Pbl Exam 3 Case 7

Front 1

1. What are the two major types of pain?

Back 1

Fast pain and slow pain.

Front 2

2. Distribution and location of pain receptors

Back 2

The pain receptors in the skin and other tissues are all free nerve endings.

They are widespread in the superficial layers of the skin as well as in certain internal tissues, such as the periosteum, the arterial walls, the joint surfaces, and the falx and tentorium in the cranial vault.

Most other deep tissues are only sparsely supplied w/pain endings; nevertheless, and widespread tissue damage can summate to cause the slow-chronic-aching type of pain in most of these areas.

Front 3

3. What are the three types of stimuli that excite pain receptors?

Back 3

1. Mechanical
2. Thermal
3. Chemical

In general, fast pain is elicited by the mechanical and thermal types of stimuli; whereas slow pain can be elicited by all three types.

Front 4

4. What are the chemicals that excite the chemical type of pain?

Back 4

1. Bradykinin
2. Serotonin
3. Histamine
4. Postassium ions
5. Acids
6. Acetylcholine
7. Proteolytic enzymes


Also, substance P and prostaglandins enhance the sensitivity of pain endings but do not directly excite them.

The chemical substances are especially important in stimulating the slow, suffering type of pain that occurs after tissue injury.

Front 5

5. Nonadapting nature of pain receptors

Why is this important?

Back 5

In contrast to most other sensory receptors of the body, pain receptors adapt very little and sometimes not at all. In fact, under some conditions, excitation of pain fibers becomes progressively greater, especially so for slow-aching-nauseous pain, as the pain stimulus continues.

This increase in sensitivity of the pain receptors is called hyperalgesia; this allow the pain to keep the person apprised of a tissue-damaging stimulus as long as it persists.

Front 6

6. Rate of tissue damage as a stimulus for pain

Back 6

Pain resulting from heat is closely correlated w/the rate at which damage to the tissues is occurring and not with the total damage that has already occurred.

The intensity of pain is also closely correlated w/the rate of tissue damage from causes other than heat, such as bacterial infection, tissue ischemia, tissue contusion, and so forth.

Front 7

7. Importance of chemical pain stimuli during tissue damage

Back 7

Bradykinin: might be the agent most responsible for causing pain following tissue damage.

Also, the intensity of pain correlates w/the local increase in potassium ion concentration or the increase in proteolytic enzymes that directly attack the nerve endings and excite pain by making the nerve membranes more permeable to ions.

Front 8

8. Tissue ischemia as a cause of pain

Back 8

The greater the rate of metabolism of the tissue, the more rapidly the pain appears.

One suggested cause is accumulation of large amts of lactic acid in the tissues; also probable that bradykinin and other proteolytic enzymes are formed in the tissues b/c of cell damage and that these, in addition to lactic acid, stimulate the pain nerve endings.

Front 9

9. Muscle spasm as a cause of pain

Back 9

Muscle spasm is the basis of many clinical pain syndromes.

This pain probably results partially from the direct effect of muscle spasm in stimulating mechanosensitive pain receptors, but it might also result form the indirect effect of muscle spasm to compress the blood vessels and cause ischemia.

Also, the spasm increase the rate of metabolism in the muscle tissue, thus making the relative ischemia even greater.

Front 10

10. Transmission of fast-sharp pain

Back 10

The fast sharp pain signals are elicited by either mechanical or thermal pain stimuli; they are transmitted in the peripheral nerves to the spinal cord by small type Aδ fibers at velocities between 6-30 m/sec.

Front 11

11. Transmission of slow-chronic pain

Back 11

Elicited mostly by chemical types of pain stimuli but sometimes by persisting mechanical or thermal stimuli.

This slow-chronic pain is transmitted to the spinal cord by type C fibers at velocities between 0.5 - 2 m/s

Front 12

12. What is the purpose of this double system of pain innervation?

Back 12

The shard pain apprises the person rapidly of a damaging influence and, therefore, plays an important role in making the person react immediately to remove himself or herself from the stimulus.

The slow pain tends to become greater over time. This sensation eventually produces the intolerable suffering of long continued pain and makes the person keep trying to relieve the cause of pain.

Front 13

13. What are the two pathways that pain signals can take to the brain?

Back 13

1. Neospinothalamic tract
2. Paleospinothalamic tract

Front 14

14. Neospinothalamic tract

Back 14

Transmits fast pain.

The fast type Aδ paid fibers transmit mainly mechanical and acute thermal pain. They terminate mainly in lamina I of the dorsal horns, and there excite second order neurons of the neospinothalamic tract.

These give rise to long fibers that cross immediately to the opposite side of the cord thru the anterior commissure and then turn upward, passing to the brain in the anterolateral columns.

Front 15

15. Where do the neospinothalamic tract fibers terminate?

Back 15

A few fibers of the neospinothalamic tract terminate in the reticular areas of the brain stem, but most pass all the way to the thalamus without interruption, terminating in the ventrobasal complex, along with the dorsal column medial lemniscal tract for tactile sensation.

A few fibers also terminate in the posterior nuclear group of the thalamus. From these thalamic areas, the signals are transmitted to other basal areas of the brain as well as to the somatosensory cortex.

Front 16

16. How does the nervous system localize fast pain in the body?

Back 16

The fast-sharp type of pain can be localized much more exactly in the different parts of the body than can slow-chronic pain.

However, only when pain receptors are stimulated, without the simultaneous stimulation of tactile receptors, even fast pain may be poorly localized, often only w/in 10 cm or so of the stimulated area.

Yet when tactile receptors that excite the DCML system are simultaneously stimulated, the localization can be nearly exact.

Front 17

17. Glutamate and pain

Back 17

It is believed that glutamate is the neurotransmitter substance secreted int he spinal cord at the type Aδ pain nerve fiber endings.

This is one of the most widely used excitatory transmitters int he CNS, usually having a duration of action lasting for only a few ms.

Front 18

18. Paleospinothalamic tract

Back 18

Transmits slow-chronic pain.

This pathway is a much older system and transmits pain mainly from the peripheral slow-chronic type C pain fibers, although it does transmit some signals from type Aδ fibers as well.

Front 19

19. Where do the paleospinothalamic tract fibers terminate?

Back 19

The peripheral fibers terminate int he spinal cord almost entirely in laminae II and III of the dorsal horns, which together are called the substantia gelatinosa.

Most of the signals then pass thru one or more additional short fiber neurons within the dorsal horns themselves before entering mainly lamina V, also in the dorsal horn.

Here the last neurons in the series give rise to long axons that mostly join the fibers from the fast pain pathway, passing first thru the anterior commissure to the opposite side of the cord, then upward to the brain in the anterolateral pathway.

Front 20

20. Substance P

Back 20

The probably slow-chronic neurotransmitter of type C endings.

Type C pain fiber terminals entering the spinal cord secrete both glutamate and substance P.

While glutamate acts instantly, substance P is released much more slowly, building up in concentration over a period of seconds or even minutes.

Thus, glutamate is responsible for transmitting fast pain into the CNS, and substance P is concerned with slow-chronic pain.

Front 21

21. Where does the paleospinothalamic pathway go?

Back 21

The pathway terminates widely in the brain stem. Only 1/10 to 1/4 of the fibers pass all the way to the thalamus.

Instead, most terminate in one of three areas.

Front 22

22. Where do the rest of the fibers in the paleospinothalamic tract go?

Back 22

1. Reticular nuclei of the medulla, pons,and mesencephalon
2. Tectal area of the mesencephalon deep to the superior and inferior colliculi
3. Periaqueductal gray region surrounding the aqueduct of Sylvius.

Front 23

23. Why are these lower regions of the brain important in pain transmission?

Back 23

These lower regions of the brain appear to be important for feeling the suffering types of pain, b/c animals whose brains have been sectioned above the mesencephalon to block pain signals form reaching the cerebrum still evince undeniable evidence of suffering when any part of the body is traumatized.

From the brian stem pain areas, multiple short-fiber neurons relay the pain signals upward into the intralaminar and ventrolateral nuclei of the thalamus and into certain portions of the hypothalamus and other basal regions of the brain.

Front 24

24. Localization of pain the slow-chronic pathway

Back 24

Localization of pain transmitted via the paleospinothalamic tract is poor.

This is in keeping with the multisynaptic, diffuse connectivity of this pathway. It explains why patients often have serious difficulty in localizing the source of some chronic types of pain.

Front 25

25. Function of the reticular formation, thalamus, and cerebral cortex in the appreciation of pain

Back 25

Complete removal of the somatic sensory areas of the cerebral cortex does not destroy an animal's ability to perceive pain.

Therefore, it is likely that pain impulses entering the brain stem reticular formation, the thalamus, and other lower brain centers cause conscious perception of pain.

It is believed that the cortex plays an especially important role in interpreting pain quality, even though pain perception might be principally the function of lower centers.

Front 26

26. Arousal effect of pain

Back 26

Electrical stimulation in the reticular areas of the brain stem and in the intralaminar nuclei of the thalamus, the areas where the slow-suffering type of pain terminates, has a strong arousal effect on nervous activity throughout the entire brain.

In fact, these two areas constitute part of the brain's principal "arousal system". This explains why it is almost impossible for a person to sleep when he or she is in severe pain.

Front 27

27. Cordotomy

Back 27

Pain nervous pathways can be cut at any one of several points. If the pain is in the lower part of the body, a cordotomy in the thoracic region of the spinal cord often relieves the pain for a few weeks to a few months.

To do this, the spinal cord on the side opposite to the pain is partially cut in its anterolateral quadrant to interrupt the anterolateral sensory pathways.

Front 28

28. Why is a cordotomy not always successful in relieving pain?

Back 28

1. Many pain fibers from the upper part of the body do not cross to the opposite side of the spinal cord until they have reached the brain, so that the cordotomy does not transect these fibers.

2. Pain frequently returns several months later, partly as a result of sensitization of other pathways that normally are too weak to be effectual.

Front 29

29. What three major components make up the analgesia system in the brain?

Back 29

(1) Periaqueductal gray and periventricular areas of the mesencephalon and upper pons surround the aqueduct of Sylvius and portions of the third and fourth ventricles.

Neurons from these areas send signals to (2) the raphe magnus nucleus, a thin midline nucleus locate din the lower pons and upper medulla, and the nucleus reticularis paragigantocellularis, located laterally in the medulla.

From these nuclei, second order signals are transmitted down the dorsolateral columns in the spinal cord to (3) a pain inhibitory complex located in the dorsal horns of the spinal cord. At this point, the analgesia signals can block the pain before it is relayed to the brain.

Front 30

30. Analgesia and electrical stimulation

Back 30

Electrical stimulation either in the periaqueductal gray area or in the raphe magnus nucleus can suppress many strong pain signals entering by way of the dorsal spinal roots.

Also, stimulation of areas at still higher levels of the brain that excite the periaqueductal gray area can also suppress pain.

Front 31

31. Stimulation of what other two areas also suppresses pain?

Back 31

1. The periventricular nuclei in the hypothalamus, lying adjacent to the third ventricle.

2. Medial forebrain bundle, also in the hypothalamus

Front 32

32. What transmitter substances are involved in the analgesia system?

Back 32

1. Enkephalin
2. Serotonin

Front 33

33. Release of these transmitter substances

Back 33

Many nerve fibers derived from the periventricular nuclei and from the periaqueductal gray area secrete enkephalin at their endings. Thus, the endings of many fibers in the raphe magnus nucleus release enkephalin when stimulated.

Fibers originating in this area send signals to the dorsal horns of the spinal cord to secrete serotonin at their endings.

The serotonin causes local cord neurons to secrete enkephalin as well.

Front 34

34. Enkephalin

Back 34

Believed to cause both presynaptic and postsynaptic inhibition of incoming type C and type Aδ pain fibers where they synapse int he dorsal horns.

Front 35

35. What are the opiate-like substances of the brain?

Back 35

1. Proopiomelanocortin
2. Proenkephalin
3. Prodynorphin
4. β-endorphin
5. Met-enkephalin
6. Leu-enkephalin
7. Dynorphin

Front 36

36. Where are these opiate like substances found?

Back 36

The two enkephalins are found in the brain stem and spinal cord, in the portions of the analgesia system.

β-endorphin is present in both the hypothalamus and the pituitary gland.

Dynorphin is found mainly in the same areas as the enkephalins, but in much lower quantities.

Front 37

37. Inhibition of pain transmission by simultaneous tactile sensory signals

Back 37

Another important event in the saga of pain control was the discovery that stimulation of large type Aβ sensory fibers from peripheral tactile receptors can depress transmission of pain signals from the same body area.

This presumably results from local lateral inhibition in the spinal cord.

This explains why rubbing your toe helps with pain after you stub it.

Front 38

38. Treatment of pain via electrical stimulation

Back 38

Stimulating electrodes are placed on selected areas of the skin or, on occasion, implanted over the spinal cord, supposedly to stimulate the dorsal sensory columns.

Also, electrodes have been placed stereotaxically in the brain to allow the patient to control the degree of stimulation.

Front 39

39. What is one of the most important differences between surface pain and visceral pain?

Back 39

Highly localized types of damage to the viscera seldom cause severe pain.

For instance, a surgeon can cut the gut entirely in two in a patient who is awake w/o causing significant pain.

Conversely, any stimulus that causes diffuse stimulation of pain nerve endings throughout a viscus causes pain that can be severe.

Front 40

40. What are some causes of true visceral pain?

Back 40

1. Ischemia
2. Chemical stimuli
3. Spasm of a hollow viscus
4. Overdistention of a hollow viscus
5. Insensitive viscera

Front 41

41. Hyperalgesia

Back 41

A pain nervous pathway sometimes becomes excessively excitable; this gives rise to hyperalgesia, which means hypersensitivity to pain.

Front 42

42. What are the two causes of hyperalgesia?

Back 42

1. Excessive sensitivity of the pain receptor themselves, which is called primary hyperalgesia
-sunburned skin

2. Facilitation of sensory transmission, which is called hyperalgesia
-results from lesions in the spinal cord or the thalamus

Front 43

43. Tic douloureux

Back 43

Lancinating pain occasionally occurs in some people over one side of the face in the sensory distribution area of CN V or CN IX nerves.

The pain feels like sudden electrical shocks, and it may appear for only a few seconds at a time or may be almost continuous.

Often it is set off by exceedingly sensitive trigger areas on the surface of the face, in the mouth, or inside the throat - almost always by a mechanoreceptive stimulus rather than a pain stimulus.

Front 44

44. Treatment for tic douloureux

Back 44

The pain can usually be blocked by surgically cutting the peripheral nerve from the hypersensitive area.

The sensory portion of the fifth nerve is often sectioned immediately inside the cranium, where the motor and sensory roots of CN V separate from each other, so that the motor portions can be spared while the sensory elements are destroyed.

Front 45

45. Brown-Séquard syndrome

Back 45

If the spinal cord is transected on only one side, this syndrome occurs.

All motor functions are blocked on the side of the transect ion in all segments below the level of the transection.

The sensations of pain, heat, and cold, (spinothalamic pathway) are lost on the opposite side of the body in all dermatomes 2-6 segments below the levels of the transection.

The sensations that are transmitted only in the dorsal and dorsolateral columns, kinesthetic and positional sensations, vibration, discrete localization and two point discrimination - are lost on the side of the transection in all dermatomes below the levels of the transection.

Front 46

46. Why is discrete touch impaired on the side of the transection in Brown-Séquard syndrome?

Back 46

The principal pathway for the transmission of light touch, the dorsal column, is transected. That is, the fibers in this column do not cross to the opposite side until they reach the medulla of the brain.

Crude touch, which is poorly localized, still persists b/c of partial transmission in the opposite spinothalamic tract.

Front 47

47. What things inside the cranial vault can cause headaches if the brain tissues themselves are totally insensitive to pain?

Back 47

Tugging on the venous sinuses around the brain, damaging the tentorium, or stretching the dura at the base of the brain can cause intense pain that is recognized as headache.

Also, any type of traumatizing, crushing or stretching stimulus to the blood vessels of the meninges can cause headache (especially the middle meningeal artery).

Front 48

48. What are the causes of intracranial headaches?

Back 48

1. Meningitis
2. Low CSF pressure
3. Migraine
4. Alcohol (irritates the meninges)
5. Constipation

Front 49

49. What are the types of extracranial headaches?

Back 49

1. Muscle spasms
2. Irritation of nasal and accessory nasal structures
3. Eye disorders

Front 50

50. What are the three types of thermal receptors?

Back 50

1. Cold receptors
2. Warmth receptors
3. Pain receptors

Thermal senses respond markedly to changes in temperature, in addition to being able to respond to steady states of temperature.

Front 51

51. What causes the thermal receptors to be stimulated?

Back 51

It is believed that cold and warmth receptors are stimulated by changes in their metabolic rates, and that these changes result form the fact that temperature alters the rate of intracellular chemical reactions more than twofold for each 10 degree change.

In other wrods, thermal detection probably results not from direct physical effects of heat or cold on the nerve endings but from chemical stimulation of the endings as modified by temperature.

Front 52

52. Spatial summation of thermal sensations

Back 52

b/c the number of cold or warm endings in any one surface of the body is slight, it is difficult to judge gradations of temp when small skin areas are stimulated.

However, when a large skin area is stimulated all at once, the thermal signals from the entire area summate.

Front 53

53. Transmission of thermal signals in the nervous system

Back 53

In general, thermal signals are transmitted in pathways parallel to those for pain signals.

On entering the spinal cord, the signals travel for a few segments up or down in the tract of Lissauer and then terminate mainly in laminae I, II, and III of the dorsal horns (same as for pain).

After a small amt of processing by one or more cord neurons, the signals enter long, ascending thermal fibers that cross to the opposite anterolateral sensory tract and terminal in both the reticular areas of the brain stema and the ventrobasal complex of the thalamus.

Occasionally, a few thermal signals are also relayed to the cerebral somatic sensory cortex from the ventrobasal complex.

Front 54

54. Where are adipose tissue TAGs derived from?

What are the major fatty acids that are oxidized?

Back 54

1. Dietary lipids
2. TAGs synthesized in the liver

The major fatty acids oxidized are the long chain fatty acids, palmitate, oleate, and stearate, b/c they are highest in dietary lipids and are also synthesized in the human.

Front 55

55. Summary of β-oxidation

Back 55

Energy is derived from oxidation of fatty acids to acetyl CoA in the pathway of β-oxidation.

The acetyl CoA produced is principally oxidized in the TCA cycle or converted to ketone bodies in the liver.

Front 56

56. Transport and activation of long-chain fatty acids

Back 56

Long-chain fatty acids are hydrophobic, and therefore, water-insoluble. In addition they are toxic to cells b/c they can disrupt the hydrophobic bonding between AA side chains in proteins.

Consequently, they are transported in the blood and in cells bound to proteins.

Front 57

57. Cellular uptake of long-chain fatty acids

Back 57

During fasting and other conditions of metabolic need, long-chain FA's are released from adipose tissue TAGs by lipases. They travel in the blood bound in the hydrophobic binding pocket of albumin, the major serum protein.

Front 58

58. How do FA's enter cells?

Back 58

FA's enter cells both by a saturable transport process and by diffusion thru the lipid plasma membrane. A fatty acid-binding protein in the plasma membrane facilitates transport.

An additional fatty acid-binding protein binds the FA intracellularly and may facilitate its transport to the mitochondrion.

The free FA concentration in cells is, therefore, extremely low.

Front 59

59. Activation of long-chain fatty acids

Back 59

Fatty acids must be activated to acyl CoA derivatives before the can participate in β-oxidation and other metabolic pathways.

The process of activation invovles an acyl CoA synthetase (AKA thiokinase) that uses ATP energy to form the fatty acyl CoA thioester bond.

In this reaction, the β-bond of ATP is cleaved to form a fatty acyl AMP intermediate and pyrophosphate.

Subsequent cleavage of pryophosphate helps to drive the reaction.

Front 60

60. Acyl CoA synthetase (AKA thiokinase)

Back 60

Activates long-chain fatty acids, 12-20 C's in length, and is present in three locations in the cells:
1. ER
2. Outer mitochondrial membrane
3. Peroxisomal membrane

This enzyme has not activity toward C22 or longer FA's, and little activity below C12.

Front 61

61. Activation of very-long-chain and medium-chain length fatty acid activation enzymes

Back 61

The synthetase for activation of very long chain FA's is present in peroxisomes, and the medium chain length fatty acid activating enzyme is present only in the mitochondrial matrix of liver and kidney cells.

Front 62

62. Fates of fatty acyl CoA's

Back 62

Fatty acyl CoA formation, like the phosphorylation of glucose, is a prerequisite to metabolism of the FA in the cell.

The multiple locations of the long-chain acyl CoA synthetase reflects the location of different metabolic routes taken by fatty acyl CoA derivatives in the cell.

In the liver and some other tissues, FA's that are not being used for energy generation are reincorporated into TAGs.

Front 63

63. Transport of long-chain fatty acids into mitochondria

What serves as the carrier?

Back 63

Carnitine serves as the carrier that transports activated long-chain fatty acyl groups across the inner mitochondrial membrane.

Carnitine acyl transferases are able to reversibly transfer an activated fatty acyl group from CoA to the hydroxyl group of carnitine to form an acylcarnitine ester.

The reaction is reversible, so the fatty acyl CoA derivative can be regenerated from the carnitine ester.

Front 64

64. Carnitine:palmitoyltransferase I (CPTI)

Back 64

This enzyme transfers long-chain fatty acyl groups from CoA to carnitine, and it is located on the outer mitochondrial membrane.

Fatty acylcarnitine crosses the inner mitochondrial membrane w/the aid of a translocase.

Front 65

65. CPTII

Back 65

The fatty acyl group is transferred back to CoA by a second enzyme, CPTII.

The carnitine relased in this reaction returns to the cytosolic side of the mitochondrial membrane by the same translocase that brings fatty acylcarnitine to the matrix side.

Long chain fatty acyl CoA, now located w/in the mitochondrial matrix, is a substrate for β-oxidation.

Front 66

66. Where is carnitine obtained?

Back 66

Obtained from the diet or synthesized from the side chain of lysine by a pathway that beings in skeletal muscle, and is completed in the liver.

Front 67

67. What other components are needed for these reactions?

Back 67

The reactions use S-adenosylmethionine to donate methyl groups, and vitamin C is also required for these reactions.

Front 68

68. Skeletal muscle and carnitine

Back 68

Skeletal muscles have a high-affinity uptake system for carnitine, and most of the carnitine in the body is stored in skeletal muscle.

Front 69

69. β-oxidation of long-chain fatty acids

Back 69

The oxidation of fatty acids to acetyl CoA int he β-oxidation spiral conserves energy as FADH₂ and NADH.

FADH₂ and NADH are oxidized in the electron transport chain, generating ATP form oxidative phosphorylation.

Acetyl CoA is oxidized in the TCA cycle or converted to ketone bodies.

Front 70

70. The β-oxidation spiral

Back 70

The fatty acids β-oxidation pathway sequentially cleaves the fatty acyl group into two carbon acetyl CoA units, beginning w/the carboxyl end attached to CoA.

Front 71

71. Before cleavage, what must occur?

Back 71

The β-carbon is oxidized to a keto group in two reaction that generate NADH and FADH₂; thus, the pathway is called β-oxidation and cleavage begins again, but each time the fatty acyl group is two carbons shorter.

Front 72

72. First step in the β-oxidation pathway

Back 72

A double bond is formed between the β- and α-carbons by an acyl CoA dehydrogenase that transfers electron to FAD.

The double bond is in the trans configuration.

Front 73

73. Second step in the β-oxidation pathway

Back 73

An -OH from water is added to the β-carbon, and an -H from water is added to the α-carbon via enoyl hydratase.

Front 74

74. Third step in the β-oxidation pathway

Back 74

The hydroxyl group on the β-carbon is oxidized to a ketone by a hydroxyacyl CoA dehydrogenase.

In this reaction, as in the conversion of most alcohols to ketones, the electrons are transferred to NAD⁺ to form NADH.

Front 75

74. Fourth and final step in the β-oxidation pathway

Back 75

The bond between the β- and α-carbons is cleaved by a reaction that attaches CoASH to the β-carbon, and acetyl CoA is released. The enzyme in this reaction is called a β-ketothiolase.

The release of two carbons from the carboxyl end of the original fatty acyl CoA produces acetyl CoA and fatty acyl CoA that is two carbons shorter than the original.

Front 76

75. Similarity between β-oxidation spiral and TCA cycle

Back 76

The β-oxidation spiral uses the same reaction types seen in the TCA cycle int he conversion of succinate to oxaloacetate.

Front 77

76. Repetition of β-oxidation spiral

Back 77

The shortened fatty acyl CoA repeats these four steps until all of its carbons are converted to acetyl CoA. β-oxidation is thus a spiral rather than a cycle.

In the last spiral, cleavage of the four-carbon fatty acyl CoA produces two acetyl CoA.

Thus, an even chain fatty acid such as palmitoyl CoA (16C), is cleaved seven times, production 7 FADH₂, 7 NADH, and 8 acetyl CoA.

Front 78

77. Energy yield of β-oxidation

Back 78

The total energy yield from the oxidation fo 1 mol of palmityl CoA to 8 mol of acetyl CoA is therefore, 28 mol of ATP:

1.5 each for the 7 FADH₂
2.5 each for the 7 NADH.

Net yield = 108 ATP; however, activation of palmitic acid to palmityl-CoA requires two high energy bonds, so the net yield is 106 mol of ATP.

Front 79

78. Chain length specificity in β-oxidation

Back 79

As the fatty acyl chains are shortened by consecutive cleavage of two acetyl units, they are transferred from enzymes that act on longer chains to those that act on shorter chains.

Medium or short chain fatty acyl CoA that may be formed from dietary fatty acids, or transferred from peroxisomes, enters the spiral at the enzyme that is most active for fatty acids of its chain length.

Front 80

79. Oxidation of unsaturated fatty acids

Back 80

Approximately 1/2 of the fatty acids in the human diet are unsaturated, containing cis double bonds, with oleate and linoleate being the most common.

In β-oxidation of saturated FA's, a trans double bond is created between the second and third carbons.

For unsaturated FA's to undergo the β-oxidation spiral, their cis double bonds must be isomerized to trans that will end up between the second and third carbons during β-oxidation, or the double bond must be reduced.

Front 81

80. Oxidation of odd-chain length fatty acids

Back 81

FA's that contain an odd number of carbons undergo β-oxidation, producing acetyl CoA, until the last spiral, when 5 C's remain in the fatty acyl CoA.

In this case, cleavage by tiolase produces acetyl CoA and a 3-C fatty acyl CoA, propionyl CoA.

Front 82

81. What happens to the propionyl CoA?

Back 82

Carboxylation of propionyl CoA yields methymalonyl CoA, which is ultimately converted to succinyl CoA in a vitamin B12 dependent reaction.

Propionyl CoA also arises from the oxidation of branched chain amino acids.

Front 83

82. Propionyl CoA-to-succinyl CoA pathway

Back 83

This pathway is a major anaplerotic route for the TCA cycle and is used in the degradation of valine, isoleucine, and a number of other compounds.

In the liver, this route provides precursors of oxaloacetate, which is converted to glucose. Thus, this small proportion of the odd-carbon-number FA chain can be converted to glucose.

Front 84

83. Oxidation of medium-chain-length fatty acids

Back 84

Dietary medium chain length FA's are more water soluble than long chain FA's and are not stored in adipose TAGs.

After a meal, they enter the blood and pass into the portal veins to the liver. In the liver, they enter the mitochondrial matrix by the monocarboxylate transporter and are activated to acyl CoA derivatives in the mitochondrial matrix.

Front 85

84. Fate of medium-chain length acyl CoAs

Back 85

Medium-chain length acyl CoAs, like long-chain acyl CoAs, are oxidized to acetyl CoA via the β-oxidation spiral.

Medium-chain acyl CoAs also can arise from the peroxisomal oxidation pathway.

Front 86

85. Medium-chain-length acyl CoA synthetase

Back 86

Has a broad range of specificity for compounds of approx the same size that contain a carboxyl group, such as drugs (aspirin).

Once the drug acyl CoA is formed, the acyl group is conjugated w/glycine to form a urinary excretion product.

Front 87

86. Regulation of β-oxidation

Back 87

The process of β-oxidation is regulated by the cells' requirements for energy (i.e. the levels of ATP and NADH), b/c FA's cannot be oxidized any faster than NADH and FADH₂ are reoxidized in the electron transport chain.

Fatty acid oxidation may also be restricted by teh mitochondrial CoASH pool size. Acetyl CoASH units must enter the TCA cycle or another metabolic pathway to regenerate CoASH required for formation of the fatty acyl CoA derivative from fatty acyl carnitine.

Front 88

87. CPTI and regulation of β-oxidation

Back 88

CPTI is inhibited by malonyl CoA, which is synthesized int he cytosol of many tissues by acetyl CoA carboxylase.

Acetyl CoA carboxylase is regulated by a number of different mechanisms, some of which are tissue dependent. In skeletal muscles and liver, it is inhibited when it is phosphorylated by protein kinase B.

In the liver, malonyl CoA inhibition of CPTI prevents newly synthesized FA's form being oxidized.

Front 89

88. Protein kinase B and AMP

Back 89

When AMP levels increase during exercise, AMP-dependent protein kinase phosphorylates acetyl CoA carboxylase, which becomes inactive.

Consequently, malonyl CoA levels decrease, CPTI is activated, and the β-oxidation of fatty acids is able to restore ATP homeostasis and decrease AMP levels.

Front 90

89. Regulation of β-oxidation when fatty acid supply is plentiful

Back 90

FA oxidation is controlled by redox state (NAD⁺/NADH ratio)

*Fat spares glucose

FA oxidation produces acetyl CoA and NADH which inhibit pyruvate dehydrogenase

Citrate inhibits PFK-1 so glycolysis is inhibited

Front 91

90. Regulation of β-oxidation when glucose supply is plentiful

Back 91

Glucose is converted to fatty acids.

Malonyl CoA (intermediate of FA synthesis) inhibits carnitine:acyltransferase I and thus inhibits the uptake of FAs into the mitochondria.

*Glucose spares fat

Front 92

91. What are the alternative routes of fatty acid oxidation?

Back 92

1. ω-oxidation
2. Peroxisomal β-oxidation

These pathway not only use fatty acids, they act on xenobiotic carboxylic acids that are large hydrophobic molecules resembling FA's.

Front 93

92. ω-oxidation of fatty acids

Back 93

Fatty acids also may be oxidized at the ω-carbon of the chain (the terminal methyl group) by enzymes in the ER.

The ω-methyl group is first oxidized to an alcohol by an enzyme that uses cytochrome P450, molecular oxygen, and NADPH.

Dehydrogenases convert the alcohol group to a carboxylic acid.

The dicarboxylic acids produced by ω-oxidation can undergo β-oxidation, forming compounds with 6-10 C's that are water soluble and may enter the blood or be excreted in urine.

Front 94

93. Peroxisomal β-oxidation

Back 94

Oxidizes very-long-chain fatty acids of 24-46 C's.

Does this exclusively in peroxisomes by a sequence of reactions similar to mitochondrial β-oxidation in that they generate acetyl CoA and NADH.

However, the peroxisomal oxidation of straight chain fatty acids stops when the chain reaches 4-6 C's in length.

First step produces H₂O₂ - no ATP; the H₂O₂ can be neutralized by free-radical defense enzyme, catalase.

Front 95

94. Oxidation of long-chain branched-chain fatty acids

Back 95

Animals do not synthesize branched chain FA's.

They are oxidized in peroxisomes to the level of a branched C8 fatty acid, which is then transferred to mitochondria.

The pathway is thus similar to that for the oxidation of straight very-long-chain fatty acids.

Front 96

95. α-oxidation of very long chain fatty acids

Back 96

Occurs in ER, especially in nervous tissue, and in peroxisomes

A peroxisomal α-hydroxylase oxidizes the α-carbon, and its subsequent oxidation to a carboxyl group releases the carboxyl carbon as CO₂.

Subsequent spirals of peroxisomal β-oxidation alternately release propionyl and acetyl CoA.

At a chain length of approx 8 carbons, the remaining FA is transferred to mitochondria as a medium chain carnitine derivative.

Front 97

96. What are the three ketone bodies?

Back 97

1. Acetoacetate
2. β-hydroxybutyrate*
3. Acetone

*major circulating ketone body

Front 98

97. Synthesis of ketone bodies in the liver

When does this occur?

Back 98

Synthesis occurs in the mitochondrial matrix from acetyl CoA generated from fatty acid oxidation.

Occurs in starvation, diabetes, high fat/low carbohydrate diet.

Front 99

98. What conditions promote ketone body synthesis?

Back 99

Glucagon/Insulin ↑

Gluconeogenesis ↑

Mitochondrial oxaloacetate ↓

Mitochondrial acetyl CoA ↑

Front 100

99. Formation of acetyl CoA and acetate

Back 100

The thiolase reaction of fatty acid oxidation, which converts one molecule of acetoacetyl CoA to 2 molecules of acetyl CoA, is a reversible reaction, although formation of acetoacetyl-CoA is not the favored direction.

It can, thus, when acetyl-CoA levels are high, generate acetyl CoA to produce 3-hydroxy-3methyglutaryl CoA (HMG-CoA).

The enzyme that catalyzes this reaction is HMG-CoA synthase.

In the next reaction of the pathway, HMG-CoA lyase catalyzes the cleavage of HMG-CoA to form acetyl CoA and acetoacetate.

Front 101

100. Acetoacetate and β-hydroxybutyrate

Back 101

Acetoacetate can enter the blood directly or can be reduced by β-hydroxybutyrate dehydrogenase to β-hydroxybutyrate, which enters the blood.

This dehydrogenase reaction is readily reversible and interconverts these two ketone bodies, which exist in an equilibrium ratio determined by the NADH/NAD⁺ ratio of the mitochondrial matrix.

Under normal conditions, the ration of β-hydroxybutyrate to acetoacetate in the blood is approximately 1:1.

Front 102

101. Alternative fate of acetoacetate

Back 102

Spontaneous decarboxylation, a nonenzymatic reaction that cleaves acetoacetate into CO₂ and acetone.

B/c acetone is volatile, it is expired by the lungs. A small amount of acetone may be further metabolized in the body.

Front 103

102. Oxidation of ketone bodies

part 1

Back 103

Acetoacetate and β-hydroxybutyrate can be oxidized as fuels in most tissues, including skeletal muscle, brain, certain cells of the kidney, and cells of the intestinal mucosa.

Front 104

103. Oxidation of ketone bodies

part 2

Back 104

Cells transport both acetoacetate and β-hydroxybutyrate from the circulating blood into the cytosol, and into the mitochondrial matrix.

Here β-hydroxybutyrate is oxidized back to acetoacetate by β-hydroxybutyrate dehydrogenase. This reaction produces NADH.

Subsequent steps convert acetoacetate to acetyl CoA.

Front 105

104. Succinyl CoA:acetoacetate CoA transferase

Back 105

In mitochondria, acetoacetate is activated to acetoacetyl CoA by succinyl CoA:acetoacetate CoA transferase.

CoA is transferred from succinyl CoA, a TCA-cycle intermediate, to acetoacetate. Although the liver produces ketone bodies, it does not use them, b/c this thiotransferase enzyme is not present in sufficient quantity.

Front 106

105. Cleavage of acetoacetyl CoA

Back 106

One mole of acetoacetyl CoA is cleaved to two molecuels of acetyl CoA by acetoacetyl CoA thiolase, the same enzyme as is involved in β-oxidation.

The principal fate of this acetyl CoA is oxidation in the TCA cycle.

Front 107

106. Energy yield from oxidation of acetoacetate

Back 107

Equivalent to the yield from oxidation of 2 moles of acetyl CoA in the TCA cycle (20 ATP) minus the energy for activation of acetoacetate (1 ATP).

Oxidation of β-hydroxybutyrate generates one additional NADH.

Therefore, the net energy yield from one molecule of β-hydroxybutyrate is approx 21.5 molecules of ATP.

Front 108

107. Alternative pathways of ketone body metabolism

Back 108

Although fatty acid oxidation is usually the major source of ketone bodies, they also can be generated from the catabolism of certain AA's: leucine, isoleucine, lysine, tryptophan, phenylalanine, and tyrosine.

These AA's are called ketogenic AA's b/c their carbon skeleton is catabolized to acetyl CoA or acetoacetyl CoA, which may enter the pathway of ketone body synthesis in liver.

Leucine and isoleucine also form acetyl CoA and acetoacetyl CoA in other tissues as well as the liver.

Cytosolic acetyl CoA is required for processes such as acetylcholine synthesis in neuronal cells.

Front 109

108. Role of FA's and ketone bodies in fuel homeostasis

Back 109

FA's are used as fuels whenever fatty acid levels are elevated in the blood, that is, during fasting, starvation, etc...

Under these conditions, a decrease in insulin and increased levels of glucagon, epinephrine, or other hormones stimulate adipose tissue lipolysis.

Front 110

109. About how long does it take for the brain to start utilizing ketone bodies for fuel?

Back 110

After 2 - 3 days of starvation, ketone bodies rise to a level in the blood that enables them to enter brain cells, where they are oxidized, thereby reducing the amount of glucose required by the brain.

During prolonged fasting, they may supply as much as 2/3's of the energy requirements of the brain.

Front 111

110. Ketone bodies and skeletal muscles during starvation

Back 111

The reduction in glucose requirements spares skeletal muscle protein, which is a major source of AA precursors for hepatic glucose synthesis from gluconeogenesis.

Front 112

111. Preferential utilization of FA's

Back 112

FA oxidation reults in high NADH/NAD⁺ ratios, acetyl CoA concentrations, and ATP/ADP or ATP/AMP levels.

In skeletal muscles, AMP dependent protein kinase adjusts the concentration of malonyl CoA so that CPTI and β-oxidation operate at a rate that is able to sustain ATP homeostasis.

With adequate levels of ATP obtained from FA (or ketone body) oxidation, the rate of glycolysis is decreased.

Front 113

112. Tissues that use ketone bodies

Back 113

Almost all tissues and cell types, with the exception of liver and RBC's, are able to use ketone bodies as fuel.

Front 114

113. Regulation of ketone body synthesis

Back 114

The decreased insulin/glucagon ration results in inhibition of acetyl CoA carboxylase and decreased malonyl CoA levels, which activates CPTI, thereby allowing fatty acyl CoA to enter the pathway of β-oxidation.

When this pathway generates enough NADH and FADH₂, to supply ATP needs of the liver, acetyl CoA is diverted from the TCA cycle into ketogenesis and oxaloacetate in the TCA cycle is diverted toward malate and into glucose synthesis.

Front 115

114. What regulates the regulation??

Huh...?

Back 115

Regulated by the NADH/NAD⁺ ratio, which is relatively high during β-oxidation.

Front 116

115. After overnight fasting, about how much of our energy supply is derived from oxidation of fatty acids?

Back 116

Approx 60-70%

Front 117

116. Classical CPTII deficiency

Back 117

Most common of inherited carnitine metabolism diseases.

Characterized by adolescent to adult onset of recurrent episodes of acute myoglobinuria precipitated by prolonged exercise or fasting.

During these episodes, the patient is weak, and may be somewhat hypoglycemic with diminished ketosis, but metabolic decomp is not severe.

Front 118

117. Clinical labs in classical CPTII deficiency

Back 118

Lipid deposits are found in skeletal muscles. CPK levels, and long chain acylcarnitines are elevated in the blood. CPTII levels in fibroblasts are approx 25% of normal.

The remaining CPTII activity probably accounts for the mild effect on liver metabolism.

Front 119

118. CPTII deficiency in infants

Back 119

In contrast, when CPTII deficiency presents in infants, CPTII levels are <10% of normal, the hypoglycemia and hypoketosis are sever.

Hepatomegaly occurs from the TAG deposits, and cardiomyopathy is also present.

Front 120

119. Carnitine deficiency

Back 120

Carnitine deficiency has been found only in infants fed a soy based formula that was not supplemented w/carnitine.

Front 121

120. Random facts that I need to know...

Back 121

Riboflavin is the vitamin precursor of FAD, which is required for acyl CoA dehydrogenases and ETFs.

CoQ is synthesized in the body, but it is the recipient in the electron transport chain for electrons passed from complexes I and II and the ETFs.

Some reports suggest that supplementation w/pantothenate, a precursor of CoA, improves performance.

Front 122

121. Medium-chain acyl CoA dehydrogenase (MCAD) deficiency

Back 122

In this disease, long chain fatty acids are metabolized by β-oxidation to a medium chain length acyl CoA,such as octanoyl CoA. B/c further oxidation of this compound is blocked in this disease, the medium chain acyl group is transferred back to carnitine.

These acylcarnitines are water soluble and appear in blood and urine.

Treatment includes the intake of a relatively high carbohydrate diet and the avoidance of prolonged fasting.

Front 123

122. MCAD deficiency prevalence

Back 123

One of the most common inborn errors of metabolism, with a carrier freq ranging from 1 in 40 to in northern European populations to <1 in 100 in Asians.

Overall the predicted disease frequency is 1/15,000 persons.

Front 124

123. MCAD deficiency genetics

Back 124

Autosomal recessive disorder caused by the substitution of a T for an A at position 985 of the MCAD gene.

This mutation causes a lysine to replace a glutamate residue in the protein, resulting in the production of an unstable dehydrogenase.

Front 125

124. Clinical characteristics of MCAD deficiency

Back 125

Intermittent hypoketotic hypoglycemia during fasting (low levels of ketone bodies and low levels of glucose in the blood.

Fatty acids normally would be oxidized to CO₂ and H₂O under these conditions. In MCAD deficiency, however, FA's are oxidized only until they reach medium chain length. As a result, the body must rely to a greater extent on oxidation of blood glucose to meet its energy needs.

Front 126

125. Hepatic gluconeogenesis and MCAD deficiency

Back 126

Hepatic gluconeogenesis appears to be impaired in MCAD.

Inhibition of gluconeogenesis may be caused by the lack of hepatic FA oxidation to supply the energy required for gluconeogenesis, or by the accumulationof unoxidized FA metabolites that inhibit gluconeogenic enzymes.

As a consequence, liver glycogen stores are depleted more rapidly, and hypoglycemia results. The decrease in hepatic FA oxidation results in less acetyl CoA for ketone body synthesis and consequently a hypoketotic hypoglycemia develops.

Front 127

126. LCAD

Back 127

Reduced activity of the long chain 3-hydroxylacyl CoA dehydrogenase cause fatty acylcarnitines to accumulate in the blood.

Those containing 14 carbons predominate. However, these do not appear in the urine.

Front 128

127. LCAD activity and mitochondrial trifunctional protein.

Back 128

LCAD activity is contained w/in the mitochondrial trifunctional protein. This complex catalyzes three steps int he oxidation of long-chain fatty acids; the long chain enoyl-CoA hydratase activity, LCAD activity, and the long chain ketothiolase activity.

Mutations in LCAD are located in the α-subunit. Although an intake protein is produced, LCAD activity is reduced and the other two activities of the complex are reduced approx 40%.

Front 129

128. Zellweger syndrome

Back 129

A peroxisomal enzyme deficiency which results from a defective peroxisomal biogenesis.

As a result, there is an accumulation of very long chain fatty acids, especially in nervous tissue.

Leads to complex developmental and metabolic phenotypes that affect principally the liver and the brain.

Front 130

129. Refsum disease

Back 130

Caused by a deficiency in single peroxisomal enzyme, the phytanoyl CoA hydroxylase that carries out α-oxidation of phytanic acid.

Symptoms include retinitis pigmentosa, cerebellar ataxia, and chronic polyneuropathy.

Placing patients on a low phytanic acid diet has resulted in marked improvement.

Front 131

130. When does ω-oxidation produce dicarboxylic acids in increased amounts?

Back 131

In conditions that interfere with β-xodiation (i.e. carnitine deficiency or deficiency in an enzyme of β-oxidation), ω-oxidation produces dicarboxylic acids in increased amounts.

These dicarboxylic acids are excreted in the urine.

Front 132

131. Are adults or children more prone to ketosis?

Back 132

Children are more prone to ketosis than adults b/c their bodies enter the fasting state more rapidly.

Their bodies use more energy per unit mass and liver glycogen stores are depleted faster.

Front 133

132. During prolonged fasting, blood ketone levels greater than _____ are considered evidence of ketoacidosis?

Back 133

Levels > 7 mM are considered evidence of ketoacidosis, b/c the acid produced must reach this level to exceed the bicarbonate buffer system in the blood and compesatory respiration (Kussmaul respiration).

Front 134

133. Posterior column-medial lemniscal pathway

Back 134

Conveys proprioception, vibration sense, and fine, discriminative touch.

Front 135

134. Anterolateral pathways

Back 135

Includes the spinothalamic tract and other associated tracts that convey pain, temperature sense, and crude touch.

Front 136

135. Posterior column-medial lemniscal (AKA DCML) pathway

Where does this pathway begin?

Back 136

Axons enter the spinal cord via the medial portion of the dorsal root entry zone. Many of these axons then enter the ipsilateral posterior columns to ascend all the way to the posterior column nuclei in the medulla.

In addition, some axon collaterals enter the spinal cord central gray matter to synapse onto interneurons and motor neurons.

Front 137

136. What is the somatotopic organization pattern of the posterior columns in the DCML pathway?

Back 137

Picture the fibers adding on laterally from higher levels as the posterior columns ascend.

Thus, the medial portion, called the gracile faculus, carries information fromt he elgs and lower trunk.

The more lateral cuneate fasciculus carries information from the upper trunk above about T6, and from the arms and neck.

Front 138

137. Nucleus gracilis and nucleus cuneatus

Back 138

The first order sensory neurons that have axons in the gracile and cuneate fasciculi synapse onto second order neurons in the nucleus gracilis and nucleus cuneatus, respectively.

Front 139

138. Internal arcuate fibers

Back 139

Axons of these second order neurons decussate as internal arcuate fibers and then form the medial lemniscus on the other side of the medulla.

Front 140

139.Ventral posterior lateral (VPL) nucleus of the thalamus

Back 140

The next major synapse occurs when the medial lemniscus axons terminate int he VPL of the thalamus.

The neurons of the VPL then project through the posterior limb of the internal capsule in the thalamic somatosensory radiations to reach the primary somatosensory cortex in the postcentral gyrus.

Front 141

140. Spinothalamic tract

Where does this begin?

Back 141

Small diameter and unmyelinated axons carrying information about pain and temp sense also enter the spinal cord via the dorsal root entry zone.

However, these axons make their first synapse immediately in the gray matter of the spinal cord, mainly in the dorsal horn marginal zone (lamina I), and deeper in the dorsal horn, in lamina V.

Some axon collaterals ascend or descend for a few segments in Lissauer's tract before entering the central gray matter.

Front 142

141. Where doe these axons go from here?

Back 142

Axons from the second order sensory neurons in the central gray cross over in the spinal cord anterior (ventral) commissure to ascend in the anterolateral white matter.

Front 143

142. About how many spinal segments does it take for the decussating fibers to reach the opposite side?

Back 143

About 2-3 spinal segments, so a lateral cord lesion will affect contralateral pain and temperature sensation beginning a few segments below the level of the lesion.

Front 144

143. What is the somatotopic organization of the anterolateral pathway?

Back 144

The feet are most laterally represented.

Picture fibers from the anterior commissure adding on medially as the anterolateral pathways ascend in the spinal cord.

Front 145

144. After the fibers ascend, where do they go?

Back 145

When the anterolateral pathways reach the medulla, they are located laterally, running in the groove between the olives and the inferior cerebellar peduncles.

They then enter the pontine tegmentum to lie just lateral to the medial lemniscus in the pons and midbrain.

The next major synaptic relay is, again, in the thalamus, which projects via the thalamic somatosensory radiations to primary somatosensory cortex in the postcentral gyrus.

Front 146

145. What are the three tracts of the anterolateral pathways?

Back 146

1. Spinothalamic tract
2. Spinoreticular tract
3. Spinomesencephalic tract

Front 147

146. Which is the best known tract of the anterolateral pathways?

Back 147

The spinothalamic tract is the best known and it mediates discriminative aspects of pain and temperature sensation such as location and intensity of the stimulus.

Front 148

147. Where is the main relay for the spinothalamic tract?

Back 148

Like the DCML pathway, the main relay for the spinothalamic tract is in the VPL nucleus of the thalamus.

However, the terminations of the spinothalamic tract and the DCML pathways in the VPL are separate.

There are also spinothalmic projections to other thalamic nuclei, including intralaminar thalamic nuclei and medial thalamic nuclei such as the mediodorsal nuclei.

Front 149

148. Spinoreticular tract

Back 149

The intralaminar thalamic nuclei and medial thalamic nuclei (i.e. mediodorsal nuclei) participate together with the spinoreticular tract in a phylogenetically older pain pathway responsible for conveying the emotional and arousal aspects of pain.

Front 150

149. Where does the spinoreticular tract terminate?

How does it project its fibers?

Back 150

Terminates on the medullary-pontine reticular formation, which in turn projects to the intralaminar thalamic nuclei (centromedian nucleu).

Unlike the VPL, which projects specifically in a somatotopic fashion to the primary sensory cortex, the intralaminar nuclei project diffusely to the entire cerebral cortex and are though to be involved in behavioral arousal.

Front 151

150. Spinomesencephalic tract

Back 151

Projects to the midbrain periaqueductal gray matter and the superior colliculi.

The periaqueductal gray participates in central modulation of pain.

Front 152

151. Summary of anterolateral pathways

Back 152

If you step on a thumb tack with your left foot, your spinothalamic tract enables you to realize "something sharp is puncturing the sole of my left foot".

Your spinothalamic intralaminar projections and spinoreticular tract cause you to feel "ouch! that hurts!".

Your spinomesencephalic tract leads to pain modulation, allowing you to eventually think "aah, that feels better".

Front 153

152. Somatosensory cortex

Back 153

From the thalamic VPL and VPM nuclei, somatosensory info is conveyed to the primary somatosensory cortex in the postcentral gyrus (Brodmann's areas 3, 1, and 2).

Like the primary motor cortex, the primary somatosensory cortex is somatotopically organized, w/the face represented most laterally, and the leg most medially.

Front 154

153. Secondary somatosensory association cortex

Back 154

Info from the primary somatosensory cortex is conveyed to the secondary somatosensory association cortex located within the Sylvian fissure, along its superior margin in a region called the parietal operculum.

The secondary somatosensory cortex is also organized somatotopically.

Front 155

154. Posterior parietal lobule

Back 155

Further processing of somatosensory information occurs in association cortex of the posterior parietal lobule.

Front 156

155. What can cause cortical sensory loss?

Back 156

Lesions of the somatosensory cortex and adjacent regions produce characteristic deficits referred to as cortical sensory loss.

Front 157

156. Gate control theory

Back 157

Sensory inputs from large-diameter, nonpain Aβ fibers reduce pain transmission thru the dorsal horn.

This is also why shaking your hand after striking your thumb with a hammer temporarily helps relieve the pain.

Front 158

157. From where does the periaqueductal gray receive inputs?

What does this have to do with the RVM?

Back 158

From the hypothalamus, amygdala, and cortex, and inhibits pain transmission in the dorsal horn via a relay in a region at the pontomedullary junction called the rostral ventral medulla (RVM).

Front 159

158. Rostral ventral medulla (RVM)

Back 159

This region includes serotonergic (5-HT) neurons of the raphe nuclei that project to the spinal cord, modulating pain in the dorsal horn.

The RVM also sends inputs mediated by the neuropeptide substance P to the locus ceruleus, which in turn sends noradrenergic (NE) projections to modulate pain the spinal cord dorsal horn.

Front 160

159. Key points in the pain modulatory pathways and their associated opiate receptors

Back 160

Enkephalin- and dynorphin-containing neurons are concentrated in the periaqueductal gray, RVM, and spinal cord dorsal horn.

β-endorphin-containing neurons are concentrated in regions of the hypothalamus that project to the periaqueductal gray.

Front 161

160. Thalamus

Back 161

An important processing station in the center of the brain. Nearly all pathways that project to the cerebral cortex do so via synaptic relays in the thalamus.

In addition to sensory info, it also conveys nearly all other inputs to the cortex, including motor inputs from the cerebellum and basal gangia, limbic inputs, widespread modulatory inputs involved in behavioral arousal and sleep-wake cycles, and other inputs.

Front 162

161. Thalamic nuclei

Back 162

Some thalamic nuclei have specific topographical projections to restricted cortical areas, while others project more diffusely.

Thalamic nuclei typically receive dense reciprocal feedback connections from the cortical areas to which they project.

In fact, corticothalamic projections outnumber thalamocortical projections.

Front 163

162. Location of the thalamus

Back 163

The thalamus is part of the diencephalon, together w/the hypothalamus and epithalamus.

The hypothalamus is located immediately ventral to the thalamus. The epithalmus consists of several small nuclei inducing the habenula, parts of the pretectum, and the pineal body.

Front 164

163. Divisions of the thalamus

Back 164

The thalamus is divided into a medial nuclear group, lateral nuclear group, and anterior nuclear group by a Y shaped white matter structure called the internal medullary lamina. Nuclei located within the internal medullary lamina itself are called the intralaminar nuclei.

Front 165

164. What are the three main categories of thalamic nuclei?

Back 165

1. Relay nuclei
2. Intralaminar nuclei
3. Reticular nucleus

Front 166

165. Relay nuclei

Back 166

Most of the thalamus is made up of relay nuclei, which receive inputs from numerous pathways and then project to the cortex.

In addition, relay nuclei receive massive reciprocal connections back from the cortex.

Projections of relay nuclei to the cortex may be fairly localized to specific cortical regions or more diffuse.

Front 167

166. Specific thalamic relay nuclei

Back 167

These specific relay nuclei lie mainly in the lateral thalamus. All sensory modalities, with the exception of olfaction, have specific relays in the lateral thalamus en route to their primary cortical areas.

Front 168

167. Lateral geniculate nucleus

Back 168

Relays visual inputs (from retina) to the primary visual cortex.

Front 169

168. Medial geniculate nucleus

Back 169

Relays auditory inputs (from the inferior colliculus) to the primary auditory cortex.

Front 170

169. Ventral lateral nucleus

Back 170

Relays basal ganglia and cerebellar inputs to the cortex.

Front 171

170. Widely projecting (nonspecific) thalamic relay nuclei

Back 171

Many thalamic nuclei have more widespread cortical projections.

For example, visual and other sensory inputs to the pulvinar are relayed to large regions of the parietal, temporal, and occipital association cortex involved in behavioral orientation toward relevant stimuli.

Front 172

171. Pulvinar

Back 172

A large, pillow-shaped nucleus that occupies most of the posterior thalamus.

Front 173

172. Mediodorsal nucleus

Back 173

AKA dorsomedial nucleus

Diffuse relays of limbic inputs, and other information involved in cognitive functions, occur in the mediodorsal nucleus.

It forms a large bulge lying medial to the internal medullary lamina, best seen in coronal sections.

The MD serves as the major thalamic relay for information traveling to the frontal association cortex.

Front 174

173. Intralaminar nuclei

Back 174

Lie within the internal medullary lamina.

Like the relay nuclei, they receive inputs from numerous pathways and have reciprocal connections with the cortex.

They are sometimes classified along with other "nonspecific" relay nuclei.

However, we have placed them in a separate category here b/c unlike relay nuclei, their main inputs and outputs are from the basal ganglia.

Front 175

174. What are the two functions regions of the intralaminar nuclei?

Back 175

1. The caudal intralaminar nuclei include the large centromedian nucleus and are involved mainly in basal ganglia circuitry.

2. The rostral intralaminar nuclei also have input and output connections with the basal ganglia.

Front 176

175. What is the other function of the rostral intralaminar nuclei?

Back 176

In addition, the rostral intralaminar nuclei appear to have an important role in relaying inputs from the ascending reticular activating systems to the cortex, maintaining the alert, conscious state.

Front 177

176. Reticular nucleus

What is so special about this nucleus?

Back 177

Forms a thin sheet located just lateral to the rest of the thalamus, and just medial to the internal capsule.

*It is the only nucleus of the thalamus that does not project to the cortex. Instead, it receives inputs mainly from other thalamic nuclei and the cortex and then projects back to the thalamus.

Front 178

177. Reticular nucleus composition

Back 178

Consists of an almost pure population of inhibitory GABAergic neurons.

This composition, together with its connections w/the entire thalamus, make it well suited to regulate thalamic activity.

Front 179

178. Paresthesias

Back 179

Lesions of the somatosensory pathways can cause abnormal positive sensory phenomena called paresthesias.

Both the character and the location of these abnormal sensations reported by the patient can have localizing value.

Front 180

179. Dejerine-Roussy syndrome

Back 180

Lesions of the thalamus can cause severe contralateral pain, called Dejerine-Roussy syndrome.

Front 181

180. Lhermitte's sign

Back 181

Lesions of the cervical spine may be accompanied by Lhermitte's sign, an electricity-like sensation running down the back and into the extremities upon neck flexion.

Front 182

181. Lesion of nerve roots

Back 182

Often produce radicular pain that radiates down the limb in a dermatomal distribution, and is accompanied by numbness and tingling, and is provoked by movements that stretch the nerve root.

Peripheral nerve lesions, similarly, often cause pain, numbness, and tingling in the sensory distribution of the nerve.

Front 183

182. Dysesthesia

Back 183

Unpleasant, abnormal sensation

Front 184

183. Hyperpathia or allodynia

Back 184

Painful sensations provoked by minor stimuli such as light touch.

Front 185

184. Hypesthesia

Back 185

Means decreased sensation.

Front 186

185. What are the most common causes of spinal cord dysfunction?

Back 186

Compression due to trauma, and metastatic cancer.

Front 187

186. Spinal shock

Back 187

In acute, severe lesions such as trauma, there is often initially a phase of spinal shock characterized by flaccid paralysis below the lesion, loss of tendon reflexes, decreased sympathetic outflow to vascular smooth muscle causing moderately decreased blood pressure, and absent sphincteric reflexes and tone.

Over the course of weeks to months, spasticity and upper motor neuron signs usually develop.

Some sphincteric and erectile reflexes may return, although often without voluntary control.

Front 188

187. Steroids and acute traumatic spinal cord lesions

Back 188

Acute traumatic spinal cord lesions may have improved outcome if treated within the first 8hrs with high doses of steroids.

Front 189

188. Rule of thumb in spinal cord lesions

Back 189

An approximate rule of thumb is that 80% of patients treated for metastatic spinal cord compression after they lose ambulation will remain permanently non-ambulatory, while 80% of patients treated before losing ambulation remain ambulatory for the rest of their lives.

Front 190

189. Myelitis

Back 190

An important and common cause of spinal cord dysfunction, which can be infectious or inflammatory in etiology.

Front 191

190. Lesions in the primary somatosensory cortex

Back 191

Deficit is contralateral to the lesion.

Discriminative touch and joint position sense are often most severely affected, but all modalities may be involved.

Front 192

191. Cortical sensory loss pattern

Back 192

Sometimes all primary modalities are relatively spared, but a pattern called cortical sensory loss is present, with extinction, or decreased stereognosis, and graphesthesia.

Front 193

192. VPL or VPM nuclei lesions

Back 193

Deficit is contralateral to the lesion.

Deficit may be more noticeable in the face, hand, and foot than in the trunk or proximal extremities.

All sensory modalities may be involved, sometimes w/no motor deficit.

Larger lesions may be accompanied by hemiparesis or hemianopia cause by involvement of the internal capsule, lateral geniculate, or optic radiations.

Front 194

193. Lesions in the thalamic somatosensory radations

Back 194

Cause contralateral hemisensory loss, which is associated w/hemiparesis b/c of the involvement of adjacent corticobulbar and corticospinal fibers.

Front 195

194. Lesions in the midbrain or upper pons

Back 195

Can cause contralateral somatosensory deficits involving the face, arm, and leg.

Front 196

195. Lesions in the lateral pons or lateral medulla

Back 196

The lesion involves anterolateral pathways and the spinal trigeminal nucleus on the same side.

It causes loss of pain and temperature sensation in the face on the same side of the lesion.

Front 197

196. Lesions in the medial medulla

Back 197

The lesion involves the medial lemniscus, causing contrlateral loss of vibration and joint position sense.

Front 198

197. Transverse cord lesions

Back 198

All sensory and motor pathways are either partially or completely interrupted. There is often a sensory level corresponding to the level of the lesion.

The pattern of weakness and reflex loss can also help determine the spinal cord level.

Common causes include trauma, tumors, multiple sclerosis, and transverse myelitis.

Front 199

198. Brown-Séquard syndrome

Back 199

Damage to the lateral corticospinal tract causes ipsilateral upper motor neuron type weakness. Interruption of the posterior columns causes ipsilateral loss of vibration and joint position sense.

Interruption of the anterolateral systems, however, causes contralateral loss of pain and temp sensation. This often begins slightly below the lesion b/c the anterolateral fibers ascend 2-3 segments as the cross int eh ventral commissure.

There may also be a strip of 1 or 2 segments of sensory loss to pain and temp ipsilateral to the lesion, caused by damage to posterior horn cells before their axons have crossed over.

Common causes include penetrating injuries, multiple sclerosis, and lateral compression from tumors.

Front 200

199. Central cord syndrome (small lesions)

Back 200

In small lesions, damage to spinothalamic fibers crossing in the ventral commissure causes bilateral regions of suspended sensory loss to pain and temp.

Lesions of the cervical cord produce the classic cape distribution, however, suspended dermatomes of pain and temp sensory loss can occur w/lesions at other levels as well.

Front 201

200. Central cord syndrome (large lesions)

Back 201

With larger lesions, the anterior horn cells are damaged, producing lower motor neuron deficits at the level of the lesion.

In addition, the corticospinal tracts are affected, causing upper motor neuron signs, and the posterior columns may be involved as well.

Common causes include spinal cord contusion, posttraumatic syringomyelia, and intrinsic spinal cord tumors such as hemangioblastoma, ependymoma, or astrocytoma.

Front 202

201. Sacral sparing in large lesions

Back 202

B/c the anterolateral pathways are compressed from their medial surface by large lesions, there may be near complete loss of pain and temperature sensation below the lesion except for in a region of sacral sparing

Front 203

202. Posterior cord syndrome

Back 203

Lesions of the posterior columns cause loss of vibration and position sense below the level of the lesion.

W/larger lesions, there may also be encroachment on the lateral corticospinal tracts, causing upper motor neuron-type weakness.

Common causes include trauma, extrinsic compression from posteriorly located tumors, and MS. In addition, vitamin B12 deficiency and tabes dorsalis (tertiary syphilis) preferentially affect the posterior cord.

Front 204

203. Anterior cord syndrome

Back 204

Damage to the anterolateral pathways can cause loss of pain and temp sensation below the level of the lesion, and damage to the anterior horn cells produces lower motor neuron weakness at the level of the lesion.

With larger lesions, the lateral corticospinal tracts may also be involved, causing upper motor neuron signs.

Incontinence is common b/c the descending pathways controlling sphincter function tend to be more ventrally located.

Common causes include trauma, MS, and anterior spinal artery infarct.

Front 205

204. What controls the pelvic floor muscles?

What controls the urethral and anal sphincters?

Back 205

Voluntary somatic motor fibers arise from anterior horn cells at S2 to S4 to control the pelvic floor muscles.

The specialized sphincteromotor nucleus of Onuf at S2 to S4 controls the urethral and anal sphincters.

Front 206

205. Where do pelvic sympathetics and parasympathetics arise from?

Back 206

Pelvic sympathetics arise from the sacral parasympathetic nuclei at S2-S4 and sympathetics arise from the intermediolateral cell column at T11-L1.

Front 207

206. Micturition

Back 207

Micturition is initiated by descending pathways from medial frontal micturition centers that activate the voiding, or detrusor, reflex.

Front 208

207. Detrusor reflex

Back 208

The detrusor reflex is mediated by intrinsic spinal cord circuits and regulated by the pontine micturition center and possibly also by cerebellar and basal ganglia pathways.

The reflex is normally initiated by voluntary relaxation of the external urethral sphincter, which triggers the inhibition of sympathetics to the bladder neck, causing it to relax,and the activation of parasympathetics, causing detrusor muscle contraction.

Front 209

208. Urethral reflex

Back 209

When the urine flow stops, the urethral sphincters contract, thereby triggering detrusor relaxation thru the urethral reflex.

Flow can also be interrupted at any time by voluntary closure of the urethral sphincter, which similarly triggers detrusor relaxation.

Front 210

209. Lesions affecting bilateral medial frontal micturition centers results in...

Back 210

Results in reflex activation of pontine and spinal micturition centers when the bladder is full.

Urine flow and bladder emptying are normal; however, they are not longer under voluntary control, and the individual may or may not be aware of the incontinence.

Common causes include hydrocephalus, parasagittal meningioma, bifrontal gliobastoma, traumatic brain injury, and neurodegenerative disorders.

Front 211

210. What cause a flaccid, acontractile (atonic) bladder?

Back 211

Lesions below the pontine micturition center and above the conus medullaris levels S2 to S4 often initially cause a flaccid, acontractile (atonic) bladder.

When the bladder is atonic, reflex contractions of the urethral sphincters often persist, resulting in urinary retention and bladder distention. Catheterization is usually necessary.

Front 212

211. Detrusor-sphincter dyssynergia

Back 212

In a hyperreflexic bladder, detrusor-sphincter dyssynergia often occurs, in which both detrusor and urethral sphincter tone are increased in an uncoordinated, and at times, antagonistic fashion.

When involuntary reflex bladder contractions occur, there may be a sense of urinary urgency or urge incontinence. Often residual volume increases b/c of incomplete emptying.

Common spinal cord lesions causing these bladder problems include trauma, tumors, transverse myelitis, and MS.

Front 213

212. Flaccid areflexic bladder

Back 213

Lesions of the peripheral nerves, or of the spinal cord at S2-S4, usually cause a flaccid areflexic bladder, or significantly impaired bladder contractility resembling an acontractile bladder.

This result can be due to loss of parasympathetic outflow to the detrusor and/or loss of afferent sensory info from the bladder and urethra.

Overflow incontinence is present.

Front 214

213. Common causes of flaccid, areflexic bladder (AKA neurogenic bladder)

Back 214

Diabetic neuropathy and compression of the conus medullaris or cauda equina by trauma, tumor, or disc herniation.

Urinary retention and incontinence can also be caused by a large variety of non-neurologic conditions, i.e. BPH, urethral strictures, and intrinsic sphincter deficiency.

Front 215

214. What can cause fecal incontinence?

Back 215

Can be caused by diffuse cerebral or medial frontal lesions, by spinal cord lesions or by lesions of the sacral nerve roots or the pelvic or pudendal nerves.

In acute spinal cord lesions, the anal sphincter is completely flaccid.

There is also loss of sacral parasympathetic outflow, causing severe constipation.

Front 216

215. What are the three important features of brain tumors?

Back 216

1. Consequences of location
-the ability to remove the neoplasm surgically may be restricted by functional anatomic considerations. Benign lesions can have lethal consequences b/c of their location.

2. Patterns of growth
-most glial tumors, including many w/histologic features of a benign neoplasm, infiltrate entire regions of the brain leading to clinically malignant behavior.

3. Patterns of spread
-some types of tumor spread through the CSF; however, even the most frankly malignant gliomas rarely metastasize outside the CNS.

Front 217

216. Tumors of the CNS in children vs. adults

Back 217

Tumors of the CNS account for as many as 20% of all cancers of childhood.

In this age group, 70% of primary tumors arise in the posterior fossa, whereas in adults, a corresponding proportion arise above the tentorium.

Among adults, there is a nearly equal incidence of primary and metastatic tumors.

Front 218

217. Fibrillary (diffuse) astrocytomas

Back 218

Fibrillary (diffuse) astrocytomas represent about 80% of adult primary brain tumors, usually in the cerebral hemispheres, but they may also occur in the cerebellum, brain stem, or spinal cord.

All astrocytomas are composed of neoplastic astrocytic nuclei, distributed amid astrocytic processes of varying density; grade is determined histologically.

Front 219

218. Features of fibrillary (diffuse) astrocytomas

Back 219

Well-differentiated tumors (astrocytomas) are poorly defined, gray-white, infiltrative tumors that expand and distort a region of the brain; they show hypercellularity and some nuclear pleomorphism.

These are WHO grade II/IV tumors.

Front 220

219. What are the four major classes of brain tumors?

Back 220

1. Gliomas
-derived from glial cells, include astrocytomas, oligodendrogliomas, and ependymomas.

2. Neuronal tumors
-includes gangliocytomas, gangliogliomas and papillary glioneuronal tumors.

3. Poorly differentiated neoplasms
-includes medulloblastomas and atypical teratoid/rhabdoid tumors

4. Meningiomas
-includes atypical meningiomas and anaplastic meningiomas

Front 221

220. Anaplastic astrocytomas

Back 221

More anaplastic and aggressive tumors (anaplastic astrocytomas) reveal increased nuclear anaplasia and the presence of mitoses and vascular cell proliferation.

These are WHO grade III/IV tumors.

Front 222

221. Glioblastomas

Back 222

Extremely high-grade tumors (gliobastomas) are composed of a mixture of firm, white areas; softer yello foci of necrosis; cystic change; and hemorrhage.

Increaded nuclear density of the highly anaplastic tumor cells along the edges of the necrotic regions is termed pseudopalisading.

These are WHO grade IV/IV tumors.

Front 223

222. Low grade astrocytomas

Back 223

May remain static or progress only slowly for a number of years. Eventually, however, patients often enter a period of rapid clinical deterioration and rapid tumor growth, corresponding to the appearance of anaplastic features.

The prognosis for patients with glioblastoma is poor: mean length of survival after diagnosis is only 8-10 months.

Front 224

223. Pilocytic astrocytomas

Back 224

Occur in children and young adults, usually in the cerebellum but also in the floor of the walls of the third ventricle, the optic nerves, and occasionally, the cerebral hemispherses.

They are often cystic with a mural nodule in the wall of the cyst.

The tumor is composed of bipolar cells w/long, thin hairlike processes. Rosenthal fibers and microcysts are often present.

These tumors are rarely infiltrative and grow slowly. They are WHO grade I/IV tumors.

Front 225

224. Pleomorphic xanthoastrocytomas

Back 225

Occur most often relatively superficially in the temporal lobes of children and young adults w/a history of seizures.

They contain neoplastic astrocytes, sometimes with bizarre forms, abundant reticulin and lipid deposits, and chronic inflammatory cell infiltrates.

Front 226

225. Brain stem gliomas

Back 226

Occur mostly in the first 2 decades of life. By the time of autopsy, about 50% have progressed to glioblastomas.

With radiotherapy, the 5-year survival rate is 20-40%.

Front 227

226. Molecular genetics of glioblastic tumors

Back 227

Secondary glioblastomas shared p53 mutations that characterized low grade gliomas, while primary glioblastomas were characterized by amplification of the epidermal growth factor receptor gene.

In addition to these two changes, there are certain other genetic alterations that mark the two pathways to gliobastoma: PDFG-A amplification in secondary gliobastomas, and MDM2 overexpression, p16 deletion, or PTEN mutations in primary glioblastomas.

Front 228

227. Oligodendrogliomas

Back 228

Constitute about 5-15% of gliomas and are most common in middle life in the cerebral white matter.

In general, patients with oligodendrogliomas have a better prognosis than patients with astrocytomas.

Current therapies yield an average survival time of 5-10 years. Cases of poorly differentiated tumors w/increased anaplasia, mitotic activity, cell density, and necrosis have a worse prognosis.

Front 229

228. Morphology of oligodendrogliomas

Back 229

Oligodendrogliomas are well-circumscribed, gelatinous, gray masses, often w/cysts, focal hemorrhage, and calcification.

The tumor consists of sheets of regular cells w/round nuclei containing finely granular chromatin, often surrounded by a clear halo of cytoplasm sitting in a delicate network of anastomosing capillaries.

Calcification, present in up to 90% of cases, ranges from microscopic foci to massive deposits.

Front 230

229. Ependymomas

Back 230

These tumors arise from the ependymal lining of the ventricular system, including the central canal of the spinal cord.

CSF dissemination is a common finding.

The NF2 gene on chromosome 22 has been examined as a candidate locus for alterations in ependymomas. It appears that alterations at this site may be involved int he pathogenesis of edendymomas in the spinal cord but not at other sites.

Front 231

230. Age of onset of ependymomas and location

Back 231

In the first 2 decades of life, ependymomas typically occur int eh fourth ventricle; in middle life, the spinal cord ins the most common location.

Front 232

231. Morphological characteristics of ependymomas

Back 232

The tumor cells have regular, round-oval nuclei w/abundant granular chromatin.

They may form ependymal rosettes (canals) or, more frequently, perivascular pseudorosettes.

Front 233

232. Myxopapillary ependymomas

Back 233

These are histologically benign lesions arising in the filum terminale of the spinal cord.

Cuboidal cells, sometimes w/clear cytoplasm, are arranged around papillary cores containing connective tissue and blood vessels.

Myxoid areas contain neutral and acidic mucopolysaccharides.

Front 234

233. Subependymomas

Back 234

These are solid, sometimes calcified, slow-growing nodules attached to the ventricular lining and protruding into the ventricle.

They have clumps of ependymomal-appearing nuclei scattered in a dense, finely fibrillar background.

Front 235

234. Choroid plexus papillomas

Back 235

These almost exactly recapitulate the structure of the normal choroid plexus, with papilae of connective tissue stalks covered with a cuboidal or columnar ciliated epithelium.

Hydrocephalus is common, as a result of either obstruction of the ventricular system or overproduction of CSF.

In children, the lateral ventricles are the most common site; in adults, the fourth ventricle is a more frequent site.

Front 236

235. Colloid cysts of the third ventricle

Back 236

These are non-neoplastic lesions of young adults; they are located at the foramina of Monro and can result in noncommunicating hydrocephalus, sometimes rapidly fatal.

The cyst has a thin, fibrous capsule and a lining of low to flat cuboidal epithelium; the cyst contents are gelatinous proteinaceous material.

Front 237

236. Ganglion cell tumors

Back 237

A type of neuronal tumor; a ganglioglioma is a neoplasm w/an admixed ganglion cell component of irregularly clustered neurons w/apparently random orientation of neurites and frequent binucleated forms.

Most occur in the temporal lobe and are slow growing, but occasionally the glial component becomes frankly anaplastic; the tumor then assumes a much more aggressive course.

Front 238

237. Gangliocytoma

Back 238

Mature-appearing neurons may constitute the entire population of a tumor, in which case it is termed a gangliocytoma.

Front 239

238. Dysembryoplastic neuroepithelial tumor

Back 239

A tumor of childhood often presenting as a seizure disorder, with a relatively good prognosis after resection.

Features include intracortical location, cystic changes, nodular growth, "floating neurons" in a pool of mucopolysaccharide-rich fluid, and surrounding neoplastic glia w/o anaplastic features.

Front 240

239. Cerebral neuroblastomas

Back 240

This is a tumor with only neuronal elements.

This rare, aggressive neoplasm occurs in the hemispheres in children and resembles peripheral neuroblastomas, with small undifferentiated cells and Homer-Wright rosettes.

Front 241

240. Neurocytomas

Back 241

This is another tumor with only neuronal elements.

This tumor is found adjacent to the foramen of Monro.

Evenly spaced, round, uniform nuclei resemble cells of an oligodendroglioma, but ultrastructural and immunohistochemical studies reveal their neuronal origin.

Front 242

241. Poorly differentiated neoplasms

Back 242

Some tumors, although of neuroectodermal origin, express few, if any, of the phenotypic markers of mature cells of the nervous system and are described as poorly differentiated.

Front 243

242. Medulloblastomas

Back 243

Medulloblastomas account for 20% of childhood brain tumors; they occur exclusively in the cerebellum.

Tumors are located in the midline in children, with lateral locations found more often in adults.

Rapid growth may occlude the flow of CSF, leading to hydrocephalus.

The tumor is highly malignant, and the prognosis for untreated neoplasm is dismal; however, it is exquisitely radiosensitive. With total excision and radiation, the 5-yr survival rate is 75%.

Front 244

243. Morphological characteristics of medulloblastomas

Back 244

They are often well circumscribed, gray, and friable. They are usually extremely cellular, with sheets of anaplastic cells exhibiting hyperchromatic nuclei and abundant mitoses.

The cells have little cytoplasm, and the cytoplasm is often devoid of specific markers of differentiation, although neuronal or glial features may be seen.

Extension into the subarachnoid space may elicit a prominent desmoplastic response.

Dissemination through the CSF is common.

Front 245

244. Primary CNS lymphoma

Back 245

Primary brain lymphomas account for approx 2% of extranodal lymphomas.

One or more dominant masses occur within the brain parenchyma; nodal or bone marrow involvement and involvement outside the CNS are extremely rare late complications.

Front 246

245. Immunosuppressed patients and primary brain lymphoma

Back 246

Within the immunosuppressed population (e.g. AIDS), all the neoplasms appear to be of B-cell origin and to contain Epstein-Barr virus genomes within the transformed B cells.

Front 247

246. Clinical characteristics of primary brain lymphoma

Back 247

The primary brain lymphoma is an aggressive disease w/relatively poor chemotherapeutic responses compared with peripheral lymphoma.

Nevertheless, it is initially responsive to radiotherapy and steroids.

Front 248

247. Morphological characteristics of primary brain lymphoma

Back 248

The morphology of the neoplastic lymphocytes is nearly always of a high grade type.

The malignant cells diffusely involve the parenchyma of the brain and accumulate around blood vessels, with some vessel walls expanded by multiple layers of malignant cells.

Front 249

248. Germ cell tumors

Back 249

These tumors occur along the midline in adolescents and young adults, with the pineal and suprasellar regions dominating the distribution.

Tumors in the pineal region show a strong male predominance, not seen in suprasellar lesions.

The histologic appearances of germ cell tumors and their classification are the same as used for other extragonadal sites.

Front 250

249. Meningiomas

Back 250

Meningiomas are predominantly benign tumors of adults that arise from the meningothelial cell of the arachnoid.

They show a moderate (3:2) female predominance within the cranial vault but a 10:1 female-male ratio within the spinal canal.

Loss of heterozygosity of the long arm of chromosome 22 is a common finding.

Front 251

250. Morphological characteristics of meningiomas

Back 251

Meningiomas tend to be rounded masses w/well-defined dural bases that compress the underlying brain but are easily separated from it.

Lesions are usually firm to fibrous and lack evidence of necrosis or extensive hemorrhage.

Many histologic patterns exist, all with generally comparable favorable outcomes

Front 252

251. What are the histologic patterns of meningiomas?

Back 252

1. Syncytial
2. Fibroblastic
3. Transitional
4. Psammomatous
5. Papillary tumors
6. Malignant meningiomas
7. Sarcomas of the meninges

Front 253

252. Synctial meningiomas

Back 253

Clusters of cells in tight groups without visible cell membranes

Front 254

253. Fibroblastic meningiomas

Back 254

Elongated cells and abundant collagen deposition.

Front 255

254. Transitional meningiomas

Back 255

Feature of the syncytial and fibroblastic types.

Front 256

255. Psammomatous meningiomas

Back 256

Abundant psammoma bodies, apparently forming from calcification of the syncytial nests of meningothelial cells.

Front 257

256. Papillary meningioma tumors

Back 257

Pleomorphic cells arranged around fibrovascular cores (tend to have worse prognosis)

Front 258

257. Anaplastic (malignant) meningiomas

Back 258

Unusual tumors that may be difficult to recognize histologically as being meningothelial.

They have abundant mitoses w/atypical forms.

Front 259

258. Sarcomas of the meninges

Back 259

Uncommon but can include malignant fibrous histiocytomas and hemangiopericytomas.

Front 260

259. Atypical meningiomas

Back 260

These are lesions with a higher rate of recurrence and more aggressive local growth that may require therapy in addition to surgery.

The Dx criteria for this requires either a mitotic index of 4 or more mitoses per 10 high power fields or 3 or more of the atypical features:
1. Increased cellularity
2. Small cells w/a high nuclear:cytoplasmic ratio
3. Prominent nucleoli
4. Patternless growth
5. Necrosis

Front 261

260. Molecular genetics of meningiomas

Back 261

The most common cytogenetic abnormality is loss of chromosome 22, especially the long arm (22q).

The deletions include the region of 22q12 that harbors the NF2 gene.

Indeed, 50-60% of meningiomas not associated w/neurofibromatosis type 2 have mutations in the NSF2 gene; the majority of these mutations are predicted to result in absence of functional protein.

Front 262

261. Meningiomas and neurofibromatosis type 2

Back 262

Lesions are usually solitary, and their presence at multiple sites, especially in association with acoustic neuromas or glial tumors, suggests a Dx of neurofibromatosis type 2.

Front 263

262. Metastatic tumors

Back 263

Among general hospital patients, metastatic lesions, mostly carcinomas, account for approx half of intracranial tumors.

Common primary sites are lung, breast, skin (melanoma), kidney, and GI tract.

The meninges are also a frequent site for involvement by metastatic disease.

Front 264

263. Morphology of intraparenchymal metastatic tumors

Back 264

Intraparenchymal metastases are sharply demarcated masses, often at the gray-white junction, usually surrounded by a zone of edema.

Meningeal carcinomatosis, with tumor nodules studding the surface of the brain, spinal cord, and intradural nerve roots, is an occasional complication particularly associated w/small cell carcinoma, adenocarcinoma of the lung, and carcinoma of the breast.

Front 265

264. Paraneoplastic syndromes

Back 265

Paraneoplastic syndromes are functional and structural changes of the brain in response to malignancy elsewhere in the body.

The major underlying mechanism involves the systemic development of an immune response against tumor antigens that can cross-react w/antigens in the CNS or PNS.

Syndromes may improve with plasmapheresis, immunosuppression, or treatment of the primary neoplasm.

Front 266

265. Paraneoplastic cerebellar degeneration

Back 266

This is the most common pattern, with loss of Purkinje cells, gliosis, and mild inflammatory infiltrate associated w/an antibody-mediated injury of Purkinje cells.

Front 267

266. Limbic encephalitis

Back 267

This is a subacute dementia, usually with a prominent component of memory disturbance.

Findings are most striking in the anterior and medial portions of the temporal lobe and resemble an infectious process w/perivascular inflammatory cuffs, microglial nodules, some neuronal loss, and gliosis.

A comparable process involving the brainstem an be seen in isolation or together with limbic system involvement.

Front 268

267. Subacute sensory neuropathy

Back 268

Occurs in association with limbic encephalitis or in isolation, with loss of sensory neurons from dorsal root ganglia, in association with inflammation.

Front 269

268. Eye movement disorders in paraneoplastic syndromes

Back 269

Eye movement disorders, most commonly opsoclonus, may be found, often in association with other evidence of cerebellar and brainstem dysfunction.

In children, this is most commonly associated w/neuroblastoma and is found along with myoclonus.

Front 270

269. Peripheral nerve sheath tumors

Back 270

A large proportion of tumors occurring within the confines of the dura are derived from cells of peripheral nerve (including Schwann cells, perineurial cells, and fibroblasts).

Comparable tumors arise along the peripheral course of nerves.

Front 271

270. Schwannomas

Back 271

Schwannomas are benign tumors of neural crest-derived Schwann cells, most commonly associated w/the vestibular branch of CN VIII at the cerebellopontine angle (vestibular schwannoma or acoutic neuroma).

Spinal tumors mostly arise from dorsal roots; tumors may extend through the vertebral foramen, acquiring a dumbbell configuration.

When extradural, schwannomas are most commonly found in association with large nerve trunks.

Front 272

271. Morphological characteristics of schwannomas

Back 272

They are well-circumscribed, encapsulated masses, attached to the nerve but separable from it. Axons are excluded from the tumors, although they may becomes entrapped in the capsule.

Electron microscopy shows basement membrane deposition encasing single cells and long-spacing collagen. Malignant change is extremely rare.

Tumors show a mixture of two growth patterns: Antoni A and Antoni B

Front 273

272. Antoni A growth pattern in schwannomas

Back 273

Elongated cells with cytoplasmic processes arranged in fascicles in areas of moderate-to-high cellularity with little stromal matrix.

Front 274

273. Antoni B growth pattern in schwannomas

Back 274

Less densely cellular tissue with microcysts and myxoid changes.

Front 275

274. Neurofibromas

Back 275

Two histologically, and perhaps biologically, distinct lesions have been termed neurofibromas.

The most common form occurs in the skin (cutaneous neurofibroma) or in peripheral nerve (solitary fibroma).

They arise sporadically or in association with neurofibromatosis Type 1.

The second type is plexiform neurofibroma, which is considered by some to occur only in patients with NF1.

Front 276

275. Cutaneous neurofibroma and solitary neurofibroma

Back 276

They occur sporadically an in association w/NF1.

The skin lesions are evident as nodules, sometimes with hyperpigmentation; these lesions may grow quite large and become pedunculated.

Present in the dermis and extending to the subcutaneous fat, these are well-delineated but unencapsulated masses composed of spindle cells in highly collagenized stroma.

Lesions within peripheral nerves are histologically similar.

Front 277

276. Plexiform neurofibromas

Back 277

They irregularly expand a nerve as fascicles are infiltrated. In contrast to schwannomas, it is not possible to separate the lesion from the nerve, making surgical removal difficult.

The lesion has a loose myxoid background w/a low cellularity, including Schwann cells, fibroblasts, perineurial cells, and a sprinkling of inflammatory cells, often including mast cells.

Axons can be found within the tumor.

Front 278

277. Malignant peripheral nerve sheath tumor (AKA malignant Schwannoma)

Back 278

These highly malignant, locally invasive sarcomas do not arise from malignant degeneration of schwannomas; instead, they arise de novo or from transformation of a plexiform neurofibroma.

Front 279

278. Morphological characteristics of malignant Schwannomas

Back 279

The lesions are poorly defined tumor masses with frequent infiltration along the axis of the parent nerve as well as invasion of adjacent soft tissues.

Tumor cells represent Schwann cells w/elongated nuclei and prominent bipolar processes; fascicle formation may be present.

Mitoses, necrosis, and nuclear anaplasia are common.

Front 280

279. Epitheliod malignant schwannomas

Back 280

These are aggressive variants derived from nerve sheaths and contain tumors cells having visible cell borders and epithelial type nests.

They are immunoreactive for S-100 but not for keratin, the latter differentiating them from epithelial tumors.

Front 281

280. Familial tumor syndromes

Back 281

These mostly autosomal dominant disorders are characterized by harmartomas and neoplasms located throughout the nervous system and skin.

Front 282

281. Neurofibromatosis type 1 (NF1)

Back 282

This autosomal dominant disorder is characterized by neurofibromas (plexiform and cutaneous), optic nerve gliomas, meningiomas, pigmented nodules of the iris (Lisch nodules), and cutaneous hyperpigmented macules (cafe au lait spots).

Even in the absence of malignant transformation of neurofibromas, lesions have disfiguring potential and the potential to create spinal deformity (i.e. kyphoscoliosis).

Front 283

282. The NF1 gene

Back 283

The NF1 gene is a tumor suppressing gene, based on evidence of loss of heterozygosity in tumors from NF1 patients.

It is located at 17q11.2 has been identified and encodes a protein termed neurofibromin.

The protein contain a region homologous to the RAS family of GTPase-activating proteins, and it is presumed that neurofibromin plays a roles in regulating signal transduction.

The protein is widely expressed, the highest levels being found in neural tissue

Front 284

283. Molecular genetics of neurofibromatosis type 1 (NF1)

Back 284

A variety of mutations involving the NF1 gene have been detected. The clinical phenotype does not correlate with the type or location of the NF1 mutation.

The course of the disease is highly variable; some individuals who carry a mutated gene have no symptoms, while other develop progressive disease with spinal deformities, disfiguring lesions, and compression of vital structures, including the spinal cord.

Front 285

284. Neurofibromatosis type 2 (NF2)

Back 285

This distinct autosomal dominant disorder (chromosome 22) has a propensity to develop bilateral eighth nerve schwannomas or multiple meningiomas.

Gliomas, typically ependymomas of the spinal cord, also occur in these patients.

This disorder is much less common than NF1, having a frequency of 1/40,000 to 1/50,000.

Front 286

285. Molecular genetics of neurofibromatosis type 2 (NF2)

Back 286

The NF2 gene is located on chromosome 22q12, and the gene product, merlin, shows structural similarity to a series of cytoskeletal proteins.

Nonsense mutations usually cause a more severe phenotype than missense mutations.

Front 287

286. Tuberous sclerosis

Back 287

Characterized by angiofibromas, seizures, and mental retardation.

Hamartomas within the CNS include cortical tubers and subependymal hamartomas.

In addition, renal angiomyolipomas; retinal glial phakomas; cardiac rhabdomyomas; hepatic, renal and pancreatic cysts; leathery cutaneous thickenings (shagreen patches); hypopigmented areas; and subungual fibromas may occur.

Front 288

287. Cortical tubers

Back 288

Areas of haphazardly arranged neurons and large cells that express phenotypes intermediate between glia and neurons.

Front 289

288. Subependymal harmartomas

Back 289

Large astrocytic and neuronal cell clusters beneath the ventricular surface that give rise to a tumor unique to tuberous sclerosis - the subependymal giant cell astrocytoma.

Front 290

289. Molecular genetics of tuberous sclerosis

Back 290

There is variable expressivity and penetrance, and at least two distinct loci are known, on chromosomes 9 (hamartin) and 16 (tuberin).

The complex containing these proteins may play a role in regulating cell proliferation.

Front 291

290. von Hippel-Lindau disease

What are the four characteristics of this disease?

Back 291

Characterized by:
1. Capillary hemangioblastomas in the cerebellar hemispheres, retina, and less commonly w/in the brain stem and spinal cord.
2. Cysts involving the pancreas, liver, and kidney, with a strong propensity to develop renal cell carcinoma of the kidney.
3. Paragangliomas
4. Hemangioblastomas containing variable proportions of delicate capillary vessels with stromal cells of uncertain histogenesis and abundant vacuolated cytoplasm between them.

Front 292

291. Morphology of von-Hippel-Lindau disease

Back 292

The cerebellar capillary hemangioblastoma, the principal neurologic manifestation of the disease, is a highly vascular neoplasm that occurs as a mural nodule associated w/a large fluid-filled cyst.

On microscopic exam, the lesion consists of a mixture of variable proportions of capillary-size or somewhat larger thin walled vessels with intervening stromal cells of uncertain histogenesis, characterized by vacuolated, lightly PAS-positive, lipid rich cytoplasm and indefinite immunohistochemical phenotype.

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292. Clinical features of von-Hippel-Lindau disease

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They commonly are cystic lesions with a mural node.

Polycythemia is an associated finding in about 10% of cases, related to erythropoietin production by the tumor.

Treatment is directed at the symptomatic neoplasms, including resection of the cerebellar hemangioblastomas and laser therapy for retinal hemangioblastomas.

Partial nephrectomy is performed for renal carcinomas when these malignant neoplasms are bilateral.