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234 Cards in this Set

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1. What are the three criteria for the Dx of diabetes?
Any one of the three criteria:

1. Random glucose level at or over 200 mg/dL, with classical signs and symptoms
2. Fasting glucose level at or over 126 mg/dL
3. Abnormal oral glucose tolerance test, in which the glucose level is at or over 200 mg/dL 2 hours after a standard carbohydrate load
2. Metabolic and mitogenic actions of insulin are mediated by the hormone binding to...?
The tetrameric insulin receptor, with consequent activation of mitogen-activated protein kinase (MAPK) signaling pathway which is responsible for its mitogenic effectors (insulin like growth factor).

The phosphatidylinositol-3-kinase (PI-3K) signaling pathway is responsible for its metabolic effects .
3. The most important stimulus that triggers insulin synthesis and release is..?

A rise in blood glucose levels results in glucose uptake into pancreatic β-cells, facilitated by GLUT-2.

Metabolism of glucose via glycolysis generates ATP, resulting in increase in cytoplasmic ATP/ADP ratios. This inhibits the activity of the ATP-sensitive K+ channel on the β-cell membrane, leading to membrane depolarization and the influx of extracellular calcium. Then, the resultant increase in calcium results in secretion of insulin, presumably from stored hormone w/in the β-cell granules.
4. Pathogenesis of Type I DM
This form of diabetes results froma severe lack fo insulin caused by an autoimmune destruction of the islet beta cells.

Type I DM most commonly develops in childhood, becomes manifest at puberty, and is progressive with age.
5. What three general mechanisms cause β-cell destruction?
1. T-lymphocytes react against β-cell antigens and cause cell damage
2. Locally produced cytokines damage β-cells
3. Autoantibodies against islet cells and insulin are also detected in the blood of 70-80% of patients
6. What T-lymphocytes are involved in β-cell destruction?
1. CD4+ cells of the TH1 subset causing tissue injury by activating macrophages, with the macrophages causing damage in a characteristic delayed-type hypersensitivity response

2. CD8+ cytotoxic T lymphocytes that directly kill β-cells and also secrete cytokines that activate macrophages
7. What cytokines are involved in β-cell destruction?

Where do they come from?
IFN-γ, produced by T cells

TNF and IL-1, produced by macrophages that are activated during the immune reaction.
8. What about the autoantibodies involved in β-cell destruction?
The autoantibodies are reactive w/a variety of β-cell antigens, including the enzyme glutamic acid decarboxylase (GAD).

In susceptible children who have not developed diabetes, the present of antibodies against islet cells is predictive of the development of Type I DM.
9. What is the genetic susceptibility of DM type I?
DM type I has a complex pattern of genetic associations, with at lest 20 genetic loci potentially contributing to the altered host immune tolerance that eventually results in autoimmunity.

By far the most important genetic association is with the class II MHC complex HLA locus.

Between 90-95% of whites w/type I DM have HLA-DR3 or DR4 haplotypes.

***Certain alleles within these haplotypes, such as DQβ*0302, demonstrate an every greater degree of association with Type I DM.
10. What about the DQβ*0602 allele?
May actually confer some protection in preventing Type I DM
11. What are the non-MHC genes associated with Type I DM disease susceptibility?
1. The insulin gene itself
2. The gene encoding the T-cell inhibitory receptor CTLA-4
12. What are some environmental factors associated with the development of type I DM?
Several viral agents, including:
a. coxsakieviruses
b. mumps
c. measles
d. cytomegalovirus
e. rubella
f. infection mononucleosis

One postulate is that the viruses produce proteins that mimic self antigens, and the immune response to the viral protein cross-reacts w/the self-tissue (molecular mimicry)
13. What are the two main metabolic defects that characterize Type II DM?
1. Insulin resistance
2. β-cell dysfunction
14. What is involved in insulin resistance?
Functional studies in individuals w/insulin resistance demonstrate quantitative and qualitative abnormalities of the insulin signaling pathway, including down-regulation of the insulin receptor, decreased insulin receptor phosphorylation and tyrosine kinase activity, reduced levels of active intermediaries in the insulin signaling pathway; and impairment of translocation, docking, and fusion of GLUT-4-containing vesicles with the plasma membrane.
15. What is the strongest association with insulin resistance?
Obesity has the strongest association.

Possible factors influencing insulin resistance in obesity include high circulating and intracellular levels of free FAs that can interfere with insulin formation (lipotoxicity) and a variety of cytokines released by adipose tissue (adipokines), including leptin, adiponectin, and resistin.
16. Peroxisome proliferator-activated receptor gamma (PPAR-γ)
Is an adipocyte nuclear recptor activated by a new class of antidiabetic agents called thiazolidinediones.

It can modulate gene expression in adipocytes, eventually leading to reduction of insulin resistance.
17. What are the manifestations of β-cell dysfunction?
Manifested as inadequate insulin secretion in the face of insulin resistance and hyperglycemia. β-cell dysfunction is both qualitative (loss in the normal pulsatile, oscillating pattern of insulin secretion and attenuation of the rapid first phase of insulin secretion triggered by elevation in plasma glucose) as well as quantitative (decreased β-cell mass, islet degeneration, and deposition of islet amyloid).
18. Maturity-onset diabetes of the young (MODY)
MODY is a primary defect in β-cell function that occurs without β-cell loss, affecting either β-cell mass or insulin transcription.

Six distinct genetic defects have been identified thus far. However, it is important to emphasize that mutations or polymorphisms in the six known MODY genes do not appear to contribute to the development of late-onset (classic) type 2 diabetes in the vast majority of pts.
19. Four characteristics of MODY
1. Autosomal dominant inheritance as a monogenic defect, with high penetrance.
2. Early onset, usually before age 25, as opposed to after age 40 for most patients w/type II DM.
3. Absence of obesity.
4. Lack of islet cell autoantibodies and insulin resistance syndrome.
20. What is mitochondrial diabetes?
Diabetes is rarely (<1% cases) associated w/point mutations in mitochondrial tRNA gene, tRNA ^Leu(UUR)

Mitochondrial diabetes is caused by a primary defect in β-cell function. ATP is required for insulin secretion in β-cells, and impairment of mitochondrial ATP synthesis results in decreased insulin secretion
21. What about diabetes associated w/insulin gene or insulin receptor mutations?
Mutations that affect insulin processing from its precursor (proinsulin), or those that affect insulin structure and binding to its receptor are a rare cause of diabetes.

The metabolic impairment in most cases is mild, since these pts are heterozygous for their mutations.

Insulin receptor mutations that affect receptor synthesis, insulin binding, or receptor tyrosine kinase activity can result in mild to severe insulin resistance and type II DM. Neither insulin gene nor insulin receptor mutations contribute significantly to the incidence of type 2 DM.
22. What is diabetic ketoacidosis?
Occurs almost always in type I diabetes as a result of severe insulin deficiency and absolute or relative increases in glucagon: excessive release of free FAs from adipose tissue and hepatic oxidation generates ketone bodies.

Ketonemia and ketonuria, with dehydration, can cause life-threatening systemic metabolic ketoacidosis.
23. What is nonketotic hyperosmolar coma?
Usually develops in type II diabetics in the setting of severe dehydration (from sustained hyperglycemic diuresis) and an inability to drink water.
24. What are the three distinct pathways involved in the pathogenesis of long-term diabetic complications?
1. Formation of advanced glycation end products
2. Activation of protein kinase C
3. Intracellular hyperglycemia w/disturbances in polyol pathways

*Most evidence suggests that the complications of diabetes are a consequence of the metabolic derangements, mainly hyperglycemia.
25. What are four long term complications of diabetes?
1. Macrovascular disease
2. Microvascular disease
3. Accelerated atherosclerosis
4. Diabetic retinopathy, nephropathy, and neuropathy
26. What is non-enzymatic glycosylation?
Glucose chemically attaches to amino groups of proteins, reflected in glycated Hb (HbA1c) blood levels.

With glycation of collagens and other long-lived proteins, irreversible advanced glycation end products (AGE) accumulate over the lifetime of blood vessel walls.
27. AGE formation of proteins, lipids, and nucleic acids leads to what three things?
1. Protein cross-linking, trapping plasma lipoproteins in vessel walls
2. Reduction in normal proteolysis
3. AGE binding to cell receptors, inducing a variety of undesired biologic activities
28. AGE's induce what four undesired biologic activities?
1. Release of cytokines and growth factors from amcrophages and mesangial cells (insulin-like growth factor2
Increased endothelial permeability
3. Increased procoagulant activity on endothelial cells and macrophages (induction of thrombomodulin and tissue factor
4. Enhanced proliferation of and synthesis of ECM by fibroblasts and SMCs
29. How do AGEs relate to endothelial dysfunction?
AGE's, by virtue of their ability to modify ECM components, as well as to activate NF-kB and its downstream targets in the vascular endothelium, are postulated to play a central role int he accelerated atherogenesis characteristic of diabetes.
30. How does intracellular hyperglycemia cause disturbances polyol pathways?
Some tissues (nerve, lens, kidney, blood vessels) do not require insulin for glucose uptake and thus accumulate increased intracellular glucose by mass action.

This glucose is then metabolized to sorbitol and then fructose, so that an equilibrium with extracellular solute is not achieved.

The accompanying osmotic load leads to influx of water and osmotic cell injury.

Sorbitol also decreases phosphoinositide metabolism and signal transduction.
31. How does the activation of protein kinase C relate to hyperglycemia?
Activation of intracellular PKC by calcium ions and the second messenger diacylglycerol (DAG) is an important signal transduction pathway in many cellular systems.

Intracellular hyperglycemia stimulates the de novo synthesis of DAG from glycolytic intermediates, and hence activates PKC.
32. What are the five downstream effects of protein kinase C activation?
1. Production of the proangiogenic molecule VEGF, implicated in the neovascularization characterizing diabetic retinopathy
2. Increased activity of the vasoconstrictor endothelin-1 and decreased activity of the vasodilator eNOS
3. Production of profibrogenic molecules like TGF-beta, leading to increased deposition of ECM and basement membrane material
4. Production of the procoagulant molecule plasminogen activator inhibitor-1 (PAI-1), leading to reduced fibrinolysis and possible vascular occlusive episodes
5. Production of pro-inflammatory cytokines by the vascular endothelium
33. What are the four major morphological changes in the pancreas in diabetes?
1. There is a reduction in number and size of islets (especially type I DM).
2. Insulitis (a heavy lymphocytic infiltrate within and about islets) in newly symptomatic type I diabetics.
3. β-cell degranulation and fibrosis of islets.
4. Deposition of extracellular amyloid (amylin protein) which replaces islets, especially in long standing type II diabetics.
34. What is the morphology of the amyloid replacements?
Amyloid replacement of islets in type 2 diabetes appears as deposition of pink, amorphous material beginning in and around capillaries and between cells.
35. What is diabetic macrovascular disease?

What is the most common cause of death in diabetics?
Accelerated atherosclerosis in the aorta and large and medium-sized arteries increases the risk for MI, cerebral stroke, aortic aneurysms, and gangrene of the lower extremities.

*The hallmark of diabetic macrovascular disease is accelerated atherosclerosis.

MI, caused by atherosclerosis of the coronary arteries, is the most common cause of death in diabetics.
36. What is the morphology of hyaline ateriolosclerosis?
Hyaline arteriolosclerosis is the vascular lesion associated w/hypertension and is both more prevalent and more sever in diabetics than in nondiabetics.

It takes the form of an amorphous, hyaline thickening of the wall of the arterioles, which causes narrowing of the lumen.
37. What is diabetic microangiopathy?
One of the most consistent morphologic features of diabetes is diffuse thickening of basement membranes.

The thickening is most evident in the capillaries of the skin, skeletal muscle, retina, renal glomeruli, and renal medulla.

It may affect nonvascular structures, such as renal tubules, Bowman capsule, peripheral nerves and placenta.
38. Are thickened diabetic capillaries more or less likely to leak proteins?
Despite the increase in the thickness of basement membranes, diabetic capillaries are more leaky than normal to plasma proteins.

*The microangiopathy underlies the development of diabetic nephropathy, retinopathy, and some forms of neuropathy.
39. What is diabetic nephropathy?

What are the three lesions encountered in this disease?
The kidneys are prime targets of diabetes. Renal failure is second only to MI as cause of death from this disease.

Three lesions:
1. Glomerular lesions
2. Renal vascular lesions, principally arteriolosclerosis
3. Pyelonephritis, including necrotizing papillitis
40. What are the most important glomerular lesions in diabetic nephropathy?
The most important are capillary basement membrane thickening, diffuse mesangial sclerosis, and nodular glomerularsclerosis (Kimmelstiel-Wilson lesion).
41. What is the morphology of diffuse mesangial sclerosis?
Diffuse mesangial sclerosis consists of a diffuse increase in mesangial matrix and is always associated w/basement membrane thickening. It is found in most pts with disease of more than 10 years duration. When glomerulosclerosis becomes marked, pts manifest the nephrotic syndrome (proteinuria, hypoalbuminemia, and edema).
42. What is the morphology of nodular glomerulosclerosis?
Nodular glomerulosclerosis describes a glomerular lesion made distinctive by ball-like deposits of a laminated matrix situated in the periphery of the glomerulus.

These nodules are PAS positive, and usually contain trapped mesangial cells. *This distinctive change has been called the Kimmelstiel-Wilson lesion.

*It is essentially pathognomonic of diabetes.
43. What are the vascular effects of diabetic nephropathy?

What about infections associated with diabetic nephropathy?
Vascular effects of diabetic nephropathy: arteriosclerosis, including benign nephrosclerosis with hypertension.

UTIs, with pyelonephritis and sometimes necrotizing papillitis.
44. What are the two types of diabetic retinopathy?
Affects the majority of diabetics.

Non-proliferative retinopathy consists of intraretinal and preretinal hemorrhages, exudates, edema, thickening of retinal capillaries, and microaneurysms.

Proliferative retinopathy is the process of neovascularization and fibrosis of the retina, which has a high propensity to cause blindness.
45. What is diabetic neuropathy?
A symmetric peripheral neuropathy affecting motor and sensory nerves of the lower extremities is attributable to Schwann cell injury, myelin degeneration, and axonal damage.

Autonomic neuropathy may lead to sexual impotence and bowel and bladder dysfunction.

Focal neurologic impairment (diabetic mononeuropathy) is most likely due to microangiopathy.
46. What is the honeymoon period of type 1 DM?
In the initial 1-2 years following manifestation of overt type 1 diabetes, the exogenous insulin requirements may be minimal to non secondary to ongoing endogenous insulin secretion (referred to as the honeymoon period").
47. What are the clinical features of type 1 diabetes?
Shortly after the honeymoon period, the β-cell reserve is exhausted and insulin requirements increase dramatically.

Type 1 DM is dominated by signs of altered metabolism: polyura, polydipsia, and polyphagia. Despite an increased appetite, catabolic effects prevail, resulting in weight loss and muscle weakness.

Chemical indices include ketoacidosis, low or absent plasma insulin, and elevated plasma glucose.

Metabolic derangement and insulin need are directly related to physiologic stress, including deviations from normal dietary intake, increased physical activity, infections, and surgery.
48. What are the clinical features of type 2 diabetes?
Type 2 DM pts are usually older than 40, with polydipsia and polyuria and freq, obesity. Metabolic derangements are usually mild, and msot frequently, the Dx is made after routine blood or urine testing in asymptomatic persons.

*Nonketotic hypersosmolar coma can occur in elderly individuals who become dehydrated secondary to osmotic diuresis and lack adequate water intake.
49. What are the most common causes of mortality in long-standing diabetics?
Cardiovascular events such as MI, renal vascular insufficiency, and cerebrovascular accidents are the most common causes of mortality in long-standing diabetics.
50. What are the characteristics of diabetic nephropathy?
Diabetic nephropathy is the leading cause of ESRD in the US. The earliest manifestations is the appearance of low amts of albumin in the urine (>30 mg/day, but less than 300 mg/day), or microalbuminuria.

W/o specific interventions approx 80% of type 1 and 20-40% of type 2 diabetics will develop overt nephropathy w/macroalbuminria (>300 mg/day) over the next 10-15 years, usually accompanied by the appearance of hypertension.
51. What are the characteristics of diabetic retinopathy?

What else besides retinopathy can cause visual problems in diabetics?
Approx 60-80% of pts with diabetes develop some form of diabetic retinopathy approx 15-20 years after Dx.

*The fundamental lesion of retinopathy - neovascularization - is probably attributable to VEGF signaling in the retina.

In addition to retinopathy, diabetics also have increased propensity for glaucoma and cataract formation, both of which contribute to visual impairment in diabetes.
52. What are pancreatic endocrine neoplasms (PENs)?
This is the preferred term for tumors of the islet cells; they are rare compared with tumors of the exocrine pancreas.

They are most common in adults and can occur anywhere along the length of the pancreas, embedded in the substance of the pancreas, or arising in the immediate peripancreatic tissues. They resemble carcinoid tumors.

PENs may be hormonally functional or nonfunctional, single or multiple, benign or malignant.
53. What are the three unequivocal criteria for malignancy?
1. Metastases to regional lymph nodes or distant organs (including the liver0
2. Angioinvasion
3. Gross invasion of adjacent viscera.
54. What are the three most common and distinctive clinical syndromes associated with functional PENs?
1. Hyperinsulinism
2. Hypergastrinemia and the Zollinger-Ellison syndrome
3. MEN
55. What are β-cell tumors (insulinomas)?

What is the characteristic triad resulting from these lesions?
Most common PEN subtype; tumors may elaborate sufficient insulin to cause hypoglycemia.

The characteristic triad is:
1. Symptomatic attacks occur w/serum glucose below 50 mg/dL
2. The attacks consist principally of such CNS manifestations as confusion, stupor, and loss of consciousness.
3. The attacks are precipitated by fasting or exercise and are promptly relieved by feeding or parenteral administration of glucose.
56. What is the morphology of β-cell tumors (insulinomas)?
Most are solitary lesions, although multiple tumors or tumors ectopic to the pancreas may be encountered.

Bona fide carcinomas are diagnosed on the basic of criteria for malignancy.

β-cell tumors are usually less than 2 cm in diameter, usually encapsulated, firm, pale to reddish-brown nodules.

Histologically, these benign tumors looks remarkably like giant islets, w/preservation of the regular cords of monotonous cells and their orientation to the vasculature.

Under the EM, neoplastic β-cells display distinctive round granules that contain polygonal or rectangular dense crystals separated from the enclosing membrane by a distinct halo.
57. What are the clinical features of β-cell tumors (insulinomas)?

What are several clinical scenarios that may result in diffuse islet hyperplasia?
Symptoms of β-cell tumors (insulinomas) include hypoglycemia induced confusion, stupor, and loss of consciousness.

Attacks are promptly relieved by glucose feeding or infusion.

*Most commonly seen in infants secondary to maternal diabetes, Beckwith-Wiedemann syndrome, and rare metabolic disorders.
58. How is maternal diabetes related to insulinomas?
In the infant, insulinomas are caused by diffuse hyperplasia of the islets. This change is usually encountered in neonates and infants.

In maternal diabetes, the fetus, long exposed to the hyperglycemia of maternal blood, responds by an increase in the size and number of its islets.

In the postnatal period, these hyperactive islets may be responsible for serious episodes of hypoglycemia.
59. What is Zollinger-Ellison syndrome (gastrinomas)?
Comprises a triad of:
1. Recalcitrant peptic ulcer disease
2. Gastric hypersecretion
3. Endocrine cell tumor elaborating gastrin

Thy are just as likely to arise in the duodenum and peripancreatic soft tissue as in the pancreas.
60. What is the morphology of the gastrinomas in Zollinger-Ellison syndrome?
Grastinomas are just as likely to arise in the duodenum and peripancreatic soft tissues as in the pancreas.

***Over 1/2 of gastrin producing tumors are locally invasive or have already metastasized at the time of Dx.

In approx 25% of patients, gastrinomas arise in conjunction with other endocrine tumors, thus conforming to the MEN-1 syndrome.

As with insulin secreting tumors of the pancreas, gastrin-producing tumors are histologically bland and rarely exhibit marked anaplasia.
61. What are the clinical features of Zollinger-Ellison syndrome?
The duodenal and gastric ulcers are often multiple; although they are identical to those found in the general population, they are often intractable to usual modalities of therapy.

In addition, ulcers may also occur in unusual locations such as the jejunum- when this happens, Zollinger-Ellison syndrome should be considered.

More than 50% of patients have diarrhea; in 30% it is the presenting symptom.

60% of gastrinomas are malignant; recurrence is very likely post surgical removal
62. What is the difference between MEN-1 gastrinomas and sporadic gastrinomas?
MEN-1 associated gastrinomas are frequently multifocal, while sporadic gastrinomas are usually single.

The histologic and ultrastructral features are similar to normal intestinal and gastric G cells.
63. What are α-cell tumors (glucagonomas)?
α-cell tumors (Glucagonomas) are associated w/increased serum levels of glucagon and a syndrome consisting of mild DM, skin rash, and anemia.

They occur most frequently in peri- and post-menopausal women and are characterized by extremely high plasma glucagon levels.
64. What are δ-cell tumors (somatostatinomas)?
δ-cell tumors (Somatostatinomas) are associated w/diabetes mellitus, cholelithiasis, steatorrhea, and hypochlorhydria.
65. What is a VIPoma (diarrheogenic islet cell tumor)?
Causes watery diarrhea, hypokalemia, achlorhydria, or WDHA syndrome.

It is caused by release of vasoactive intestinal peptide from the tumor. Some of these tumors are locally invasive and metastatic.

*They are associated w/neural crest tumors, such as neuroblastomas, ganglioneuroblastomas, and ganglioneuromas, and pheochromocytomas.
66. What are pancreatic carcinoid tumors and pancreatic polypeptide-secreting islet cell tumors?
Both are very rare

Pancreatic carcinoid tumors are serotonin producing.

Pancreatic polypeptide-secreting islet cell tumors are asymptomatic, despite the high levels of hormone in plasma.
67. α-Glucosidase inhibitors

What are they?
These are carbohydrate analogues that bind 1,000x more avidly than dietary carbohydrates to intestinal brush border α-glucosidase enzymes.

They act by delaying the digestion of carbs, thereby decreasing glucose absorption.

These drugs are taken at the beginning of meals, but are not effective at other times.
68. How do α-glucosidase inhibitors work?
Glucosidases - maltase, isomaltase, sucrase, and glucoamylase - aid absorption by cleaving complex carbohydrates to yield glucose.

By reversibly inhibiting these enzymes, α-glucosidase inhibitors increase the time required for absorption of carbs such as starch, dextrin, and disaccharides.
69. What other effects do α-glucosidase inhibitors have on glucose levels?
These drugs also increase the intestinal surface area for absorption b/c carbs that would have been absorbed in the upper intestine are absorbed instead - in smaller quantities - throughout the length of the small intestine.

Therefore, these drugs help reduce the postprandial peak in blood sugar.
70. What are the three α-glucosidase inhibitors?
1. Acarbose
2. Miglitol
3. Voglibose
71. Acarbose, Miglitol, Voglibose
MOA: Carb analogues that bind avidly to intestinal brush border α-glucosidase enzymes, slowing breakdown and absorption of dietary carbs such as starch, dextrin, and disaccharides

PURPOSE: Type 2 diabetes

ADVERSE: Abdominal pain, diarrhea, flatulence, elevated serum ALT and AST levels, elevated plasma triglycerides

CONTRA: Cirrhosis, diabetic ketoacidosis, severe digestive problems, inflammatory bowel disease, bowel obstruction
72. What are five therapeutic considerations for the α-glucosidase inhibitors?
1. There is no risk of hypoglycemia with these agents
2. These drugs are most useful for patients w/predominantly postprandial hyperglycemia, and for new-onset patients with mild hyperglycemia.
3. The GI distress usually diminishes w/continued use
4. Serum aminotransferase levels should be monitored during therapy
5. Modest increases in plasma triglycerides may occur w/therapy
73. What is exogenous insulin?
Insulin is the only treatment for patients w/type I DM.

It is also used for patients with type II DM if diet and other therapies are not sufficiently effective at controlling the hyperglycemia.

Insulin preparations are classified according to onset of action, duration of action, and species of origin.
74. How is exogenous insulin administered?
B/c insulin is a protein that is subject to rapid degradation in the GI tract, it is not effective as an oral agent.

Instead, insulin is administered parenterally, typically by subcutaneous injection that creates a small depot of insulin at the site of injection.

The rate at which this depot of insulin is absorbed depends on a variety of factors, including the solubility of the insulin preparation and the local circulation.
75. What are the four categories of exogenous insulin preparations?
1. Ultrarapid-acting

2. Short-acting
-Regular insulin

3. Intermediate-acting

4. Long acting
76. What is regular insulin (short acting)?
This is a short and rapid acting preparation and is structurally identical to endogenous insulin, but zinc ions are added for stability.

It rapidly lower the blood sugar, and can be used safely in pregnancy only if clearly needed.

Regular insulin tends to aggregate into hexamers, and dissociation of the hexamers to monomers is the rate limiting step for absorption.
77. What is lispro insulin (ultrarapid)?
This is an ultra-rapid acting insulin. It was designed to keep the molecule in a monomeric form in order to speed absorption.

It is structurally similar to regular insulin, except that a sequence of two AAs (proline and lysin) near the carboxy terminus of the B-chain has been switched.

Lispro offers flexibility and convenience for patients b/c it can be injected minutes before a meal, whereas the proper use of longer-acting insulins requires a time lag between insulin injection and the consumption of a meal.
78. What is NPH insulin?
Neutral protamine Hagedorn (NPH) insulin is an intermediate-acting preparation.

Insulin is combined w/protamine at neutral pH. Protamine is a protein isolated from rainbow trout sperm - in a zinc suspension.

Protamine prolongs the time required for absorption of insulin b/c it remains complexed w/insulin until proteolytic enzymes cleave the protamine from the insulin. Thus, it provides basal insulin and overnight coverage.

Should only be given subcutaneously (never via IV), and is useful in treating all forms of diabetes except diabetic ketoacidosis or emergency hyperglycemia.
79. What is ultralente insulin?
A long acting preparation that is sometimes referred to as extended zinc insulin.

It is a crystalline suspension of insulin and zinc in an acetate buffer. This formulation delays the onset of action of insulin, resulting in a long-lasting hypoglycemic effect.

Also provides basal insulin and overnight coverage.
80. What is semilente insulin?
This is semicrystalline, or "amorphous", and is short-acting.

Used for meals or for acute hyperglycemia
81. What is lente insulin?
This is a combination of crystalline (i.e. ultralente) and semicrystalline (i.e. semilente) insulin and zine suspended in an acetate buffer.

This formulation is slower acting than semilente but faster acting than ultralente, and is therefore in the intermediate acting category.

Also provides basal insulin and overnight coverage.

Not suitable for IV administration
82. What is glargine insulin (long acting)?
This is regular insulin in which a glycine replaces an asparagine on the A-chain and two additional arginines are added at the carboxy terminus of the B-chain.

These modifications makes the pKa of the insulin more neutral, thus slowing its absorption into the neutral environment of the blood.

Glargine has the advantages of long duration of action and steady release w/o a peak (mimicking so-called "basal" insulin secretion"

Must be given subcutaneously.
83. What is the major danger associated with insulin therapy?
Administration of insulin in the absence of adequate carbohydrate intake can result in hypoglycemia.

Thus, patients, both type I and type II diabetics, must be cautioned not to take too much insulin.
84. What are the two categories of insulin secretagogues?
1. Sulfonylureas
2. Meglitinides
85. Sulfonylureas

How do they work?
They have been the major oral agents available in the US for the treatment of Type II diabetes.

Sulfonylureas stimulate insulin release from pancreatic beta cells, thereby increasing circulating insulin to levels sufficient to overcome the insulin resistance.
86. What are the two classes of sulfonylureas?
First generation:
1. Acetohexamide
2. Chlorpropamide
3. Tolazamide
4. Tolbutamide

Second generation
1. Glimepiride
2. Glipizide
3. Glibenclamide (Glyburide)
4. Gliclazide
5. Gliquidone
87. What is the main difference between the first and second generation sulfonylureas?
Because first generation sulfonylureas bind w/lower affinity to SUR1 than second-generation agents do, first generation agents must be administered in higher doses to achieve the same degree of glucose lowering.

Also, tolbutamide (1st gen) has the shortest duration of action (6-12 hours), whereas the 2nd gen agents last about 24 hours.
88. Sulfonylureas
MOA: Inhibit the β cell ATP-sensitive K+ channels at the SUR1 subunit, thereby stimulating insulin release from pancreatic β cells and increasing circulating insulin to levels sufficient to overcome insulin resistance.


ADVERSE: Hypoglycemia, rash, diarrhea, nausea, dizziness

CONTRA: Diabetic ketoacidosis
89. What are four therapeutic considerations for sulfonylureas?
1. Sulfonylureas are the mainstay of treatment for type II diabetes
2. The major adverse effect is hypoglycemia resulting form oversecretion of insulin
3. Can cause weight gain secondary to increased insulin activity in adipose tissue; (not a good choice for the obese!)
4. Because first generation sulfonylureas bind w/lower affinity to SUR1 than second-generation agents do, first generation agents must be administered in higher doses to achieve the same degree of glucose lowering
90. What are the meglitinides?
As with sulfonylureas, meglitinides stimulate insulin release by binding to SUR1 and inhibiting the beta cell K+/ATP channel.

Although both sulfonylureas and meglitinides act on the SUR1 subunit, these two classes of drugs bind to distinct regions of the SUR1 molecule. (They have a more rapid onset and a shorter duration of action when compared to sulfonylureas)

The absorption, metabolism, and adverse effect profiles of meglitinides are similar to those of sulfonylureas
91. What are the meglitinide analogues?
1. Nateglinide
2. Repaglinide
92. Nateglinide and repaglinide
MOA: Meglitinides stimulate insulin release by binding to SUR1 and inhibiting the beta cell K+/ATP channel.


ADVERSE: Hypoglycemia, diarrhea, nausea, upper respiratory infection

CONTRA: Diabetic ketoacidosis and type 1 DM

NOTES: Meglitinides have similar therapeutic considerations as sulfonylureas
93. What are the two classes of insulin sensitizers?
1. Thiazolidinediones
2. Biguanides
94. What are thiazolidinediones (TZD)?
These drugs are a relatively new class of oral medicaction for Type II diabetes; the two currently avialable in the US is rosiglitazone and pioglitazone.

The TZDs do not affect insulin secretion, but rather enhance the action of insulin at target tissues.
95. How do TZDs work?
TZDs are agonists for nuclear hormone receptor peroxisome proliferator activated receptor-γ (PPARγ).

This can improve insulin sensitivity in not only adipocytes but also in muscle and liver cells.
96. What is PPARγ?
PPARγ functions as a heterodimer with the retinoid X receptor to activate transcription of a subset of genes involved in glucose and lipid metabolism.

PPARγ is expressed primarily in adipose tissue and is involved in adipocyte differentiation.

Studies show that cells made to overexpress PPARγ accumulate TAG and acquire other adipocyte markers when treated with TZDs.
97. How do TZDs help type II diabetics?
Ligands for PPARγ regulate adipocyte production and secretion of fatty acids as well as glucose metabolism, resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle.

Hyperglycemia, hyperinsulinemia, hypertriacyglycerolemia and elevated HbA1c levels are improved.
98. TZDs: pioglitazone and rosiglitazone
MOA: Bind and stimulate the nuclear hormone receptor PPARγ, thereby increasing insulin sensitivity in adipose tissue, liver, and muscle

PURPOSE: Type 2 DM; polycystic ovarian syndrome

ADVERSE: Heart failure, cholestatic hepatitis, hepatotoxicity, diabetic macular edema; edema, weight gain, increased HDL and LDL, decreased circulating TAGs and free FA's.

CONTRA: Hypersensitivity

NTOES: TZDs do not increase insulin levels and therefore do not induce hypoglycemia; Newer TZDs appear to have less hepatotoxicity.
99. What are biguanides?
Like TZDs, biguanides act by increasing insulin sensitivity.

The molecular target of the biguanides appears to be the AMP-dependent protein kinase (AMPPK).

Biguanides activate AMPPK to block the breakdown of fatty acids and to inhibit hepatic gluconeogenesis and glycogenolysis.

Secondary effects include increased insulin signaling as well as increased metabolic responsiveness by the liver and skeletal muscle to insulin.
100. What is the only currently available biguanide?

It increases glucose uptake and utilization by target tissues, which essentially reduces hepatic glucose output.

Like the sulfonylureas, metformin requires insulin for its action, but it differs from the sulfonylureas int hat it does not promote insulin secretion.
101. Metformin
MOA: Activates AMP-dependent protein kinase (AMPPK) to block breakdown of fatty acids and to inhibit hepatic gluconeogenesis and glycogenolysis; increases insulin receptor activity and metabolic responsiveness in liver and skeletal muscle

PURPOSE: Type 2 DM; polycystic ovarian syndrome

ADVERSE: Lactic acidosis, diarrhea, dyspepsia, flatulence, nausea, vomiting, cobalamin deficiency

CONTRA: Heart failure, septicemia, EtOH abuse, hepatic disease, respiratory disease, renal impairment, iodinated contrast media if acute alteration in renal function is suspected; metabolic acidosis
102. What are four therapeutic considerations for metformin?
1. GI distress associated w/metformin use is usually transient and can be minimized by slow titration of the dose
2. Incidence of lactic acidosis is low and predictable; lactic acidosis typically occurs with metformin use in pts who have other conditions that predispose to metabolic acidosis
3. Dose not induce hypoglycemia
4. Lowers serum lipids and decreases weight
103. What are GLP-1 agonists and mimetics?
Glucagon like peptide-1 (GLP-1) receptor agonist that enhances glucose dependent insulin secretion, inhibits glucagon secretion, delays gastric emptying, and decreases appetite.

Sitagliptin is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that slows the proteolytic inactivation of GLP-1 and other incretin hormones
104. What are the names of the two GLP-1 agonists and mimetics?
1. Exenatide
2. Sitagliptin
105. Exenatide
MOA: Glucagon like peptide-1 (GLP-1) receptor agonist that enhances glucose dependent insulin secretion, inhibits glucagon secretion, delays gastric emptying, and decreases appetite.


ADVERSE: Hypoglycemia, nausea, vomiting, diarrhea, nervousness, dizziness, headache

CONTRA: Type 1 DM, diabetic ketoacidosis

NOTES: Not orally available and must be injected

*Typically used in combination with metformin or a sulfonylurea to improve glucose control
106. Sitagliptin
MOA: Sitagliptin is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that slows the proteolytic inactivation of GLP-1 and other incretin hormones


ADVERSE: Upper respiratory tract infection, nasopharyngitis, headache, nausea, diarrhea, mild increase in serum creatinine level

CONTRA: Type 1 DM, diabetic ketoacidosis
107. What are three therapeutic considerations for sitagliptin?
1. Dose adjustment is necessary in patients with moderate or severe kidney disease
2. May cause hypoglycemia in combination with sulfonylureas and insulin
3. Digoxin levels should be monitored in patients receiving digoxin and sitagliptin.
108. Diazoxide
MOA: Binds to SUR1 subunit of K+/ATP channels in pancreatic beta cells and stabilizes the ATP bound (open) state of the channel so that the beta cells remain hyperpolarized; this decreases insulin secretion by the cells.

PURPOSE: Hypoglycemia due to hyperinsulinism; malignant hypertension

ADVERSE: Heart failure, fluid retention, diabetic ketoacidosis, hypernatremia, bowel obstruction, pancreatitis, neutropenia, thrombocytopenia, extrapyramidal disease; angina, hypotension, tachyarrhythmia, hirsutism, hyperglycemia, dyspepsia, dizziness, glucosuria

CONTRA: Hypersensitivity

NOTES: Diazoxide also hyperpolarizes SUR2-containing channels in cardiac and smooth muscle cells, and can be used to decrease blood pressure in hypertensive emergencies.
109. Octretide
MOA: Inhibits GHRH release

Is a somatostatin analogue that is longer acting than endogenous somatostatin.

As with somatostatin, this agent blocks hormone release from endocrine secreting tumors, such as insulinomas, glucagonomas, and thyrotropin-secreting pituitary adenomas.
110. Glucagon
MOA: a polypeptide hormone, produced by alpha cell sin the islets of Langerhans in the pancreas, that stimulates gluconeogenesis and glycogenolysis in the liver, resulting in an increase in blood sugar.

PURPOSE: Hypoglcemia, intestinal relaxant before radiography of GI tract

ADVERSE: Rash, nausea, vomiting

CONTRA: Pheochromocytoma

NOTES: Used to treat severe hypoglycemia when oral or IV glucose administration is not possible. Also, the hyperglycemic action of glucagon is transient, and it requires a sufficient hepatic store of glycogen.
111. What is proptosis?
Any disease process that increases orbital contents results in the forward displacement of the eye, proptosis.

Aside from the obvious cosmetic concerns, the proptotic eye might not be covered completely by the eyelids, and the tear film might now be distributed evenly across the cornea. This can predispose to corneal infection.
112. What conditions can produce positional proptosis?
Any enlargement of the lacrimal gland from inflammation or neoplasm (e.g lymphoma or epithelial neoplasm such as pleomorphic adenoma or adenoid cystic carcinoma) produces a proptosis that displaces the eye inferiorly and medially b/c the lacrimal gland is positioned supertemporally w/in the orbit.
113. What conditions produce axial (forward) proptosis?
Masses contained w/in the cone formed by the horizontal rectus muscles generate axial proptosis.

The two most common primary tumors of the optic nerve, glioma and meningioma, produce axial proptosis.
114. What causes proptosis in Graves disease?
Proptosis is caused by the accumulation of ECM proteins and variable degrees of fibrosis in the rectus muscles.
115. How does Wegener granulomatosis affect the orbit?
Wegener granulomatosis and extension of maxillary or ethmoid sinus infections can cause proptosis.

*The presence of necrotic collagen along with vasculitis should raise the suspicion of Wegener granulomatosis.
116. What is idiopathic orbital inflammation (aka orbital inflammatory psuedotumor)?
Idiopathic orbital inflammation (orbital inflammatory pseudotumor) is characterized by chronic inflammation and variable fribosis.
117. What is the morphology of idiopathic orbital inflammation (aka orbital inflammatory psuedotumor)??
Idiopathic orbital inflammation is characterized histologically by chronic inflammation and variable degrees of fibrosis. The inflammatory infiltrate typically includes lymphocytes and plasma cells and possibly eosinophils.

It is typically confined to the orbit but may develop concomitantly w/sclerosing inflammation in the retroperitoneum, the mediastinum, and the thyroid.
118. What are the most frequently encountered primary neoplasms of the orbit?
Those that are vascular in origin: the capillary hemangioma of infancy and early childhood and the lymphangioma (both of which are unencapsulated) and the encapsulated cavernous hemangioma found typically in adults.

Only a handful of orbital masses are encapsulated and the recognition of encapsulation on imaging studies allows the surgeon to anticipate pathologic findings.
119. How do metastases to the orbit yield clues to their origin?
They present with distinctive signs and symptoms that point to their origin.

For example, metastatic prostatic CA may present clinically like idiopathic orbital inflammation; metastatic neuroblastoma and Wilms tumor - richly vascular neoplasms - may produce characteristic periocular ecchymoses.

Neoplasms may also invade from the sinuses into the orbit.
120. What is blepharitis and a chalazion?
If the draining system of the sebaceous glands is obstructed by chronic inflammation at the eyelid margin (blepharitis) or, less commonly, by neoplasm, then lipid may extravasate into surrounding tissue, and provoke a granulomatous response: a lipogranuloma, or chalazion.
121. What is the most common malignancy of the eyelid?

Second most common?
Most common is basal cell CA. The second most common is sebaceous CA.

Regardless of histogenesis, eyelid neoplasms may distort tissue and prevent the eyelids from closing completely.

*Basal cell CA has a distinct predilection for the lower eyelid and the medial canthus.
122. What is sebaceous CA of the eyelid?
Sebaceous CA may form a local tumefaction and thus mimic chalazion or may diffusely thicken the eyelid.

This neoplasm may mimic inflammatory processes that such as blepharitis or ocular cictricial pemphigoid b/c of epithelial spread resembling that seen in Paget disease of the nipple or vulva.

Sebaceous CA tends to spread first to the parotid and submandibular nodes.
123. What is the morphology of sebaceous CA of the eyelid?
In moderately differentiated or well-differentiated sebaceous CA, vacuolization of the cytoplasm is present and helps in the Dx. This cancer may, however, mimic a variety of other malignancies.

Pagetoid spread may mimic Bowenoid actinic keratosis in the eyelid and carcinoma in situ in the conjunctiva.

It may spread thru the conjunctival epithelium and the epidermis to the lacrimal drainage system and the nasopharynx. It may also extend into the lacrimal gland ductules and thereby into the main lacrimal gland.
124. What do Kaposi sarcomas in the eyelid look like in AIDS pts?
In pts w/AIDS, Kapsosi sarcoma may develop in either the eyelid or the conjunctiva.

In the eyelid, the lesion may appear clinically to have a purple hue b/c the vascular lesion is embedded in the dermis, but in the thin mucous membrane of the conjunctiva, Kaposi sarcoma appears bright red and may be confused with a subconjunctival hemorrhage.

However, the subconjunctival hemorrhages are clinically flat, while the conjuctival Kpasoi sarcoma typically thickens the conjunctiva.
125. What causes conjunctival scarring?

Four major things...
1. Infections with Chlamydia trachomatis may produce significant scarring
2. Immune-mediated conditions, such as ocular cicatricial pemphigoid
3. Chemical agents, especially akalis
4. Excessive surgical resection of conjunctival tissue
126. What is a pterygium?
A pterygium appears as submucosal elevation on the conjunctiva. It results from actinic damage, and is therefore located in the sun-exposed regions of the conjunctiva.

Pterygium typically originates in the conjunctiva astride the limbus.

**It is formed by a submucosal growth of fibrovascular connective tissue that migrates onto the cornea, dissecting into the plane occupied normally by Bowman's layer.
127. What are the clinnical features of a pterygium?
Pterygium do not cross the pupillary axis, and, aside from t possible induction of mild astigmatism, does not pose a threat to vision.

These lesions are commonly excised to relieve pts of the white blemish over the surface of the eye, which may be mildly irritating and cosmetically unacceptable. Although most are benign, on occasion squamous cell CA and melanoma are detected in these lesions.
128. What is a pinguecula?
Pinguecula, which like pterygium, appears astride the limbus, is a small, yellowish submucosal elevation.

Although the pinguecula does not invade the cornea as pterygium does, the presence of a focal conjunctival elevation near the limbus can result in an uneven distribution of the tear film over the adjacent cornea. As a consequence of focal dehydration, a saucer-like depression in the corneal tissue - a dellen - may develop.
129. What causes the yellow color of a pinguecula?
The yellow color of the pinguecula originates not from the accumulation of lipid, but rather from the accumulation of focal zones of sun-damaged collagen w/elastic like properties - solar elastosis.
130. What is an actinic grauloma?
On occasion, pinguecula may become inflamed secondary to a foreign body granulomatous reaction against the elastotic collagen: actinic granuloma.
131. Where do neoplasms of the conjunctiva tend to develop?
Both squamous and melanocytic neoplasms and their precursors tend to develop at the limbus.
132. What causes squamous cell CAs of the conjunctiva?
Squamous cell CAs are associated with HPV types 16 and 18.

Most tend to follow indolent course, except for mucoepidermoid CA of the conjunctiva, which follows a much more aggressive course.
133. What are conjunctival nevi?
Conjunctival nevi are common and typically benign, rarely invading the cornea or appearing in the fornix. Pigmented lesions in these zones most likely represent melanomas or melanoma precurosrs.

Chronic inflammation with eosinophils may occur during adolescence (inflamed juvenile nevus).
134. What are conjunctival melanomas?
Conjunctival melanomas are unilateral neoplasms, typically affecting fair-complexioned individuals in middle age.

Most cases develop thru a phase of intraepithelial growth termed primary acquired melanosis w/atypia, which is roughly analogous to melanoma in situ.
135. What are the clinical features of conjunctival melanomas?
Conjunctival melanomas will develop in 50-90% of primary acquired melanosis w/atypia, metastasizing first to the parotid or submandibular lymph nodes with 25% mortality rate. The best treatment is precursor lesion extirpation.
136. What are the characteristics of the sclera?
Sclera is relatively deficient in blood vessels and fibroblasts; thus, wounds and surgical incisions heal poorly. It is thinned physiologically at the limbus, behind the rectus muscle insertion, and near the optic nerve so that blunt force trauma can cause ruptures there.

Also, immune complex deposits within the sclera, such as in rheumatoid arthritis, and may produce a necrotizing scleritis.
137. What can cause the sclera to appear blue?
It may become thin following episodes of scleritis, and the normally brown color of the uvea may appear blue clinically b/c of the optical Tyndall effect.

In eyes with high intraocular pressure, the sclera may become thin, and b/c this zone of scleral ectasia is lined by uveal tissue, the resulting lesion, known as a stphyloma, also appears blue clinincally. The sclera may appear blue in osteogenesis imperfecta.
138. What is congenital melanosis oculi?

What is a nevus of Ota?
Finally, the sclera may appear blue b/c of a heavily pigmented congenital nevus of the underlying uvea, a condition known as congenital melanosis oculi.

When accompanied by periocular cutaneous pigmentation, this condition is known as nevus of Ota.
139. What is the functional anatomy of the cornea?

The cornea and its overlying tear film compose the major refractive eye surface. The corneal stroma lacks blood vessels and lymphatics, contributing to conreal transparency as well as the success of corneal transplantation. Precise collagen alignment is also necessary to maintain transparency; consequently, scarring or edema markedly affects vision. Anteriorly, the cornea is covered by epithelium overlying a basement membrane and the acellular Bowman's layer.
140. What is the functional anatomy of the cornea?

Posteriorly, the cornea is bounded by corneal endothelium derived from neural crest; it sits on a basal lamina Descemet membrane.

Endothelial loss or malfunction causes stromal edema that can progress to bullous separation of the epithelium (bullous keratopathy).
141. Where is the site of copper deposition in the Kayser-Fleischer ring of Wilson disease?
In the Descemet membrane.
142. What causes corneal ulceration and keratitis?
Various pathogens, bacterial, fungal, viral, especially HSV and herpes zoster), and protozoal (Acanthamoeba) may cause corneal ulceration.

Exudate and cells leaking from iris and ciliary body vessels into the anterior chamber may be visible by slit-lamp exam (hypopyon).

Although the corneal ulcer may be infectious, the hypopyon seldom contains organisms.
143. What is involved in the process of keratitis?
In all forms of keratitis, dissolution of the corneal stroma may be accelerated by activation of collagenases w/in corneal epithelium and stroma fibroblasts (aka keratocytes).

*Some forms of keratitis may have certain distinctive features. For example, chronic herpes simplex keratitis may be associated w/a granulomatous reaction to Descemet's membrane.
144. What are the two traditional categories of corneal disorders?
1. Degenerations
-may be unilateral or bilateral and are typically non-familial

2. Dystrophies
-typically bilateral and are hereditary. They may affect selective corneal layers (e.g., Reis-Buckler dystrophy affects Bowmans layer, and posterior polymorphous dystrophy affects the endothelium).
145. What is the corneal degeneration called calcific band keratopathy?
Calcific band keratopathy is characterized by deposition of calcium in Bowman's layer. This condition may complicate chronic uveitis, especially in pts with chronic juvenile rheumatoid arthritis.
146. What is the corneal degeneration called actinic band keratopathy?
Actinic band keratopathy develops in pts who are exposed chronically to high levels of ultraviolet light. In this condition, extensive solar elastosis develops in the superficial layers of corneal collagen in the sun-eposed interpalpebral fissure, hence hence the horizontally distributed band of pathology.

Similar to pinguecula, the sun-damaged collagen of the cornea appears clinically to be yellow to the point that this condition is sometimes erroneously called "oil-droplet keratopathy".
147. What is keratoconus?
Kertoconus is a rather common degeneration disorder. It is characterized by progressive thinning and ectasia of the cornea w/o evidence of inflammation or vascularization. Such thinning reuslts in a cornea that have a conical rather than spherical shape.

This abnormal shape generates irregular astigmatism that is difficult to correct with spectacles. Contacts may provide refractive relief. Corneal transplantation can be used for Tx.
148. What are the clinical correlates of keratoconus?
Unlike many degenerations, it is typically bilateral, and in some pts, there is an association between keratoconus, Down syndrome, and Marfan syndrome, as well as with atopic disorders. Activation of collagenases, gelatinases, and MMPs has been implicated in the pathogenesis of this condition.
149. What is the morphology of a keratoconus?
***Thinning of the cornea with break in Bowman's layer are the histologic hallmarks of keratoconus.

Acute corneal hydrops (rupture of the Descemet membrane) can also contribute to visual loss, elevations of intraocular pressure in infantile glaucoma, or following the now uncommon obstretical forceps injury to the eye.
150. What is Fuchs endothelial dystrophy?
The two major clinical manifestations of Fuchs endothelial dystrophy - stomal edema and bullous kertopathy - are both related to a primary loss of endothleial cells.

Consequently, the stroma becomes edematous and thickens; it acquires a ground-glass appearance clinically, and vision is blurred. B/c of chronic edema, the stroma may eventually become vascularized.
151. What is the pathogenesis of Fuchs endothelial dystrophy?
Early in the course of the disease, endothelial cells produce droplike deposits of abnormal basement membrane material (guttata) that resemble the fetal component of Descemet's membrane ultrastructurally.

With disease progression, there is a decrease in th etotal number od endothleial cells, and the residual cells are incapable of maintaining stromal deturgescence.

Consequently, the stroma becomes edematous and thickens; it acquires a ground-glass appearance clinically, and vision is blurred.
152. What is the morphology of Fuchs endoethelial dystrophy?
Thickened Descemet's membrane and numerous droplike excrescenses - guttata - protrude downward from Descemet's membrane.

Epithelial bullae are present, reflecting corneal edema. Fibrous connective tissue may be deposited between the epithelium and Bowman's layer (degenerative pannus) either by ingrowth from the limbus or perhaps thru fibrous metaplasia of the corneal epithelium.
153. What are the clinical features of Fuchs endothelial dystrophy?
Although the signs and symptoms of Fuchs dystrophy (blurring and loss of vision) first manifest themselves in late middle age, ultrastructural evidence suggests that the endothelium and Descemet's membrane are abnormal even in young, asymptomatic pts w/this disorder.

Therefore, these pts may develop frank corneal edema following intraocular surgery; the loss of even a minimal number of endothelial cells during surgery may tip the balance and lead to corneal edema.
154. What is pseudophakic bullous keratopathy?
On occasion, the number of endothelial cells may decrease following cataract surgery even in pts who do not have early forms of Fuchs dystrophy, and the condition is then known as pseudophakic bullous keratopathy.
155. What is macular corneal dystrophy?
This is a stromal dystrophy in which stromal deposits generate discrete opacities in the corneal stroma, which may compromise vision.

Scarring in the vicinity of Bowman's layer may generate an irregular corneal surface, further compromising vision.

Macular corneal dystrophy is so named b/c early in the disease, small nummular (macular) deposits of keratan sulfate is distributed diffusely throughout the stroma and may affect the endothelium.
156. What are the genetic mutations associated with stromal dystrophies?
The development of lattice dystrophy, granular dystrophy, and combos of these called Avellino dystrophy; has now been attributed to defects in the gene encoding β-keratoepithelin.
157. What is Meratoja syndrome?

What is polymorphic amyloid degeneration?
The depositions in the cornea may be without systemic manifestations (such as in lattice corneal dystrophy) or may be accompanied by conditions such as peripheral neuropathies (Meratoja syndrome).

However, amyloid may also be deposited focally deep w/in the cornea of elderly pts in a condition known as polymorphic amyloid degeneration.
158. What are cataracts?
The term cataract describes lenticular opacities that may be congenital or acquired.

Systemic diseases (e.g., diabetes, atopic dermatitis, Wilson disease, galactosemia), drugs (especially corticosteroids), raditiona, trauma, and many intraocular disorders (e.g., uveitis) cause cataracts.
159. What causes age related cataracts?
Age related cataract typically results from opacification of the lens nucleus (nuclear sclerosis).

The accumulation of urochrome pigment may render the lens nucleus brown, thus distorting the pts perception of blue color. (This is why Rembrandt's patients later in life have a dominance of yellow hues...)
160. What is a posterior subcapsular cataract?
Migration of the lens epithelium posterior to the lens equator may result in posterior subcapsular cataract secondary to enlargement of abnormally positioned lens epithelium.
161. What causes inflammatory reactions to lens material?
Inflammatory reactions to lens material may develop as the result of the exposure of intact lens cortex by rupture of the elns capsule (either by trauma or as part of cataract extraction).

***It has been suggested that antigen-antibody complexes develop to lens cortical material, especially in the presence of Propionibacterium acnes as an adjuvant, generating a lens-induced uveitis.
162. What is a Morgagnian cataract?
Occasionally, the lens cortex may liquefy nearly entirely, a condition known as hypermature or Morgagnian cataract.
163. What is phacolysis?
HMW proteins from liquefied lens cortex may leak thru the lens capsule (phacolysis).

This phacolytic protein - either free or contained w/in macrophages - may clog the trabecular meshwork and contribute to elevation in intraocular pressure and optic nerve damage; phacolytic glaucoma is an example of secondary open angle glaucoma.
164. What is glaucoma?
The term glaucoma refers to a collection of diseases characterized by distinctive changes in the visual field and in the cup of the optic nerve.

Most are associated w/elevated intraocular pressure, although some pts with normal intraocular pressure may develop characteristic optic nerve and visual field changes (normal or low-tension glaucoma)
165. What is the pathophysiology of glaucoma?
It has to do with the ways in which the aqueous humor fluid can egress from the anterior chamber. The fluid is produced in the ciliary body and passes from the posterior chamber thru the pupil into the anterior chamber. Although there are multiple ways for the fluid to drain, most of the aqueous humor drains thru the trabecular meshwork.

There are two major categories:
1. Open angle glaucoma
2. Angle closure glaucoma.

Both open angle and angle closure glaucoma may be subclassified into primary and secondary types.
166. What is open angle glaucoma?
In open angle glaucoma, the aqueous humor has complete physical access to the trabecular meshwork, and the elevation in intraocular pressure results from an increased resistance to aqueous outflow in the open angle.
167. What is angle closure glaucoma?
In angle closure glaucoma, the peripheral zone of the iris adheres to the trabecular meshwork and physically impedes the egress of aqueous from the eye.
168. What is the most common form of glaucoma?
Primary angle glaucoma is the most common form of glaucoma.

In this form, the angle is open, pressure builds in the posterior chamber, bowing the iris forward, and occluding the trabecular meshwork.

The changes are apparent structurally, relating to genetic alterations.
169. What are the genetic alterations associated with primary open angle glaucoma?
Mutations in the GLC1A gene have been associated with a subset of pts with juvenile and adult primary open angle glaucoma.

The function of the gene product, myocilin, is unknown. Myocilin is distributed not only in the trabecular meshwork and other anterior segment tissues, but also within the optic nerve, suggesting that the pathogenesis of optic nerve damage in open angle glaucoma may be complex.
170. What are five causes of secondary open angle glaucoma?
1. Particulate material such as HML lens proteins in phacolysis, senescent RBCs after trauma (ghost cell glaucoma)
2. Iris pigment epithelial granules (pigmentary glaucoma)
3. Fragements of oxytalan fibers (exfoliation glaucoma)
4. Nectrotic tumors (melanomalytic glaucoma)
5. Elevations in the pressure on the surface of the eye (episcleral venous pressure)

-All of these may clog the trabecular meshwork in the presence of an open angle and cause secondary open angle glaucoma.
171. Elevations in the pressure on the surface of the eye (episcleral venous pressure) in the presence of an open angle contribute to what type of glaucoma?

What is it associated with?
This type of glaucoma is associated with surface ocular vascular malformations seen in Sturge-Weber syndrome or as a consequence of arterialization of the episcleral veins following a spontaneous or traumatic carotid-cavernous fistula.
172. What causes primary angle closure glaucoma?

What is the pathogenesis?

Primary angle closure glaucoma typically develops in eyes with shallow anterior chambers, often found in pts with hyperopia.

Transient apposition of the pupillary margin of the iris to the anterior surface of the lens may result in obstruction to the flow of aqueous humor thru the pupillary aperture (pupillary block).
173. What causes primary angle closure glaucoma?

What is the pathogenesis?

Continued production of aqueous humor by the ciliary body thus elevates pressure in the anterior chamber and may bow the iris periphery forward (iris bombe), opposing it to the trabecular meshwork. These anatomic changes provoke a dramatic elevation in intraocular pressure.
174. What are the consequences of elevated intraocular pressure in primary angle closure glaucoma?
Since the crystalline lens is avascular and the lens epithelium receives its nutrition from the aqueous humor, unremitting elevation in intraocular pressure in primary angle glaucoma can damage the lens epithelium. This leads to minute anterior subcapsular opacities that are visible by slit-lamp exam (glaukomflecken).

*Sustained elevated pressures can produce corneal edema and bullous keratopathy.
175. What are the causes of secondary angle closure glaucoma?
Contraction of various types of pathologic membranes that form over the surface of the iris can draw the iris over the trabecular meshwork, occluding aqueous outflow.

This includes:
1. Neovascular glaucoma
2. Iridocorneal endothelial syndrome
3. Epithelial downgrowth membranes
4. Necrotic tumors, especially retinoblastomas
176. What is neovascular glaucoma?
For example, chronic retinal ischemia is associated w/the up-regulation of VEGF and other proangiogenic factors.

The appearance of VEGF in the aqueous humor is thought to induce the development of thin, clinically transparent fibrovascular membranes over the surface of the iris.

***Contraction of myofibroblastic elements in these membranes leads to occlusion of the trabecular meshwork by the iris: neovascular glaucoma.
177. What is iridocorneal endothelial syndrome?
Abnormal corneal endothelium may migrate over the trabecular meshwork and onto the surface of the iris in a group of disorders known collectively as the iridocorneal endothelial syndrome.

Contraction of this abnormal endothelial membrane is another cause of secondary angle closure glaucoma.
178. What is epithelial downgrowth?

What causes it?
Following intraocular surgery or penetrating trauma to to the anterior segment, conjunctival or corneal epithelium may grow thru the wound and into the anterior chamber, and the contraction of these epithelial downgrowth membranes may yet cause secondary angle glaucoma.
179. What causes anterior segment inflammation?
Anterior segment inflammation can develop as a consequence of blunt trauma,(traumatic iridocyclitis), corneal infections, or uveal inflammation (uveitis).
180. What is endophthalmitis?
Endophthalmitis is inflammation involving the vitreous in the posterior pole of the eye.

The retina lines the vitreous cavity, and suppurative inflammation in the vitreous humor (endophthalmitits) is poorly tolerated by the retina; after only a few hours of exposure to acute inflammation, the function of the retina may be irreversibly damaged.

Can be exogenous or endogenous.
181. What is panophthalmitis?
The term pnophthalmitis is applied to inflmmation within the eye that inolves the retina, choriod, and sclera and extends into the orbit. The accumulation of inflammatory exudate and cells within the orbit may produce proptosis of the inflamed eye.
182. What is the uvea?
Together with the iris, the choroid and ciliary body constitute the uvea. The choroid is among the most richly vascularized sites in the body.

As in the retina, there are no lymphatics within the uvea.
183. What is uveitis?
The term uveitis can be applied to any type of inflammation in one or more of the tissues that comprise the uvea.

It can be infectious, idiopathic (e.g. sarcoidosis), or autoimmune (e.g., sympathetic ophthalmia); it can be part of a systemic process, or involve only the eye.
184. Where is uveal inflammation present in juvenile RA?
Uveal inflammation may be manifest principally in the anterior segment in juvenile RA.
185. What is granulomatous uveitis?

What is the well-known ophthalmic sign?
Granulomatous uveitis is a common complication of sarcoidosis. In the anterior segment, it gives rise to an exudate that evolves into "mutton-fat" keratic precipitates.

In the posterior segment, sarcoid may involve the chorioid and retina.

*Retinal pathology is characterized by perivascular inflammation; this is responsible of the well known sign of "candle wax drippings".
186. What are the causes of infectious uveitis?
Inflammation in one compartment is typically associated with inflammation in the other.

Retinal toxoplasmosis is usually accompanied by uveitis and even scleritis. Pts with AIDS who are immunocompromised may CMV retinitis and exotic forms of uveal infection such as pneumocystis or Mycobacterium avium choroiditis.
187. What is sympathetic ophthalmia?
Sympathetic ophthalmia is an example of noninfectious uveitis limited to the eye. This condition is characterized by bilateral granumomatous inflammation affecting all components of the uvea: a panveitis.

In the injured eye, retinal antigens sequestered from the immune system may gain access to lymphatics in the conjunctiva and thus set up a delayed hypersensitivity reaction that affects not only the injured eye, but also the contralateral, noninjureerd eye.

*Enucleation of a blind eye may yield diagnostic findings.
188. What is the morphology of sympathetic ophthalmia?
Sympathetic ophthalmia is characterized by diffuse granulomatous inflammation of the uvea (choroid, ciliary body, and iris).

Plasma cells are typically absent, but eosinophils may be identified in the infiltrate.
189. What is the most common intraocular malignancy of adults?
Metastasis to the uvea, typically to the choroid. The appearance of metastases to the eye is suggestive of extremely short survival, and treatment of ocular metastases is usually palliative and delivered by radiation therapy.
190. What is the most common primary intraocular malignancy of adults?
Uveal melanoma is the most common primary intraocular malignancy of adults.

Uveal nevi, especially choroidal nevi, are rather common. The progression of an uveal nevus to melanoma is therefore likely to be an exceptionally uncommon event.
191. How do uveal melanomas spread?
There are no lymphatics w/in the eye, hence, uveal melanomas, with very rare exception, spread exclusively by a hematogeneous route.

Most uveal melanomas spread first to the liver, thereby providing an excellent example of organ specific metastasis.
192. What is the morphology of uveal melanomas?
Histologically, uveal melanomas may contain two types of cells, spindle and epithelioid, in various proportions. Spindle cells are fusiform in shape and have little atypia, whereas epithelioid cells are spherical and have greater cytologic atypicality.

Melanomas situated exclusively in the iris tend to follow a relatively indolent course, whereas melanomas of the ciliary body and choroid are more aggressive.
193. What five factors are associated with a poor prognosis in uveal melanomas?
1. Tumors containing epithelioid cells have a worse prognosis than do those containing exclusively spindle cells.
2. Large numbers of tumor infiltrating lymphocytes are associated with an adverse outcome.
3. Extraocular extension is rlated to poor prognosis
4. Monosomy 3 and trisomy 8 are seen with a poor prognosis
5. *The presence histologically of looping patterns rich in laminin that surround packets of tumor cells is also associated with an adverse outcome (the patterns are formed by aggressive tumor cells in a process termed vasculogenic mimicry).
194. What is the clinical course for uveal melanomas?
Uveal melanomas can have an adverse effect on vision, producing changes ranging from retinal detachment to glaucoma.

There is currently no effective treatment for metastatic uveal melanoma. Although the five-year survival rates approach 80%, cumulative mortality rate is 40% at ten years.
195. What is the definition of a retinal detachment?
The retinal pigment epithelium, like the retina, is derived embryologically from the primary optic vesicle, an outpouching of the brain.

Separation of the neurosensory retina from the retinal pigment epithelium defines a retinal detachment.
196. What is the role of RPE (retinal pigment epithelium)?
The RPE plays an important role physiologically in the maintenance of the outer segments of the photoreceptors.

Disturbances in the RPE-photoreceptor interface may play important roles in hereditary retinal degenerations such as retinitis pigmentosa.
197. What is a rhegmatogenous retinal detachment?
A rhegmatogenous retinal detachment is associated with a full-thickness retinal defect.

Retinal tears may develop after the vitreous collapses structurally, and the posterior hyaloid exerts traction on points of abnormally strong adhesion to the retinal internal limiting membrane. Liquefied vitreous humor then seeps thru the tear and gains access to the potential space between the neurosensory retina and the retinal pigment epithelium.
198. What is proliferative vitreoretinopathy?
Rhegmatogenous retinal detachment may be complicated by proliferative vitreoretinopathy, the formation of epiretinal or subretinal membranes by retinal glial cells (Muller cells) or retinal pigment epithelial cells.
199. What is non-rhegmatogenous retinal detachment?
Retinal detachment without retinal break.

It may complicate retinal vascular disorders associated w/significant exudation and any condition that damages the RPE and permits fluid to leak from the choroidal circulation beneath the retina.
201. How does hypertension affect the retinal vasculature?
In retinal ateriolosclerosis, the thickened arteriolar wall changes the ophthalmic perception of circulating blood.

Vessels may appear narrowed, and the color of the blood columns may change from bright red to copper and to silver. Also, the arteriole may compress the vein at points where both vessels cross (AV nicking)
202. How does malignant hypertension affect the retinal vasculature?
In malignant hypertension, the vessels may be damage. Damage to choroidal vessels may produce focal choroidal infarcts, seen clinically as Elschnig's spots.

Also, there may be exudate accumulation between the neurosensory retina and pigmented epithelium (causing retinal detachment) - *signified by a "macular star".

Occlusion of retinal arteries may produce infarcts of the retinal nerve fiber layer (producing cystoid bodies - the cotton wool spots).
203. What is a reliable histologic marker of diabetes in the eye?
The thickening of the basement membrane of the epithelium of the pars plicata of the ciliary body is a reliable histologic marker of DM in the eye and is reminiscent of similar changes in the glomerular mesangium.
204. How does diabetes mellitus affect the vasculature of the retina?
Diabetes causes microvascular injury with thickened basement membrane (and physiologic breakdown of the blood-retina barrier with edema and hemorrhage) as well as pericyte loss leading to characteristic microaneurysms.

The retinal vasculopathy of DM may be classified into background (preproliferative) diabetic retinopathy and proliferative diabetic retinopathy.
205. What is background (preproliferative) diabetic retinopathy?
Background (preproliferative) diabetic retinopathy includes a spectrum of changes from structural and functional angiopathic abnormalities to angiogenesis located w/in the retina (beneath the internal limiting membrane of the retina).

The basement membrane of retinal blood vessels is thickened. Microaneurysms are an important finding. Macular edema is a common cause of visual loss in these pats.
206. Nonperfusion of the retina due to the microcirculatory change in background (preproliferative) diabetic retinopathy is associated with...?
Up-regulation of VEGF and retinal angiogenesis. The development of intraretinal angiogenesis - new vessels confined within the retina beneath the internal limiting membrane - may be included with lesions termed intraretinal microangiopathy.
207. What is proliferative diabetic retinopathy?
Proliferative diabetic retinopathy is defined by the appearance of new vessels that sprout from existing vessels - angiogenic vessels - on the surface of either the optic nerve head, which is termed neovascularization of the disc, or the surface of the retina, which is designated as neovascularization elsewhere. These vessels then breach the retinal internal limiting membrane.
208. What is retinopathy of prematurity (retrolental fibroplasia)?
Immature retinal vessels respond to increased oxygen tension (administered to premature infants) by constricting, resulting in local ischemia.

With significant contraction, the retina may detach.
209. What is sickle retinopathy?
There are type types: nonproliferative (intraretinal angiopathic changes) and proliferative (retinal neovascularization). The final common pathway in both types is vascular occlusion.

It is caused by reduced oxygen tension which leads to erythrocyte sickling and microvascular occlusions.

*Can five the appearance of salmon patches, iridescent spots, and black sunburst lesions.

**PEDF may inhibit angiogenesis in this condition and may contribute to the regression of sea-fans.
210. What is the final common pathway of "retinal vasculopathy-occlusion-ischemia-up-regulation of angiogenic factors"?
May be associated w/neovascularization in a variety of clinical settings such as peripheral retinal vasculitis, and in radiation used to treat intraocular tumors.

The feature common to these conditions is damage to retinal vessels, producing zones of retinal ischemia that drive retinal angiogenesis and its complications, hemorrhage and traction.
211. What about retinal artery and vein occlusions?
Arterial occlusions due to atherosclerosis or to atheroembolism cause retinal infarction; since onset is typically sudden, there is no prolonged ischemia, and hence no significant neovascularization.

Retinal vein occlusion (e.g., due to arteriolar thickening in hypertension that comprising the venous lumen where the vessels cross) typically leads to ischemia and subsequent neovascularization.
212. What are Hollenhorst plaques?
Fragments of atherosclerotic plaques may lodge within the retinal circulation called Hollenhorst plaques.
213. Total occlusion of the central retinal artery may produce...?
A diffuse infarct of the retina.

This produces the cherry-red spot that is also seen in rare storage diseases such as Tay-Sachs and Niemann-Pick disease.
214. What is age-related macular degeneration (ARMD)?
ARMD is the most common cause of irreversible visual loss in the US.

ARMD is most commonly (80-90%) atrophic (dry), associated with geographic atrophy of the retinal pigment epithelium.

The remainder of ARMD are exudative (wet) associated w/leaky choroidal neovascular membranes.
215. So what is the ARMD atrophic (dry) form?
Atrophic ARMD is identified ophthalmoscopically by diffuse or discrete deposits in Bruch's membrane (drusen) and geographic atrophy of the retinal pigment epithleium.
216. What is the exudative (wet) form of ARMD?
Approx 10-20% of pts w/atrophic ARMD develop choroidal neovascular membranes, the hallmark of exudative ARMD.
217. What is choroidal neovascularization?
Choroidal neovascularization is defined by the presence of angiogenic vessels that presumably originate from the choriocapillaris and penetrate thru Bruch's membrane beneath the retinal pigment epithelium.

This neovascular membrane may also penetrate the retinal pigmetn epithelium and become situated directly beneath the neurosensory retina.

The vessels in this membrane may leak or cause macular scars. Occasionally, hemorrhage from these neovascular membranes may be massive, leading to the localized suffusion of blood
218. What causes cancer-associated retinopathy and melanoma-associated retinopathy?
Cancer pts may also develop symptoms of night blindness, photopsia (flashes of light), and compromise of the visual field.

The symptoms associated with cancer associated retinopathy and melanoma-associated retinopathy result from the production of autoantibodies to the tumor that cross react with corresponding epitopes within the retina.
219. What is retinitis pigmentosa?
This term is used to describe a collection of fairly commno inherited disorders that affect various aspects of vision including visual cascade and cycle, structural genes, transcription factors, catabolic pathways, and mitochondrial metabolism.
220. What are the characteristics of retinitis pigmentosa?
*Typically, both rods and cones are lost to apoptosis, although in varying proportions. Loss of rods may lead to early night blindness and constricted visual fields. As cones are lost, central visual acuity may be affected as well.

Clinically, retinal atrophy is accompanied by constriction of retinal vessels and optic nerve head atrophy ("waxy pallor" or the optic disk) and the accumulation of retinal pigment around blood vessels.
221. What is retinitis?
A variety of pathogen scan contribute to the development of infectious retinitis. For example, Candida may disseminate to the retina hematogenously, especially in the setting of IV drug abuse or in systemic candidemia from other causes.

Hematogenous dissemination of pathogens to the retina typically results in multiple retinal abscesses. CMV retintis is an important cause of visual morbidity in immunocompromised pts.
222. What is retinoblastoma?
Retinoblastoma is the most common primary intraocular malignancy of children. The cell of origin is neuronal.

In approx 40% of cases, retinoblastoma occurs in individuals who inherit a germ-line mutation of one RB allele. Retinblastomas arising in the context of germ line mutations not only may be bilateral, but also may be associated with pinealoblastoma (so called "trilateral" retinoblastoma") which is associated w/a dismal outcome.
223. What is the morphology of retinoblastoma?
Tumors may contain both undifferentiated and differentiated elements. The former appear as collections of small, round cells with hyperchromatic nuclei. In well-differentiated tumors there are Flexner-Wintersteiner rosettes and fleurettes reflecting photoreceptor differentiation.

Viable tumors cells are found encircling tumor blood vessels with zones of necrosis typically found in relatively avascular areas. Focal zones of dystrophic calcification are characteristic of retinoblastoma.
224. The appearance of retinoblastoma in one eye and retinocytoma in the other is characteristic of...?
Heritable retinoblastoma.
225. What is retinal lymphoma?

What are the two types?
Systemic lymphoma tends to involve the uvea (iris, ciliary body, and choroid).

By contrast, primary retinal lymphoma is analogous to primary large cell lymphoma of the brain; therefore, it involves the two retinal layers derived from the brain: the neurosensory retina and the retinal pigment epithelium. The underlying choroid is typically filled with a cytologically benign lymphoid infiltrate.
226. What are the most common primary neoplasms of the optic nerve?
Gliomas (typically pilocytic astrocytomas) and meningiomas.
227. What is anterior ischemic optic neuropathy?
The optic nerve blood supply can be interrupted by vascular inflammation (e.g., temporal arteritis), or by embolism or thrombosis.

Transient partial interruptions in blood flow to the optic nerve may produce transient vision loss. On the other hand, bilateral total infarcts of the optic nerve result in total blindness.
228. What is papilledema?
Optic nerve edema can be due to compression (e.g., by neoplasm) or to elevated CSF pressure. The latter is typically bilateral and called papilledema.

*Typically, acute papilledema from increased intracranial pressure is not associated w/visual loss.
229. What is glaucomatous optic nerve damage (aka normal tension glaucoma)?
Glaucomatous optic nerve damage is characterized by atrophy (due to increased intraocular pressures) accompanied by optic nerve head cupping.

Interestingly, mutations in the optineurin gene are seen in pts with normal-tension glaucoma but are not sen in pts with primary open angle glaucoma.
230. What is the morphology of glaucomatous optic nerve damage (aka normal-tension glaucoma)?
Characteristically, there is a diffuse loss of ganglion cells and thinning of the retinal nerve fiber layer. In advanced cases, the otpic nerve is both cupped and atrophic.
231. What is buphthalmos and megalocornea?

What is staphyloma?
Elevated intraocular pressure in infants and children can lead to diffuse enlargement of the eye (buphthalmos) or enlargement of the cornea (megalocornea).

After the eye reaches its adult size, prolonged elevation of intraocular pressure may lead to focal thinning of the sclera, and uveal tissue may line ectatic sclera (staphyloma). In adults, the cornea may become edematous, and degenerative pannus may form.
232. What is Leber's hererditary optic neuropathy?

What causes it?
Optic neuropathy may be inherited. The predilection for LHON to develop in young men is explained by inheritance of mitochondrial gene mutations. Studies show that acquired impairment of mitochondrial function thru exposures to toxins, low folate, and high formic acid levels produce a syndrome that is phenotypically similar to LHON.

*The factor common to these optic neuropathies, inherited or acquired, appears to be derangement in mitochondrial function.
233. What is optic neuritis?
Optic neuritis is used to describe a loss of vision secondary to demyelinization of the optic nerve.

*One of the most important causes of optic neuritis is MS, and it may be the first manifestation of the disease.
234. What is phthisis bulbi?
Trauma, intraocular inflmmation, chronic retinal detachment, and many other conditions may give rise to an eye that is both small (atrophic) and internally disorganized called phthisis bulbi.
235. What is the morphology of phthisis bulbi?
Phthisical eyes typically feature the following changes:
1. The presence of exudate or blood in the potential space between the cililary body and sclera and the choroid and sclera (ciliochoroidal effusion)
2. The presence of a membrane extending across the eye from one aspect of the ciliary body to the other (cyclitic membrane)
3. Chronic retinal detachment
4. Optic nerve atrophy
5. The presence of intraocular bone, which is thought o arise from osseous metaplasia of the retinal pigment epithelium
6. Ciliochoroidal effusion is typically associated w/the physiologic state of low intraocular pressure (hypotony).

*The normal pull of the EOM on a hypotonous eye may render the appearance of the eye as square rather than round.