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Neurotrophic keratopathy

Neurotrophic keratopathy-ophthalmology

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Neurotrophic keratopathy

  1. 1. Dr . M. Dinesh NEUROTROPHIC KERATOPATHY
  2. 2. • Neurotrophic keratitis is a • Non infectious • degenerative disease of corneal epithelium • characterized by impaired healing. • prevalence < 50/lac individuals • Absence of corneal sensitivity is the hallmark of the condition, which ultimately lead to corneal stromal melting and perforation
  3. 3. • Reduced corneal sensation renders • the corneal surface prone to occult injury • decreases reflex tearing • decrease healing rates of corneal epithelial injuries • formation of nonhealing epithelial defects that tend to ulcerate and ultimately perforate (secondary to corneal sensory denervation )
  4. 4. Causes of corneal hypoesthesia Ocular causes : Infection • Herpes keratitis ( simplex & zoster ) -MC • Leprosy Congenital • Familial dysautonomia (Riley-Day syndrome) • Goldenhar-Gorlin syndrome • Möbius syndrome • Familial corneal hypesthesia • Congenital insensitivity to pain with anhidrosis
  5. 5. Topical medications • Anaesthetics (MC cocaine abuse ) • Timolol • Betaxolol • Sulfacetamide 30% • Diclofenac sodium Corneal dystrophies • Lattice • Granular (rare)
  6. 6. Iatrogenic • Contact lens wear • Corneal incisions/surgeries • LASIK • Trauma to ciliary nerves by laser and surgery (primarily for retinal conditions) • Vitrectomy for retinal detachment • photocoagulation to treat DR • Routine, single session, indirect laser for PDR a/ with development or worsening of NK
  7. 7. Toxic • Chemical burns • Carbon disulfide exposure • Hydrogen sulfide exposure Miscellaneous • Increasing age • Dark eye color • Adie's syndrome • Dihydroxypyrimidine dehydrogenase (DHPD) deficiency • Any condition causing chronic corneal epithelial injury or inflammation
  8. 8. Non-ocular causes Fifth nerve palsy • neurosurgical procedures or trauma damaging V CN • Neoplasia (acoustic neuroma) • Aneurysms • Facial trauma • multiple sclerosis • Stroke • Congenital hypoplasia of the trigeminal nerve Systemic causes • diabetes (NK can be a presenting sign in DM) • vitamin A deficiency • drugs (narcoleptics and antipsychotics)
  9. 9. BIOCHEMICAL BASIS : • In1954 animal study showed that sectioning the trigeminal nerve results in characteristic corneal findings of neurotrophic keratitis despite tarsorrhaphy. • Cavanagh and colleagues theorized that • “corneal epithelial proliferation is regulated bidirectionally by controls linked to the • sensory and sympathetic nerves and their neurotransmitters “
  10. 10. Epithelial mitosis in both the cornea and skin by intracellular cAMP by intranuclear cGMP Eg.,Adrenergic neurotransmitters & prostaglandins Eg.,Acetylcholine (ACh) derived from sensory neurons So prostaglandins delay in corneal wound healing in the presence of significant inflammation So sensory denervation of the cornea, depletes ACh (in ACh-rich tissue ) decrease in epithelial growth
  11. 11. decrease in epithelial cell mitosis deficit in corneal epithelial cells even in the absence of a pre-existing defect Epithelial defect occurs centrally because the corneal epithelium is persistently regenerated centripetally from the periphery and sheds old cells at its apex, as described by Thoft
  12. 12. • sensory neurons directly affect the • development of corneal epithelial cell characteristics (that inturn) • maintenance of good epithelial layer integrity • corneal limbal stem cell deficiency is also seen in eyes with neurotrophic keratitis • In animal studies corneal anesthesia is obtained either chemically or surgically, corneal epithelial effects are modified by cervical sympathetic denervation. • These findings support Cavanagh's proposed dual and antagonistic control system of corneal epithelial regeneration
  13. 13. Animal models on using capsaicin substance P show classic changes of neurotrophic keratitis So substance P act as a direct trophic molecule on corneal epithelial growth
  14. 14. • Substance P is a neuropeptide present in the cornea • depleted with sensory denervation, • depleted with capsaicin specifically. • Capsaicin is a chilli pepper extract with analgesic properties ,used topically in controlling peripheral nerve pain. • Substance P also • stimulate DNA synthesis & • Stimulate corneal epithelial cell growth. • calcitonin gene-related peptide (CGRP), which is present in nearly all substance P-containing neurons in the cornea, showed synergism with substance P but no trophic effect on its own.
  15. 15. HISTOPATHOLOGIC FINDINGS Corneal changes • Epithelial thickness is decreased • complete loss of the normal surface desquamating layer • epithelial cell glycogen depletion • Surface cells lose all microvilli, leading to impaired tear film adherence • Remaining surface epithelial cells show intracellular swelling. • Abnormal synthesis of basal lamina helps to explain defective epithelial adhesion
  16. 16. Conjunctival changes • decreased goblet cell density • increased length of surface microvilli • Impression cytology reveals loss of goblet cells as well as their migration onto the corneal surface • These corneal and conjunctival epithelial changes are found in keratitis sicca as well, but they are more severe in neurotrophic keratitis.
  17. 17. Symptoms • patients do not commonly complain of ocular surface symptoms because corneal sensory innervation is impaired • patients seek medical advice months or years after the disease has started ,this makes NK challenging, • blurred vision can be reported due to • irregular epithelium • epithelial defects (PED), • scarring, or • edema
  18. 18. CLINICAL FINDINGS • The initial clinical appearance of an anaesthetic cornea • loss of the usual corneal epithelial sheen • mild disruptions in the tear surface. punctate keratitis epithelial loss finally stromal ulceration anaesthetic cornea (even in the absence of injury)
  19. 19. Due to lack of the afferent limb of the reflex • Reflex tearing decreases • Blink rates decreases • Tear surface abnormalities • Tear mucus secretions increase • tear film become more viscous • Progressive abnormalities of corneal epithelial microvilli impair ocular surface lubrication irrepairable corneal injury
  20. 20. • The earliest sign of sensory denervation is rose Bengal staining of the inferior palpebral conjunctiva. • The tear surface is disrupted several seconds after each blink, forming geographic dry spots on the corneal epithelium (seen with aid of topical fluorescein). • Increased viscosity of tear mucus abnormal surface wetting. • punctate fluorescein staining of the corneal epithelium may be present, but only after several minutes of fluorescein exposure. • Some anesthetic corneas may even show gray punctate superficial lesions that stain readily.
  21. 21. rose Bengal staining of the inferior palpebral conjunctiva.
  22. 22. • Gaule spots • Small facets of drying epithelium • seen in retro illumination. • compared to dellen • appear at the limbus in early neurotrophic keratitis. • constitute Mackie's stage I of neurotrophic keratitis
  23. 23. • This stage may become chronic resulting in • superficial vascularization, • stromal scarring, • epithelial hyperplasia and • irregularity. • Rarely, a hyperplastic precorneal membrane will grow centrally from the limbus to cover intact corneal epithelium
  24. 24. Clinical stages of neurotrophic keratitis Mackie classification : Stage 1 - characterized by mild, nonspecific signs and symptoms • Rose Bengal staining of the inf palpebral conjunctivae • Decreased tear break-up time • Increased viscosity of tear mucus • Punctate epithelial staining with fluorescein • Scattered small facets of dried epithelium (Gaule spots)
  25. 25. Slit-lamp photograph of punctate epithelial erosions Stage 1
  26. 26. Stage 1 Early central epithelial changes
  27. 27. Stage 2 - involves a nonhealing corneal epithelial defect • Acute loss of epithelium, usually under the upper lid • Surrounding rim of loose epithelium • Stromal edema • DM folds • a punched-out oval or circular shape defect– chr of stage 2 • Edges of the defect become smooth and rolled with time • Aqueous cell and flare Stage 3 • Corneal ulcer • Stromal melting • corneal perforation
  28. 28. Central, circular, punched-out epithelial defect secondary to and classic for neurotrophic keratitis Stage 2
  29. 29. Stage 2 persistent epithelial defect with rolled edges
  30. 30. The endings of the deficit area have smooth, rolled, and loose epithelium Stage 2
  31. 31. Stage 3 punched-out epithelial defect with stromal oedema & early melting;
  32. 32. Stage 2 • involves the acute loss of epithelium, often in an area covered by the upper lid. • The mechanism of loss is similar to that for recurrent erosions and is encouraged by the milieu of poor tear wetting of a rough and abnormal corneal epithelium. • The area of epithelial loss is usually surrounded by a large area of loose epithelium. • Descemet’s Folds develop as the stroma begins to swell. • Often, aqueous cell and flare are present.
  33. 33. A border of hazy epithelium surrounds a large inferior epithelial defect, which demonstrates impaired healing secondary to corneal anesthesia Stage 2
  34. 34. • Rarely, a sterile hypopyon will form • This stage is an indication for urgent and appropriate treatment. • As this stage persists, the surrounding epithelial cells become hazy, edematous, and poorly adherent to Bowman's membrane. Epithelial defect features in neurotrophic keratitis • punched-out horizontal, oval, or circular shape (chr of NK ) • The edges of the defect become smooth and rolled as the defect ages without appreciable epithelial growth.
  35. 35. Neurotrophic ulceration with hypopyon.
  36. 36. • Stage 3 often ensues • in the absence of adequate treatment of stages 1 and 2, and • sometimes despite appropriate treatment. • Stromal lysis is the hallmark of this stage, sometimes perforation ensues Inflammation, secondary infection • The imprudent use of topical corticosteroids promote stromal lysis and increase the risk for perforation.
  37. 37. Complete corneal necrosis secondary to topical anesthetic abuse Stage 3
  38. 38. Stromal lysis with thinning in a cornea that suffers decreased sensation Stage 3
  39. 39. Clinical evaluation : • A careful ocular examination supplemented by thorough medical and surgical history taking should enable one to determine the cause for any loss of sensation • The medical and surgical history may reveal • previous surgical or traumatic injury to the trigeminal nerve, • diabetes mellitus • use of topical medications known to decrease corneal sensation • previous ocular laser or surgical procedures • contact lens use.
  40. 40. • Direct ocular exposure to caustic chemicals or chronic exposure to carbon disulfide and hydrogen sulfide must be identified • The absence of any identifiable cause for corneal anesthesia, in the setting of severe corneal damage with advanced stromal lysis, would suggest possible topical anesthetic abuse, with a history of recent corneal injury.
  41. 41. • The presence of other neurologic deficits may help to localize neoplasms, injuries, or vascular accidents, which include the fifth cranial nerve or its brainstem nucleus, among other local structures. Acoustic neuromas • seventh and eighth nerve dysfunction • Corneal hypesthesia is the second most common finding (after decreased hearing) in acoustic neuromas Ocular motility : • may reveal associated dysfunction of CN III, IV, and VI that may localize an aneurysm or cavernous sinus pathology.
  42. 42. Pupillary abnormalities • give clues to status of II cranial nerve • any defects in the sympathetic innervation of the iris. • The presence of a relative afferent pupillary defect (RAPD) in association with corneal hypesthesia would localize the lesion to the intraconal orbit. • Pupillary reactions of the Adie's type have also been associated with alterations in corneal sensation
  43. 43. Evaluation Localise Pathology to III, IV, VI Ocular motility Aneurism Cavernous sinus pathology VII, VIII Facial N ex. and hearing Acoustic neurinoma II Aferent pupillary defect Lesion in intraconal orbit Sympathetic inervation iris Anisocoria (Eferent pupillary defect) Lesion in intraconal orbit
  44. 44. • Normal eyelid function is critical to the prognosis of NK Conditons that hastening the progression to stage 3 NK • Eyelid defects • Scarred lids • secondary to removal of periocular infiltrative tumors or • chemical and thermal burns • Lagophthalmos (promote corneal epithelial exposure and drying) • from cranial nerve VII palsy after resection of an acoustic neuroma • proptosis and upper eyelid retraction • In Thyroid ophthalmopathy
  45. 45. Ocular surface examination • careful analysis of qualitative and quantitative tear function. • Absence of the nasal-lacrimal tearing reflex along with i/l loss of sensation in the nasal mucosa presents a high- risk for neurotrophic corneal ulceration and can even affect the tear production of the unaffected eye.
  46. 46. Corneal examination • assessment of pattern and degree of corneal sensory deficit with esthesiometer of Cochet-Bonnet • It measures corneal sensitivity by the length of nylon line (b/w 0 & 6 cm in length) required to elicit lid blink or patient response. • Patchy hypesthesia indicate- previous HZV keratitis • Measuring the depth of corneal anesthesia is important, since lower levels of sensation tend toward more severe corneal epithelial disease • Only corneas with readings of 2 cm or less underwent epithelial sloughing and stromal ulceration in h zoster keratitis
  47. 47. Biomicroscopic examination of the cornea • essential to identify corneal conditions that predispose to corneal sensory deficits. • dendritic lesion - herpetic disease as the likely cause • A healing epithelial defect may assume a dendritic shape but distinguished from herpetic keratitis by the absence of branching or end bulbs. • Stromal scarring indicate previous infection. • Prominence and beading of the corneal nerves may be subtle signs of lepromatous anterior segment involvement • Advanced stromal dystrophies • lattice • Granular a/with corneal hypoesthesia
  48. 48. Other ocular findings help identify underlying causes of corneal sensory deficit are • Iris atrophy with or without AC inflammation • Mild AC cell and flare - seen with neurogenic causes of corneal anesthesia. • Poor accommodation - signal HZV as the cause for corneal sensory loss, since the virus may damage ciliary ganglion motor nerve fibers. • HZV and HSV keratouveitis • leprosy
  49. 49. • Fundus examination – • optic nerve pallor or swelling on the affected side. • These findings may localize the lesion to the orbit or retro- orbital region. • Background diabetic retinopathy or laser scars from treatment of retinopathy may also shed light on the cause of corneal sensory loss.
  50. 50. Indications for immediate and aggressive treatment • significant fluorescein staining or a frank epithelial defect • stromal lysis and thinning • Dense anterior stromal infiltrate indicate infectious keratitis & cultures should be taken before starting broad-spectrum topical antibiotic therapy.
  51. 51. Diagnostic Procedures • Corneal sensitivity should be evaluated • roughly assessed using a cotton swab or • quantitatively determined with a corneal aesthesiometer (e.g. Cochet-Bonnet contact aesthesiometer, CRCERT- Belmonte non-contact aesthesiometer) • Corneal staining with fluorescein
  52. 52. • To evaluate corneal/conjunctival integrity, other vital stains like lissamine green or rose Bengal • Schirmer test to evaluate tear production, which can be impaired as a result of reduction in corneal sensitivity. • Any eye drops should be applied AFTER having tested corneal sensitivity as they could otherwise alter this measurement. • Corneal scrapings and cultures can be performed to exclude bacterial, viral, fungal or parasitic infections, which may be associated with reduced corneal sensitivity.
  53. 53. Differential Diagnosis • The finding of a corneal lesion in absence of ocular symptoms (due to corneal anesthesia) is highly suspicious of NK. • Stage 1 NK should be differentiated from • dry eye • topical drug toxicity, • exposure keratitis, • contact lens abuse, • chemical injury and • limbal stem cells deficiency, which can also be associated with some degree of NK.
  54. 54. • Herpes infections also reduce corneal sensitivity, pure NK is sterile. • Acanthamoeba keratitis often causes intense ocular pain, but it can also be associated with some degree of corneal anesthesia.
  55. 55. Management • should emphasize on prevention of epithelial defects because of profoundly impaired healing of the epithelium • depends on the epithelial condition at initial presentation and the degree of corneal hypesthesia. • An epithelial defect in the setting of corneal anesthesia is a serious ocular condition requiring prompt and aggressive therapy to prevent ulceration and possible perforation
  56. 56. STAGE 1 : punctate keratopathy • therapeutic goal • to improve the quality and transparence of epithelium & • to avoid epithelial breakdown Treatment includes 1. Use of unpreserved artificial tears, lubricant ointments, to prevent preservative-induced epithelial toxicity. 2. Therapeutic soft contact lenses at this stage may be effective but increases the risk for infectious keratitis 3. Eyelid dysfunction must be remedied to prevent exposure keratopathy and progression
  57. 57. stage 2 : persistent epithelial disease • therapeutic goal • to promote PED healing and • prevent the development of a corneal ulcer. Treatment includes 1. the use of unpreserved artificial tears, lubricant ointments 2. therapeutic soft contact lenses or patching 3. topical autologous serum application 4. amniotic membrane grafting 5. lateral tarsorrhaphy or botulinum induced ptosis (levator inj) Even in the absence of eyelid defects or dysfunction 6. topical Nerve Growth Factor application.
  58. 58. 7. Silicone plugs of both puncta can greatly improve tear function 8. Antibiotic eye drops can be prescribed to prevent bacterial infections. • topical tetracycline - speeds healing of epithelial defects. 8. Topical corticosteroids can be administered to control inflammation cautiously, as they could induce stromal melting.
  59. 59. Stage 3 : neurotrophic keratitis • therapeutic goal • Promote ulcer healing and • prevention of corneal perforation • therapy suggested for stages 1 and 2 • N-acetylcysteine, • oral tetracycline and medroxyprogesterone can be prescribed in case of stromal melting.
  60. 60. • When an eye is initially seen at stage 3, preserving the structural integrity of the globe takes precedence over visual rehabilitation. • progression of stromal lysis to perforation can be prevented by 1. Amniotic membrane transplantation 2. Cyanoacrylate glue 3. Tectonic lamellar keratoplasty, 4. Conjunctival flaps
  61. 61. 1.Amniotic membrane transplantation : • shows additional effectiveness for arresting progressive melting • eliminates surrounding stromal infiltrate • Amniotic membrane in combination with a bandage lens or stretched across a rigid ring (ProKera) has also become an effective tool for the management of nonhealing epithelial defects
  62. 62. 2.Cyanoacrylate glue : • Application of cyanoacrylate glue followed by a bandage soft contact lens is a noninvasive and effective approach to address impending perforation • Small perforation < 2 mm - glue is applied • Larger defects > 2mm - lamellar or penetrating keratoplasty.
  63. 63. 3. Tectonic lamellar keratoplasty • For larger defects > 2mm • lower rejection rate • more rapid healing, • preserve most of the endothelium • Good results have been reported with lamellar grafting using multilayer amniotic membrane. so procedure of choice
  64. 64. 4. Conjunctival flaps • despite their effectiveness at arresting stromal lysis and creating a new epithelial barrier, have a diminished role in the approach to these ulcerations and perforations because of the poor cosmetic and visual result. • In any eye that has suffered ulceration, neurotrophic or otherwise, a 6-month period of clinical stability is recommended before considering penetrating keratoplasty
  65. 65. Stromal lysis and thinning with perforation in a corneal graft performed on a patient with previous herpes zoster keratitis
  66. 66. • Recent human studies have shown • substance P and IGF-1 together, • R nerve growth factor alone & • thymosin beta4 • umbilical cord serum and • autologous serum (both 20% and 50%) eyedrops are also used for treatment of neurotrophic ulcers accelerate epithelial healing in neurotrophic corneas.
  67. 67. • The therapeutic effect is secondary to • growth factors, • fibronectin, • vitamins, and • immunoglobulins found in serum enhanced epithelial healing in recalcitrant corneal ulcers.
  68. 68. • Theoretically the use of topical nonsteroidal agents would block the influence of prostaglandins locally on corneal epithelial growth, but their use has not had dramatic trophic effects on wound healing.
  69. 69. Summary • A corneal surface lacking adequate sensory innervation is at risk for • progressive epitheliopathy • epithelial sloughing, • stromal lysis, and • subsequent corneal perforation in the absence of timely and appropriate therapy. • Herpetic infections & damage to V1 are MCC of clinical ds • Trophic effects of cholinergic sensory nerve fibers on corneal epithelial cells are lost in any condition that impairs corneal sensation
  70. 70. • Decrease in epithelial growth rate slows wound healing and may cause epithelial defects even in the absence of frank trauma. • Initial evaluation should • identify the cause of the corneal sensory loss, • Identify potential pathology of the central nervous system along the path of the trigeminal nerve. • In the absence of an obvious cause, topical anesthetic abuse should be considered.
  71. 71. • Treatment should be directed toward preventing epithelial defects and promoting epithelial cell regeneration. • Preservative-free lubricants, • autologous serum, and • tarsorrhaphy • Autologous serum provides growth factors that research may eventually provide in pharmacologic form. mainstays of approach
  72. 72. • cyanoacrylate glue - impending and small perforations and with lamellar or penetrating keratoplasty - larger defects. • Prompt identification of corneal anesthesia in the setting of an epithelial defect will allow appropriate and aggressive therapy directed toward avoidance of severe stage 3 neurotrophic keratitis.
  73. 73. Topical and systemic tetracyclines can effectively inhibit MMPs in animal and human subjects in a mechanism independent of their antimicrobial activity.81 High levels of MMPs cause corneal stromal lysis via collagen degradation and injury to the epithelial basement membrane adhesion complexes resulting in poor epithelial adherence. MMP-9, a gelatinase in corneal epithelial cells, has been detected at the edges of nonhealing corneal ulcers.82 Oral doxycycline at 50 mg twice a day has been demonstrated to inhibit MMP-9, resulting in rapid healing and preventing recurrences of recurrent corneal erosions • Oral doxycycline or minocycline • serves to remedy qualitative tear dysfunction through its action in the meibomian glands • even aid in preventing corneal stromal lysis
  74. 74. Specially compounded preservative-free topical steroids, medroxyprogesterone 1% and methylprednisolone 1% may prevent stromal lysis, but must be kept refrigerated to avoid contamination. Medroxyprogesterone prevents stromal melting by inhibiting local collagenases that degrade the corneal stroma, while at the same time exhibiting a mild antiinflammatory property.86–89 Both doxycycline and corticosteroids can inhibit MMP-9. In patients with recurrent corneal erosions unresponsive to the conventional therapy, administration of oral doxycycline and topical corticosteroids reduces pain and heals epithelial defects within 2–10 days.83 Methylprednisolone also provides symptomatic relief and resolution of filaments in severe keratoconjunctivitis associated with Sjögren syndrome.90
  75. 75. Autologous serum drops: These are made from the patient’s own serum and contain collagenase inhibitors such as alpha-1, alpha-2 macroglobulins and, in their undiluted form, were showned to heal trophic herpetic ulcers in 1973.209 Since then, a number of studies have reported the usefulness of this approach. Two studies from Bonini’s group using murine nerve growth factor (NGF) (1–10 micrograms of highly purified murine NGF in 50 mL of physiological saline) to treat human anesthetic neurotrophic ulcers found that corneal healing began 2–14 days after starting treatment of 10 times daily for 2 days and then six times daily until the ulcers healed. All patients had complete healing of their corneal ulcers after 10 days to 6 weeks of treatment. Corneal sensitivity improved in 13/14 eyes, and returned to normal in two of the 13 eyes. Corneal integrity and sensitivity were maintained during the follow-up period (range, 3–12 months
  76. 76. THAN Q

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