd:YAG cyclophotocoagulation, after laser-iridotomy or -sclerotomy 
  • Implantation of a large optic intra-ocular lens (>7 mm).
  • Use of miotics in predisposed eyes.

Idiopathic cases of malignant glaucoma (MG) have also been reported.

Prevalence:
2-4% angle closure glaucoma patients undergoing GFS develop malignant glaucoma.
2.3% post-keratoplasty patients and 1.3% patients who undergo GFS alone or combined with cataract extraction develop MG.
Females have 3 times higher risk of developing MG, as compared to men (apparently due to smaller ocular dimensions).

Predisposing factors:
  • Axial hyperopia
  • Nanophthalmos
  • Chronic angle closure with plateau iris configuration 
  • H/O malignant glaucoma in fellow eye
  • A thick sclera may cause partial stenosis of vortex veins, impairing normal venous outflow and cause engorgement of choroid. Opening of anterior chamber during surgery lowers IOP suddenly with forward movement of the lens-iris diaphragm. This triggers MG in these eyes.
  • A lens which is too large for the eye (disproportion between the volumes of the lens and eyeball predispose the eye to MG). The choroid gets edematous due to accumulation of blood when outflow is impaired. The ciliary body and iris rotate to the front closing access to the filtration angle from the back.
  • In nanophthalmos the lens is larger in volume; there is decreased axial length and thickened choroido-scleral layer. This causes crowding of the anterior segment.
  • A peripheral iridotomy does not prevent overfilling of the choroid (which leads to progressive angle closure).
  • Eyes predisposed to develop MG have connective tissue related pathologies and accumulation of glycosaminoglycans in the vitreous.

  
Pathogenesis:

There are different theories which explain the development of malignant glaucoma=

I. Schaffer and Hoskins theory (“Posterior pooling of aqueous”): Aqueous flow is diverted posteriorly causing pooling (accumulation) of aqueous behind a posterior vitreous detachment. This shifts the lens-iris diaphragm anteriorly causing a pupillary block.

II. Chandler and Grant theory (“Slackness of lens zonules”): Laxity of lens zonules coupled with positive vitreous pressure causes a forward movement of lens. This sets up a vicious cycle in which the higher the pressure in the posterior segment, the more firmly is the lens pushed forward.

III. Quigley et al. (“Choroidal expansion”): The precipitating event is choroidal expansion which increases vitreous pressure. The initial compensatory outflow of aqueous along the postero-anterior pressure gradient causes shallowing of the anterior chamber.

IV. Final common pathway:
Establishment of vicious cycle whereby the transvitreal pressure cannot be established by outflow of aqueous humor -> Fluid buildup behind the vitreous leads to vitreous condensation which exerts a forward force -> Anterior displacement of the lens-iris diaphragm 


Classification:

Classical malignant glaucoma: It is a rare complication of incisional surgery for primary angle-closure glaucoma. It is independent of the type of surgery and preoperative IOP. It can occur immediately after surgery to many years later. In the early postoperative period it is related to cessation of cycloplegic drugs. There is partial or total closure of the drainage angle at the time of surgery and axial hypermetropia is associated with increased risk of MG.

Nonphakic malignant glaucoma: Develops in patients after cataract extraction. It may occur with or without antecedent glaucoma.
   
Malignant glaucoma in aphakia
Malignant glaucoma in pseudophakia

Miotic induced malignant glaucoma: Perhaps associated with contraction of ciliary body or associated with forward shift of the lens leading to shallowing of anterior chamber. 

Others: Malignant glaucoma associated with bleb needling, infection and inflammation and other ocular disorders.

Spontaneous malignant glaucoma: MG may develop spontaneously in the absence of previous surgery, miotic therapy or any other apparent cause. 

Evaluation:

Medical history=
1. Determination of predisposing factors
2. Symptoms: Patients usually present with red, painful eye, decreased vision (similarly to pupillary-block glaucoma). Headache, nausea and vomiting may also occur, depending on IOP. Myopic shift related to anterior movement of lens-iris diaphragm, with secondary improvement of near vision occurs. Persistent symptoms due to anterior synechiae associated with long-standing shallowing of anterior chamber.

Slit-lamp examination:
Anterior chamber depth= Central & peripheral shallowing of the anterior chamber.
Patency of iridotomy should be examined. If none is visible, an iridotomy should be attempted.
Iris is not bowed anteriorly (iris bombe’ of Angle Closure Glaucoma)
Vitreous may have optically clear spaces. This can also be seen on B-scan ultrasound.
Seidel test should be performed to exclude filtering bleb leaking after filtration surgery. Such cases present with hypotony.
Posterior segment should be examined or assessed by ultrasound to rule out choroidal detachment or suprachoroidal hemorrhage.
Tonometry and gonioscopy should be performed.


Ultrasound Biomicroscopy (UBM):
Anterior rotation of ciliary processes, which press against the lens equator (or the anterior hyaloid in aphakia) and prevents forward flow of aqueous (hence the term ciliary block glaucoma). 
In some cases UBM has shown the size of the lens to be smaller than normal, that may allow the lens to move forward within the eye.


Differential diagnosis:
  1. Acute angle closure glaucoma: Anterior chamber depth is not uniform (centre deeper). Responds to peripheral iridotomy. 
  2. Choroidal detachment/effusion: Usually inflammatory in nature (trauma, following surgery, scleritis, chronic uveitis, Vogt-Koyanagi-Harada disease, following cyclo-photocoagulation/cryotherapy). IOP is normal or reduced. 
  3. Suprachoroidal hemorrhage: Shallowing of anterior chamber, increased IOP, sudden pain, hemorrhagic/non-serous detachment of the choroid. Usually occurs within one week of surgery.


Management:

Shallow AC beyond 5 days may cause formation of peripheral anterior synechiae, posterior synechiae, cataract and damage to corneal endothelium.
  • Medical
  • Laser
  • Surgery
  • Management of fellow eye


Hyperosmotic agents= 20% mannitol IV reduces the pressure exerted by vitreous (oral glycerol can also be substituted if mannitol is not available or contraindicated).

Mydriatic-cycloplegic= Combination therapy with 1% Atropine and 10% phenylephrine drops causes relaxation of ciliary muscle and tighten the zonules, pulling the anteriorly displaced lens backwards.

Aqueous suppressants= Beta-blockers or alpha2-agonists or carbonic anhydrase inhibitors are utilized to reduce the IOP.

Anti-inflammatory agents= Topical steroids are used to control the inflammation. 

Maintenance therapy= The patient is put on life-long atropine drops to prevent recurrence. Atropine can be instilled once every 4-6 weeks and every time patient notices any refractive change due to AC shallowing the treatment can be re-instituted. 

Miotics are contraindicated for life.

In case there is no response within 5 days, laser and/or surgery is employed.

Laser treatment= Nd-YAG laser hyaloidectomy, to disrupt the anterior vitreous face and establish proper flow of aqueous, can be undertaken in aphakic and pseudophakic eyes. (3-11 mJ energy). 

Argon laser for photocoagulation of the ciliary processes to destroy the ciliary processes and reduce aqueous production can be attempted. If not possible through an iridotomy, trans-scleral cyclphotocoagualtion can be done.

Surgery= When Medical or laser therapy fails surgical intervention is required. It involves vitrectomy to reduce the vitreous volume and promote aqueous flow into the anterior chamber. Usually a combination of posterior scelerectomy and air injection in the anterior chamber, anterior pars plana vitrectomy and lens extraction is done.

Prophylactic measures:

Cessation of miotic drops should be done as soon as possible.

Conclusion:

Malignant glaucoma is a therapeutic challenge.
Patients with H/O malignant glaucoma in fellow eye and PACG should be closely followed after glaucoma surgeries.
Patients have relatively good prognosis with current therapeutic modalities. More than 50% patients apparently respond to conservative management.



Monday, June 10, 2019

VISUAL PATHWAY


GUEST AUTHOR

SWALEHA AKHTAR

AJMAL KHAN TIBBIYA COLLEGE
ALIGARH
INDIA


INTRODUCTION

The visual pathway is the part of the central nervous system (CNS) responsible for processing visual details and several photo response functions. Non-image forming visual functions, independent of visual perception includes pupillary light reflex and circadian photoentrainment. With the development of binocular stereoscopic vision in humans, it has become possible to adapt more efficiently to the surrounding environment. This “visual perception” is vital for our daily tasks and any deterioration in this phenomenon can affect the quality of life of the individual. Glaucoma is a condition which causes progressive loss of retinal function. This directly influences the psycho-physical condition of the individual.

This blog post focuses on how visual perception is achieved by the propagation of visual impulses from the retinal ganglion cells (RGCs) to the visual cortex. The visual pathway is important in understanding the anatomical relations in image acquisition and processing. The visual cortex corresponds to approximately 55% of the entire cortical area of the primate brain. Thus, visual stimuli are directly or indirectly responsible for more than half of all information stored in the brain.





RETINA

The cornea and lens act as a compound lens and focus an inverted image of the object onto the retina.
The RGCs constitute the first neurons of the visual pathway.
They are located in the innermost layers of the retina.
Thus, light needs to cross all the layers to reach the photoreceptors without interference from blood vessels or other structures of the retina.
There are 2 types of photoreceptors viz. rods (130 million) and cones (7 million).
Rods are present in periphery and used to see in low levels of light (scotopic vision).
Cones (3 types, depending on wavelength they absorb viz. blue, green and red) are present in centre (fovea). They are responsible for vision in bright light (photopic vision).
Five types of ganglion cells have been identified in the retina:
  • 1.       M cells, large center-surround receptive fields sensitive to depth.
  • 2.       P cells, smaller center-surround receptive fields sensitive to color and shape.
  • 3.       K cells, with very large center-only receptive fields that are sensitive to color.
  • 4.       Intrinsically photosensitive cell population.
  • 5.       Cell population used for eye movements.

The photoreceptors contain a photopigment (protein) composed of opsin (a membrane protein) and 11-cis-retinal (a chromophore).
A photon has the capability of producing conformational changes (hyper-polarization) in cis-retinal (bent form), converting it to trans-retinal (straight form). This bleaching of pigment leads to a cascade of chemical reactions that convert electromagnetic energy into an electrical stimulus (signal transduction pathway).
This electrical stimulus is propagated to other retinal layers via neurotransmitters.
From the photoreceptors the impulse travels to the bipolar cells and then onto the RGCs.
Other neurons in the retina (e.g. horizontal and amacrine cells) transmit information laterally (from one neuron to the other side by side in the same layer). This results in more complex receptive fields.
The axons of the RGCs form the retinal nerve fiber layer and travel towards the optic nerve head (ONH).
Blood supply:
Outer 1/3rd of retina: Posterior ciliary arteries
Inner 2/3rd of retina: Central retinal artery (a branch of ophthalmic artery)

OPTIC NERVE

It contains approximately 1 million axons (nearly 40% of all axons in the CNS).
It is formed of 4 main regions:
1.       Nerve fiber layer
2.       Prelaminar region
3.       Lamina cribrosa
4.       Retrolaminar region
The optic nerve exits the eye through the lamina cribrosa.
The optic nerve in the retrobulbar area:
·         Gets invested with meninges (pia- and dura-mater).
·         Myelinated by oligodendrocytes.
The optic nerve consists of the following parts:
  • 1.       Intra-ocular (scleral) portion (3-4 mm) [This mainly forms the ONH and is supplied by the arterial circle of Zinn-Haller (composed of anastomotic branches of the posterior ciliary arteries), the pial arteriolar plexus and peripapillary choroid].
  • 2.       Intra-orbital portion (25 mm)
  • 3.       Intracanalicular portion (6-7 mm; within the optic canal and lesser wing of sphenoid bone)
  • 4.       Intracranial portion (18-20 mm)

Blood supply: Intra-cranial and intra-canalicular parts by superior hypophyseal artery (branch of internal carotid artery). Intra-orbital and intra-ocular parts are supplied predominantly from the ophthalmic artery and the Circle of Willis.

OPTIC CHIASM

The optic nerves travel backwards to cross at the optic chiasm.
Anatomical relations of the optic chiasm:

  • ·         Anteriorly:
  • ·         Posteriorly: Infundibulum.
  • ·         Inferiorly: Sella turcica, pituitary gland and cavernous sinus.
  • ·         Superiorly: Hypothalamus.
In the chiasm, the nerve fibers originating in the nasal retina decussate to the opposite side and join the temporal retinal fibers of the fellow eye.
Blood supply: Anastomotic arteries from the Circle of Willis.

OPTIC TRACT

The axons originating in the RGCs travel through the optic chiasm onto the optic tract to synapse with neurons in the Lateral Geniculate Nucleus (LGN).
Blood supply: From anastomotic branches of the posterior communicating and anterior choroidal artery (branch of internal carotid artery).

LATERAL GENICULATE NUCLEUS

The axons of the optic tract synapse with neurons in the LGN, which form the second neurons of the visual pathway.
These neurons in the LGN are distributed in 6 layers.
RGC axons from the ipsilateral eye (temporal retina) synapse in layer 2,3,5.
RGC axons from contralateral eye (nasal retina) synapse in layers 1,4,6.
There are 2 types of neurons in LGN:
  • 1.       Large neurons, forming the “magnocellular layers” (located in layers 1 & 2)
  • 2.       Small neurons, forming the “parvocellular layer” (located in layers 3,4,5 & 6)
  • 3.       “Koniocellular layer” is irregularly distributed between the magnocellular and parvocellular layers.

In the LGN the central portion (hilum) receives macular fibers, while the lateral and medial horns receive fibers from the inferior and superior retina respectively.
Blood supply: Branches of internal carotid artery (mainly anterior choroidal artery) and posterior cerebral arteries (2-3 posterior choroidal arteries).

SUPERIOR COLLICULI, PRETECTAL NUCLEI AND SUPRACHIASMATIC NUCLEUS

Some of the fibers from the optic tract connect to midbrain nuclei (related to autonomic functions).
Superior colliculi are responsible for: Coordinating eye and head movements to sudden visual and other sensory stimuli and saccadic gaze. Also receive input from other sensory organs and visual cortex.
Pretectal nuclei receive afferent input from RGCs, which travel in dual connections to Edinger-Westphal nucleus.
Parasympathetic fibers from the Edinger-Westphal nuclei travel through the oculomotor nerves to the ciliary ganglion and control pupillary size and consensual reflex.
Some RGCs contain melanopsin and these axons travel to the suprachiasmatic nucleus (at the base of anterior hypothalamus). This centre is sensitive to changes in ambient light and sends fibers to the pineal gland. It regulates physiologic functions related to circadian rhythms.

OPTIC RADIATIONS

The second neuron axons from the LGN reach the visual cortex via the optic radiations.
These fibers initially project anteriorly and then posteriorly towards the occipital lobe.
Blood supply:

  • ·         Anterior portion: Branches of Circle of Willis and middle cerebral artery.
  • ·         Distal portion: Anastomotic branches of the posterior cerebral artery.

VISUAL CORTEX

Axons from the 6 layers of the LGN travel along the optic radiations to synapse in the primary visual cortex (called V1).
Axons from the parvocellular layers of the LGN synapse at layer IV-C-β.
Axons from magnocellular layers synapse at layer IV-C-α.
The vertical meridian of the visual field is represented medially within the calcarine lips.
The horizontal meridian of the visual field is represented deep within the calcarine fissure.
The macula (central visual field) is represented in the posterior pole of calcarine cortex.
The macular representation is greatly magnified in the visual cortex retinotopic map.
Blood supply: Posterior cerebral arteries and branches.
Occipital lobe: Has dual blood supply to the area corresponding to central vision. These include: anastomoses between branches of the posterior cerebral artery and branches of the middle cerebral artery.

FEEDBACK MECHANISMS AND THE HIGHER-ORDER VISUAL CORTEX

Stimuli from the retina reach the visual cortex, where they are regulated and processed before being finally perceived as an image.
Up-down connections between the thalamic and higher-order cortical levels provide an accurate perceptual interpretation of the visual stimuli.
Some of these connections include those between V1 and LGN, as well as those between different mesencephalic nuclei.
From V1 the information travels to extrastriate areas responsible for different features of vision, such as color, motion, depth, contrast and memory.
From V4 and V5 the information is conducted and/or stored in different areas which are related with other functions (e.g somatosensory, speech and hearing), motor activity and emotions.





PERIPAPILLARY RETINOSCHISIS IN GLAUCOMA

  Peripapillary changes on OCT scans are being increasingly reported in glaucoma patients. This could be due to better awareness of these ch...