Pbl Exam 9 Case 7

Front 1

1. What are the characteristics of basal ganglia disorders?

Back 1

Pts with basal ganglia lesions can have either hyperkinetic or hypokinetic movement disorders.

Hyperkinetic = Huntington's disease

Hypokinetic = Parkinson's disease

Front 2

2. What are the components of the basal ganglia?

Back 2

THe main components are:

1. Caudate*
2. Putamen*^
3. Globus pallidus^
4. Subthalamic nucleus
5. Substantia nigra

Front 3

3. What is the striatum?

Back 3

The caudate and putamen are histologically and embryologically related and can be though of as a single large nucleus called the striatum, which receives all inputs to the basal ganglia.

Front 4

4. What is the caudate nucleus?

Back 4

The caudate is divided into three parts, the head, body, and tail. The amygdala lies just anterior to the tip of the caudate tail, in the temporal lobe.

Front 5

5. What is the putamen?

Back 5

The putamen is a large nucleus forming the lateral portion fot he basal ganglia. Anteriors and ventrally the putamen fuses w/the head of the caudate. This region, called the ventral striatum, is important in limbic circuitry and is often considered part of the striatum b/c of its similar embryological development and I/O connections. Most of the vental stritum consists fo the nucleus accumbens.

Front 6

6. What is the globus pallidus?

Back 6

Just medial to the putamen lies the globus pallidus, which has many myelinated fibers. The globus pallidus has an internal segment and an external segment.

Front 7

7. What is the lentiform or lenticular nucleus?

Back 7

The putamen and globus pallidus together make up the lenticular or lentiform nucleus. These nuclei more or less resemble an ice cream cone lying on its side, w/the putamen representing the ice cream and the globus pallidus the cone.

Front 8

8. Moving from lateral to medial in the horizontal brain section, name the 10 structures you will encounter

Back 8

1. Insula
2. Extreme capsule
3. Claustrum
4. External capsule
5. Putamen
6. External medullary lamina
7. External segment of the globus pallidus
8. Internal medullary lamina
9. Internal segment of the globus pallidus
10. Internal capsule

Front 9

9. What is the internal capsule?

Back 9

The internal capsule is a V shaped collection of fibers going to and from the cortex.

The anterior limb of the internal capsule passes btwn the lentiform nucleus and the head of the caudate. The posterior limb of the internal capsule passes btwn the lentiform nucleus and the thalamus.

Front 10

10. Where is the caudate, thalamus, and lentiform nucleus in relation to the internal capsule?

Back 10

The caudate and thalamus are always medial to the internal capsule while the lentiform nucleus is always lateral to the internal capsule.

Front 11

11. The head and body of the caudate form a bulge where...?

Back 11

The head and body of the caudate form a bulge on the lateral wall of the lateral ventricle, while the tail of the caudate runs along the roof of the temporal horn.

Front 12

12. Where is the thalamus again in relation to the ventricles?

Back 12

The thalamus forms the lateral walls of the third ventricle and lies along the floor of the body of the lateral ventricle.

In a coronal section, if the thalamus is not yet visible, we are still in the anterior limb of the internal capsule.

On the other hand, fi the thalamus can be seen, we are at the level fo the posterior limb of the internal capsule, separating thalamus from lentiform nucleus.

Front 13

13. Where is the substantia niga and the substantia nigra pars reticulata?

Back 13

By following the internal capsule downward, we see the beginnings of the cerebral peduncles of the midbrain. The substantia nigra is visible, just dorsal to the cerebral peduncles.

The substantia nigra has a ventral portion called the substantia nigra parts reticulata, which contains cells very similar to those of the internal segment of the globus pallidus.

Front 14

14. What separates the internal segment of the globus pallidus from the sustantia nigra pars reticulata?

Back 14

The internal capsule.

Front 15

15. Review: what borders the anterior limb of the internal capsule?

Back 15

The anterior limb of the internal capsule is bordered by the head of the caudate medially and the lentiform nucleus laterally.

Front 16

16. Review: what borders the posterior limb of the internal capsule?

Back 16

The posterior limb of the internal capsule is bordered by the thalamus medially and by the lentiform nucleus laterally.

Front 17

17. What is the subthalamic nucleus?

Back 17

Under the thalamus lies the spindle shaped subthalamic nucleus. Unlike the thalamus, the subthalamic nucleus is derived embryologically from the midbrain rather than the forebrain.

Front 18

18. Where do the striatum and globus pallidus get their blood supply?

Back 18

The blood supply to the striatum and globus pallidus is mainly from the lenticulostriate branches of the MCA, although the medial globus pallidus is often supplied by the anterior choroidal atery (branch of internal carotid artery), and the caudate head and anterior potions of the lentiform nucleus are often supplied by the recurrent artery of Heubner (branch of ACA).

Front 19

19. Virtually all inputs to the basal ganglia arrive where?

Outputs leave where?

Back 19

Vitually all inputs to the basal ganglia arrive via the striatum (caudate, putamen, and nucleus accumbens).

Outputs leave the basal ganglia via the internal segment of the globus pallidus and the closely related substantia nigra pars reticulata.

I/O's of the basal ganglia are thus easily visualized as a funnel, w/the spout pointing medially.

Front 20

20. What are the 4 major sources of input to the basal ganglia? For each input, list the major neurotransmitter.

Back 20

1. Projections from entire cerebral cortex (putamen is the most important for motor control) - excitatory pathway and uses glutamate TO STRIATUM
2. Substantia nigra pars compacta (dopaminergic nigrostriatal pathway) excitatory and inhibitory TO STRIATUM
3. Glutamatergic inputs from intralaminar nuclei (centromedian and parafascicular nuclei) - excitatory TO STRIATUM
4. Raphe nuclei provides serotonergic inputs TO BASAL GANGLIA

Front 21

21. Where do basal ganglia outputs arise from?

Which controls which?

Back 21

From the internal segment of the globus pallidus and from the substantia nigra parts reticulata. These pathways use GABA and they are inhibitory.

For motor control, the substantia nigra pars reticulata appears to convey info for the head and neck, while the internal segment of the globus pallidus conveys info for the rest of the body.

Front 22

22. What is the main output of these pathways?

Back 22

The main output of these pathways are to the ventral lateral (VL) and ventral anterior (VA) nuclei of the thalamus via the thalamic fasciculus.

*The more anterior parts of the thalamic fasciculus carry outputs from teh basal ganglia to the anterior portion of VL, whiel the more psoterior parts of the thalamic fasciculus carry cerebellar outputs of the posterior VL.

*Caudal parts of VL receives inputs from Cerebellum

Front 23

23. What are the other thalamic nuclei in which basal ganglia outputs also travel to?

Back 23

The intralaminar nuclei, which project back to teh striatum, and the mediodorsal nucleus, which is inolved primarily in limbic pathways.

In addition, the internal segment fo the globus pallidus and the substantia nigra pars reticulata project to the pontomedullary reticular formation, thereby influencing the descending reticulospinal tract. The substantia nigra pars reticulata also projects to the superior colliculus, to influenc etectospinal pathways.

Front 24

24. What are the 2 predominant pathways from input to output nuclei through the basal ganglia?

Back 24

1. The direct pathway travels from the striatum directly to the internal segment of the globus pallidus or the substantia nigra pars reticulata.

2. The indirect pathway takes a detour from the striatum, first to the external segment of the globus pallidus and then to the subthalamic nucleus, before finally reaching the internal segment of the globus pallidus or the substantia nigra pars reticulata.

Front 25

25. What is the net effect of excitatory input from the cortex thru the direct pathway?

Back 25

Excitation of the thalamus, which will facilitate movements through its connections w/the motor and premotor cortex.

Front 26

26. What is the net effect of excitatory input from the cortex thru the indirect pathway?

Back 26

On the other hand, the net effect of excitation of the indirect pathway will be inhibtion of the thalamus, resulting in inhibition of movements thru connections back to the cortex

*Indirect inhibits

Front 27

27. What are the neurotransmitters in the direct pathway?

Back 27

Striatal projection neurons for both pathways are primarily inhibitory spiny neurons, which contain GABA. In the direct pathway, spiny striatal neurons project to the internal segemtn of the globus pallidus and contain the peptide substance P in addition to GABA.

Output neurons from the internal globus pallidus and substantia nigra pars reticulata to the thalamus are also inhibitory and contain GABA.

Front 28

28. What are the neurotransmitters in the indirect pathway?

Back 28

In the indirect pathway, striatal neurons project to the external segment of the globus pallidus and contain the inhibitory neurotransmitter GABA, plus the peptide enkephalin.

Neurons of the external globus pallidus, in turn, send inhibitory GABAergic projections to the subthalamic nucleus. Excitatory neurons in the subthalamic nucleus containing glutamate then project to the internal segment of the globus pallidus and to the substantia nigra pars reticulata.

Front 29

29. What is dopamine's effect on the direct pathway?

Indirect pathway?

Back 29

Dopamine appears to have excitatory effects on the neurons of the direct pathway, but inhibitory effects on the indirect pathway, which normally has a net excitatory effect on the thalamus.

*Therefore, loss of dopamine will result in net inhibition of the thalamus, through both the direct and the indirect pathways, which may account for the paucity of movement seen in Parkinson's disease.

Front 30

30. What is acetylcholine's effect on the indirect pathway?

Back 30

There are large interneurons in the striatum calls aspiny neurons, some of which contain ACh. Some evidence suggests that these cholinergic interneurons preferentially form excitatory synapses onto striatal neurons of the indirect pathway.

*Removal of cholinergic excitation of the indirect pathway produces a net decrease in inhibition of the thalamus, which may account for the beneficial effects of anticholinergic agents in parkinsonism.

Front 31

31. What is the importance of hemiballismus?

Back 31

In hemiballismus, there are unilateral wild flinging movements of the extremities contralateral to a lesion in the basal ganglia, typically involving the subthalamic nucleus.

*Damage to the subthalamic nucleus could decrease excitation of the internal segment of the globus pallidus, resulting in less inhibition of the thalamus, causing a hyperkinetic movement disorder (Huntingtons).

Front 32

32. What are the 4 channels that the basal ganglia contains for info processing?

Back 32

1. Motor channel
2. Oculomotor channel
3. Prefrontal channel
4. Limbic channel

Front 33

33. Which ones are the dorsal striatal pathways?

Ventral?

Back 33

The motor, oculomotor, and prefrontal channels are the dorsal striatal pathways, while the limbic is the ventral striatal pathways.

Front 34

34. What is the role of the motor channel?

Back 34

The motor is the best known; Cortical inputs travel mainly to the putamen, and output targets are the VL and VA of the thalamus.

From the thalamus, the motor channel continues to the supplementary motor area, premotor cortex, and primary motor cortex.

Front 35

35. What is the role of the oculomotor channel?

Back 35

This channel subserves basal ganglia regulation of eye movements.

The input is from the body of the caudate nucleus. Output is to the frontal eye fields and supplementary eye fields of the frontal lobes; areas important for the higher control of eye movements.

Front 36

36. Prefrontal channel?

Back 36

The prefrontal channel is probably important in cognitive processes involving the frontal lobes.

Input is primarily from the head of the caudate, and output reaches the prefrontal cortex.

Front 37

37. Limbic channel?

Back 37

The limbic channel is an important ventral pathway thru the basal ganglia that is involved in limbic regulation of emotions and motivational drives.

Inputs arise from major areas for the limbic system, such as the nucleus accumbens, ventral caudate, and ventral putamen. Output targets are the anterior cingulate gyrus and medial orbital frontal gyri.

Front 38

38. What is an important relay station for the limbic channel?

Back 38

The mediodorsal nucleus is particularly important to limbic circuitry. Projections from these thalamic nuclei reach the limbic cortex of the anterior cingulate gyrus and medial orbital frontal gyri.

Front 39

39. What is another role of the limbic channel?

Back 39

The limbic channel through the basal ganglia is likely to play a central role in many neurobehavioral and psychiatric disorders.

Front 40

40. What is the importance of the ventral tegmental areas?

Back 40

Another component of this pathway is the dopaminergic projection from the ventral tegmental area, which lies just medial and dorsal to the substantia nigra of the midbrain, at the base of the interpeduncular fossa.

The ventral tegmental area provides dopaminergic inputs to the nucleus accumbens, as well as to other limbic structures and to the frontal lobes. The dopaminergic projections of the ventral tegmental area may be affected in the pathophysiology of schizophrenia and other psychotic disorders.

Front 41

41. The internal segment of the globus pallidus sends outputs to the thalamus through two different pathways. What are they?

Back 41

1. Ansa lenticular
2. Lenticular fasciculus

Front 42

42. What is the ansa lenticularis?

Back 42

This pathway is so named b/c it takes a loop ventrally under the internal capsule before passing dorsally to reach the thalamus.

The ansa lenticularis actually passes slightly rostrally as it loops around the inferior medial edge of the internal capsule, and then it turns back toward the thalamus.

Front 43

43. What is the lenticular fasciculus?

Back 43

Instead of taking a looping course, fibers of the lenticular fasciculus penetrate straight thru the internal capsule. They then pass dorsal to the subthalamic nucleus and ventral to the zona incerta before turning superiorly and laterally to enter the thalamus.

Front 44

44. OK then, what is the zona incerta?

Back 44

The zona incerta is the inferior extension of the reticular nucleus of the thalamus (not the reticular formation).

Front 45

45. Where do the fibers of the ansa lenticularis and lenticular fasciculus join?

Back 45

They join together to form the thalamic fasciculus, which enters the thalamus.

The thalamic fasciculus also contains fibers ascending to the thalamus from the deep cerebellar nuclei.

Front 46

46. What is the H1 field of Forel?

H2?

Back 46

H1 is the thalamic fasiculus

H2 is the lenticular fasciculus, where it lies dorsal to the subthalamic nucleus.

Front 47

47. What is the H field of Forel?

Back 47

This is the region where the ansa lenticularis and lenticular fasciculus join together.

Front 48

48. What is the subthalamic fasciculus?

Back 48

In addition to the ansa lenticularis, lenticular fasciculus, and thalamic fasciculus, there is the subthalamic fasiculus.

This carries fibers of the indirect pathway from the external segment of the globus pallidus to the subthalamic nucleus, and from the subthalamic nucleus to the internal segment of the globus pallidus.

Front 49

49. Again, what is hemiballismus?

Back 49

In hemiballismus there are unilateral wild flinging movements of the extremities contralateral to a lesion in the basal ganglia, typically involving the subthalamic nucleus.

Damage to the subthalamic nucleus could decrease excitation of the internal segment of the globus pallidus, resulting in less inhibition of the thalamus, causing a hyperkinetic movement disorder.

Front 50

50. What is chorea?

Back 50

Chorea is multiple quick, random movements, usually most prominent in the appendicular muscles.

Caused by atrophy of the striatum as in Huntington chorea.

Front 51

51. What is athetosis?

Back 51

Athetosis is slow, swriting movements, which are usually more severe in the appendicular muscles.

Caused by diffuse hypermyelinization of the corpus striatum and thalamus cerebral palsy.

Front 52

52. What are the movement disorders ranked from slowest to fasted movement speed?

Back 52

SLOWEST
↓
1. Bradykinesia, hypokinesia
2. Rigidity
3. Dystonia
4. Athetosis
5. Chorea
6. Ballismus
7. Tics
8. Myoclonus
9. Tremor
↓
FASTEST

Front 53

53. How can dopamine neurons effect both the direct and indirect pathways?

Back 53

The effect of dopamine excites or drives the direct pathway, increasing cortical excitation. Dopamine excites the direct pathway through D1 receptors and inhibits the indirect pathway through D2 receptors.

Front 54

54. What effect do cholinergic neurons have on the indirect pathway?

Back 54

Cholinergic neurons have the opposite effect. ACh drives the indirect pathway, decreasing cortical excitation.

Front 55

55. What is dystonia?

Back 55

Dystonia refers to a slow, prolonged movement involving predominantly the truncal musculature. Dystonia often occurs with athetosis.

Blepharospasm and writer's cramp are all examples of dystonic movements.

Front 56

56. What causes palatal myoclonus (clinking sounds)?

Back 56

Palatal myoclonus is typically caused by lesions of the central tegmental tract, most commonly w/brainstem infarcts.

Front 57

57. What is pallidotomy?

Back 57

For Parkinson's disease that has progressed to severe on-off swings despite medical therapy, pallidotomy can provide substantial improvement in bradykinesia, rigidity, and medication -related dyskinesias. In this procedure a lesion is placed stereotactically in the ventral posterior portion of the globus pallidus. The lesion interrupts the inhibitory output pathway carried by the ansa lenticularis from the medial globus pallidus to the ventral lateral nucleus of the thalamus.

Removal of this inhibition may explain why bradykinesia and rigidity are improved.

Front 58

58. What is a thalmotomy?

Back 58

For debilitating tremor, especially in cases of severe essential tremor not responding to medications, thalamotomy can be beneficial. In this procedure a lesion is placed sterotactically in the posterior portion of the ventral lateral nucleus of the thalamus.

Front 59

59. Involuntary, wild flinging movements of the right arm and leg

Back 59

The most likely clinical localization is left subthalamic nucleus or left stratum.

Front 60

60. Irregular jerking movements, slightly decreased tone, and unsteady gait; moderately slowed saccadic eye movements; flat affect, argumentative, and denied having nay involuntary movements

Back 60

This pt has a bilateral hyperkinetic movement disorder, best described as mild tic or chorea. The most likely Dx is Huntington's disease.

Front 61

61. Asymmetric bradykinesia, cogwheel rigidity, and resting tremor; stooped gait w/short steps, decreased arm swing, en bloc turning, and retropulsion; significant benefit from levodopa; gradual progression over a period of years

Back 61

Idiopathic Parkinson's disease.

Front 62

62. Bilateral bradykinesia and waxy rigidity; no tremor; gait slow, shuffling w/retropulsion; no significant benefit from levodopa; gradual progression over a period of years; masked facies, slow saccades, slow dysarthric speech

Back 62

Atypical Parkinsonism. ***Atypical parkinsonism alone, w/o other significant abnormalities, can be seen in striatonigral degeneration (a form of multisystem atrophy)

Front 63

63. How does one differentiate striatonigral degeneration from Parkinson's?

Back 63

In striatonigral degeneration, as in idiopathic Parkinson's disease, there is loss of dopaminergic neurons from the substantia nigra pars compacta.

*In striatonigral degeneration, however, the striatal neurons degenerate as well. Therefore, administration of levodopa is usually not as beneficial to these pts as in Parkinson's disease.

Front 64

64. What are demyelinating diseases?

Back 64

Demyelinating diseases of the CNS are acquired conditions characterized by preferential damage to myelin, with relative preservation of axons.

The clinical deficits are due to the effect of myelin loss on the transmission of electrical impulses along axons.

Front 65

65. What is MS?

Back 65

MS is an autoimmune demyelinating disorder characterized by distinct episodes of neurological deficits separated in time, attributable to white matter lesions that are separated in space.

Affects 1/1,000 persons in most of US and Europe. Women are affected 2x more than men.

Front 66

66. What is the typical presentation of a pt w/MS?

Back 66

The clinical course of the illness evlolves as relapsing and remitting episodes of neurologic deficit during variable interval of time (wks to mos to yrs) followed by gradual, partial recovery of neurologic function.

The frequency of relapses tends to decrease during the course of time, but there is a steady neurologic deterioration in most patients.

Front 67

67. What causes the lesions in MS?

Back 67

The lesions of MS are caused by a cellular immune response that is inappropriately directed against the components of the myelin sheath.

Front 68

68. Genetic susceptibility of MS

Back 68

The likelihood of developing this autoimmune process is influenced by genetic and environmental factors.

Risk is 15x higher when the disease is present in a first degree relative and higher for twins.

Genetic linkage of MS susceptibility to the DR2 extended haplotype of the MHC is also well established.

The molecular basis for influence of this particular haplotype on the risk of developing MS is unknown, other genetic local are involved as well.

Front 69

69. What initiates the immune response in MS?

Back 69

The available evidence indicates that the disease is initiated by CD4+ TH1 cells that react against self myelin antigens and secrete cytokines, such as IFN-γ, that activate macrophages.

The demyelination is caused by these activated macrophages and their injurious products.

The infiltrate in plaques and surrounding regions of the brain consists of T cells (mainly CD4+, some CD8+), and macrophages.

Antibodies are also freq present. Therapies are being developed that modulate or inhibit TH1 responses and block the recruitment of T cells into the brain.

Front 70

70. Morphology of MS

Back 70

Since MS is a white matter disease and gray matter covers much of the surface of hemispheres, macroscopic exam of the outer cortex is unremarkable.

Evidence of disease may be found on the surface of the brainstem or along the spinal cord, where myelinated fiber tracts course superficially; here lesions appear as multiple, well-circumscribed, somewhat depressed, glassy, gray-tan, irregularly shaped plaques, both on external exam and on section.

In the fresh state, these have firmer consistency than the surrounding white matter (sclerosis).

Front 71

71. Morphology of the MS plaques

Back 71

Lesions (plaques) are sharply defined areas of gray discoloration of white matter occurring esp around the ventricles but potentially located anywhere in the CNS.

Active plaques show myelin breakdown, lipid-laden macrophages, and relative axonal preservation. Lymphocytes and mononuclear cells are prominent at the edges of plaques and around venules in and around plaques.

Inactive plaques lack the inflammatory cell infiltrate and show gliosis; most axons within the lesion persist but remain unmyelinated.

Front 72

72. Location of MS plaques

Back 72

Plaques can be found throughout the white matter of the neuraxis; they may also extend into the gray matter structures, as these have myelinated fibers running through them.

Plaques commonly occur beside the lateral ventricles and may be demonstrated to follow the course of paraventricular veins when the surface of the ventricle is inspected en face. They are also frequent in the optic nerves and chiasm, brain stem ascending and descending fiber tracts, cerebellum, and spinal cord.

Front 73

73. What is the morphology of active plaques?

Back 73

In an active plaque, there is evidence of ongoing myelin breakdown with abundant macrophages containing lipid-rich, PAS-positive debris.

Inflammatory cells, including both lymphocytes and monocytes, are present, mostly as perivascular cuffs, especially at the outer edge of the lesion.

Small active plaques are often centered on small veins.

Front 74

74. What happens w/in an active plaque?

Back 74

W/in a plaque, there is relative preservation of axons and depletion of oligodendrocytes. In time, astrocytes undergo reactive changes.

Front 75

75. What about an inactive plaque?

Back 75

As lesions become quiescent, there is lessening of the inflammatory cell infiltrate and of macrophages.

W/in the center of an inactive plaque, ***little to no myelin is found, and there is a reduction in the number of oligodendrocyte nuclei; instead astrocytic proliferation and gliosis are prominent.

Front 76

76. What are shadow plaques? What is their significance?

Back 76

In some MS plaques known as shadow plaques, the border btwn normal and affected white matter is not sharply circumscribed.

In this type of lesion, some abnormally thinned-out myelin sheaths can be demonstrated at the outer edges. This has been interpreted either as evidence of partial and incomplete myelin loss or as remyelination by surviving oligodendrocytes.

Front 77

77. What are the 4 patterns of active plaques?

Back 77

I. Those that are sharply demarcated and centered on blood vessels, WITH deposition of Ig and complement
II. Those that are sharply demarcated and centered on blood vessels, W/O deposition of Ig and complement
III. Those that are less demarcated and are not centered on vessels with widespread oligocendrocyte apoptosis
IV. Those that are less demarcated and are not centered on vessels with only central oligocendrocyte apoptosis

Front 78

78. What is the significance of these 4 patterns of active plaques?

Back 78

Autopsy studies have shown that only one pair of patterns (I/II or III/IV) is present in a given individual.

Front 79

79. Clinical features of MS

Back 79

Although MS lesions can occur anywhere in the CNS and, as a consequence, may induce a wide range of manifestations, certain patterns of neurologic symptoms are commonly observed.

Unilateral visual impairment during the course of a few days, due to involvement of the optic nerve (optic neuritis) is a frequent initial manifestation of MS.

Involvement of the brainstem produces cranial nerve signs, ataxia, nystagmus, and internuclear ophthalmoplegia from interruption of the fibers of the medial longitudinal fasciculus (MLF).

Spinal cord lesions give rise to motor and sensory impairment of trunk and limbs, spasticity, and difficulties w/the voluntary control of bladder function.

Front 80

80. CSF in patients with MS shows...?

Back 80

Exam of the CSF in MS patients shows a mildly elevated protein level, and in one third of cases, there is moderate pleocytosis. The proportion of gamma globulin in increased, and most MS patients show ***oligoclonal bands***.

This increase in CSF immunoglobulin is the result of proliferation of B cells within the nervous system; the target epitopes of these antibodies are wildly variable.

Front 81

81. What is neruromyelitis optica (Devic disease)?

Back 81

Some individuals, especially Asians, develop a demyelinating disease similar to MS with presenting symptoms of bilateral optic neuritis and prominent spinal cord involvement.

This disease is referred to as neuromyelitis optica or Devic disease.

It may be rapidly and relentlessly progressive, following a relapsing-remitting course, or manifest as a single episode without subsequent relapses.

The lesions in Devic disease are similar in histologic appearance to MS, *although they are considerably more destructive, and gray matter involvement of the spinal cord can be striking*.

Front 82

82. What is acute MS (Marburg form)?

Back 82

Acute MS (Marburg form) tends to occur in *young individuals and is characterized clinically by a fulminant course during a period of several months.*

On pathological examination, the plaques are large and numerous, and there is widespread destruction of myelin with some axonal loss.

Front 83

83. What is acute disseminated encephalomyelitis (ADEM)?

Back 83

ADEM is a monophasic demyelinating disease that follow either a viral infection or, rarely, a viral immunization. Symptoms typically develop a week or two after the antecedent infection and include evidence of diffuse brain involvement with headache, lethargy, and coma rather than focal findings, as seen in MS.

Symptoms progress rapidly, with a fatal outcome in as many as 20% of cases; in the remaining patients there is complete recovery.

Front 84

84. Morphology of ADEM

Back 84

Macroscopic exam of the brain shows only *grayish discoloration around white matter vessels. On microscopic exam, myelin loss with relative preservation of axons can be found throughout the white matter. In the early stages of the disease, polymorphonuclear leukocytes can be found within the lesions; later, mononuclear infiltrates predominate.

The breakdown of myelin is associated w/the accumulation of lipid laden macrophages.

Front 85

85. What is acute necrotizing hemorrhagic encephalomyelitis (ANHE)?

Back 85

ANHE is a fulminant syndrome of CNS demyelination, typically affecting young adults and children.

*The illness is almost invariably preceded by a recent episode of upper respiratory infection.*

Sometimes, it is due to Mycoplasma pneumoniae, but often it is of indeterminate cause.

The disease is fatal in many patients, but some have survived with minimal residual symptoms.

Front 86

86. Morphology of ANHE

Back 86

Shows histologic similarities with ADEM, including perivenular distribution of demyelination and widespread dissemination throughout the CNS.

*However, the lesions are much more devastating than those of ADEM and include destruction of small blood vessels, disseminated necrosis of white and gray matter with acute hemorrhage, fibrin deposition, abundant neutrophils, and scattered lymphocytes recognizable in less severely damaged areas and in foci of demyelination.*

Front 87

87. ADEM vs. ANHE

Back 87

ADEM may represent an acute autoimmune reaction to myelin and ANHE may represent a hyperacute variant, although no inciting antigens have been identified.

Front 88

88. What is central pontine myelinolysis?

Back 88

Characterized by loss of myelin (with relative preservation of axons and neuronal cell bodies) in a roughly symmetric pattern involving the basis pontis and portions of the pontine tegmentum but sparing the periventricular and subpial regions.

Lesions may be found more rostrally; it is extremely rare for the process to extend below the pontomedulalry junction.

Extrapontine lesions occur in the supratentorial compartment, with similar appearance an apparent etiology.

Front 89

89. What causes central pontine myelinolysis?

Back 89

The condition is believed to be caused by rapid correction of hyponatremia; however, alternative pathogenetic hypotheses attribute the disorder to extreme serum hyperosmolarity or other metabolic imbalance.

Front 90

90. Clinical presentation of central pontine myelinolysis

Back 90

It is that of a rapidly evolving quadriplegia; radiologic imaging studies localize the lesion to the basis pontis.

It occurs in a variety of clinical settings, including alcoholism, severe electrolyte or osmolar imbalance, and orthotopic liver transplantation.

Front 91

91. What is Marchiafava-Bignami disease?

Back 91

This is a rare disorder of myelin characterized by relatively *symmetric damage* to the myelin of central fibers of the corpus callosum and anterior commissure.

Front 92

92. What are degenerative diseases?

Back 92

These are diseases of gray matter characterized principally by the progressive loss of neurons w/associated secondary changes in white matter tracts.

Front 93

93. What are 2 general characteristics of degenerative diseases?

Back 93

1. The pattern of neuronal loss is selective, affecting one or more groups of neurons while leaving others intact.

2. The diseases arise w/o any clear inciting event in pts w/o previous neurologic deficits.

Front 94

94. What is a common theme among the neurodegenerative disorders?

Back 94

A common theme is the development of protein aggregates that are resistant to normal cellular mechanisms of degradation thru the ubiquitin-proteasome system.

These aggregates can be recognized histologically as inclusions, which often form the diagnostic hallmarks of these different diseases.

Front 95

95. What is Alzheimer disease?

Back 95

AD is the most common cause of dementia in the elderly. The disease usually becomes clinically apparent as insidious impairment of higher intellectual function, w/alterations in mood and behavior.

Later, progressive disorientation, memory loss, and aphasia indicate severe cortical dysfunction, and eventually, in 5-10 years, the pt becomes profoundly disabled, mute, and immobile.

Front 96

96. Who is most likely to get AD?

Back 96

Pts rarely become symptomatic before 50, but the incidence of the disease rises w/age, and the prevalence doubles every 5 years.

Most cases are sporadic, although at least 5-10% of cases are familial. Pathologic changes identical to those observed in AD occur in almost all individuals w/trisomy 21 who survive beyond 45 years.

Front 97

97. What does the gross exam of the brain look like in AD?

Back 97

Macroscopic exam shows a variable degree of cortical atrophy w/widening of the cerebral sulci that is most pronounced in the frontal, temporal, and parietal loves.

With significant atrophy, there is compensatory ventricular enlargement (hydrocephalus ex vacuo) secondary to loss of parenchyma.

Front 98

98. What are the 3 major microscopic abnormalities of AD?

Back 98

1. Neuritic (senile) plaques
2. Neurofibrillary tangles
3. Amyloid angiopathy

All of these may be present to a lesser extent in the brains of elderly nondemented individuals.

Front 99

99. What brain regions are affected first in AD?

Back 99

Pathologic changes (specifically plaques, tangles, and the associated neuronal loss and glial reaction) are evident earliest in the entorhinal cortex, then spread thru the hippocampal formation and isocortex, and then extend into the neocortex.

Front 100

100. What are neuritic plaques?

Back 100

Senile or neuritic plaques are focal, spherical collections of dilated, tortuous, silver staining neuritic processes (dystrophic neurites) often around a central amyloid core, which ma be surrounded by a clear halo. Microglial cells and reactive astrocytes are present at their periphery.

Front 101

101. Where are these neuritic plaques located?

Back 101

They can be found in the hippocampus and amygdala as well as in the neocortex, although there is usually relative sparing of primary motor and sensory cortices (this also applies to neurofibrillary tangles).

Front 102

102. What the hell are these plaques composed of?

Back 102

The dystrophic neurites contain paired helical filaments as well as synaptic vesicles and abnormal mitochondria. The amyloid core, which can be stained by Congo red, contains several abnormal proteins.

The dominant component of the plaque core is Aβ, a peptide derived through specific processing events from a larger molecule, amyloid precursor protein (APP).

Front 103

103. What are diffuse plaques in AD? What is their significance?

Back 103

Immunostaining of Aβ demonstrates the existence in some pts of amyloid peptide deposits in lesions lacking the surrounding neuritic reaction.

These lesions are called diffuse plaques and they are found in superficial portions of cerebral cortex as well as in basal ganglia and cerebellar cortex.

*Diffuse plaques appear to represent an early stage of plaque development.

Front 104

104. What is the main difference between neuritic and diffuse plaques?

Back 104

While neuritic plaques contain both Aβ₄₀ and Aβ₄₂, diffuse plaques are predominantly made up of Aβ₄₂.

Front 105

105. What are neurofibrillary tangles?

Back 105

Neurofibrillary tangles are bundles of filaments in the cytoplasm of the neurons that displace or encircle the nucleus. In pyramidal neurons, they often have an elongated "flame" shape; in rounder cells, the basket weave of fibers around the nucleus takes on a rounded contour ("globose" tangles).

*Neurofibrillary tangles are visible as basophilic fibrillary structures but are clearly seen with silver staining.

Front 106

106. Where are neurofibrillary tangles found?

Back 106

They are commonly found in cortical neurons, esp in the entorhinal cortex, as well as in other sites such as pyramidal cells of the hippocampus, the amygdala, the basal forebrain, and the raphe nuclei.

*They are insoluble and resistant to clearance, thus remaining visible in tissue sections as "ghost" or "tombstone" tangles long after the death of the parent neuron.

Front 107

107. What the hell are neurofibrillary tangles made of?

Back 107

These tangles and composed predominantly of paired helical filaments along w/some straight filaments that appear to have a comparable composition.

A major component of paired helical filaments is abnormally hyperphosphorylated forms of the protein tau, an axonal microtubule-associated protein that enhances microtubule assembly.

Other antigens include MAP2, and ubiquitin.

Front 108

108. What are neuropil threads?

Back 108

Paired helical filaments are also found in the dystrophic neurites that form the outer portions of neuritic plaques and in axons coursing through the affected gray matter as neuropil threads.

Front 109

109. What is central amyloid angiopathy (CAA)?

Back 109

CAA is an almost invariable accompaniment of Alzheimer disease; however, ti can also be found in brains of individuals w/o AD.

Vascular amyloid is predominantly Aβ₄₀, as is also true when CAA occurs w/o AD.

Front 110

110. What is granulovaculoar degeneration?

Back 110

Granulovaculoar degeneration is the formation of small, clear intraneuronal cytoplasmic vacuoles, each of which contains an argyrophilic granule. While it occurs w/normal aging, it is most commonly found in great abundance in hippocampus and olfactor bulb in AD.

Front 111

111. What are Hirano bodies? Where are they most commonly found?

Back 111

Hirano bodies, found especially in AD, are elongated, glassy, eosinophilic bodies consisting of paracrystalline arrays of beaded filaments, with actin as their major component.

They are found most commonly w/in hippocampal pyramidal cells.

Front 112

112. What correlates better w/the degree of dementia in AD - neurofibrillary tangles or neuritic plaques?

Back 112

Neurofibrillary tangles

Front 113

113. What is the best correlation of the severity of dementia in AD?

Back 113

The loss of synapses.

Aβ is a critical molecule in the pathogenesis of this dementia.

Front 114

114. How does Aβ cause AD?

Back 114

Aβ aggregates readily, forming β-pleated sheets, and binds Congo red. It is relatively resistant to degradation, elicits a response from astrocytes and microglia, and can be directly neurotoxic.

Front 115

115. Where does Aβ come from?

Back 115

The Aβ peptides are derived through processing of APP. APP is a protein of uncertain cellular function that is expressed on the cell surface. A soluble form of APP can be released from the cell surface by proteolytic cleavage, by an enzymatic activity termed α-secretase. Molecules of APP that have undergone this cleavage cannot give rise to the Aβ fragment.

*However, surface APP can also be endocytosed and may then undergo processing to generate Aβ peptides that are less soluble and tend to aggregate into amyloid fibrils. These are generated through cleavage by β-secretase and cleavage w/in the transmembrane domain by γ-secretase. It is suggested that this γ-secretase gives rise to Aβ.

Front 116

116. What are the four genes involved in AD?

Back 116

1. The gene for APP on chromosome 21. Mutations in the APP gene all result in increased generation of Aβ.
2. Presenilin-1 (PS1) on chromsome 14
3. Presenilin-2 (PS2) on chromosome 1
4. Apolipoprotein E (ApoE) on chromosome 19

Front 117

117. What is the significance of the presenilin gene mutations?

Back 117

The presenilin gene mutations are linked to early-onset familial Alzheimer disease and probably account for the majority of early onset familial AD pedigrees.

***The cellular phenotype of these mutations was an increased level of Aβ generation, particularly Aβ₄₂.

Front 118

118. How does presenilin affect Aβ generation?

Back 118

The presenilins are a component of γ-secretase and possibly are the portion of a multiprotein complex containing the active proteolytic site.

Front 119

119. What is the importance of Apolipoprotein E (ApoE) mutations?

Back 119

ApoE mutations increases the risk of AD and lowers the age at onset of the disease.

People w/these mutations have a greater Aβ burden in their brains, as ApoE can bind Aβ and is present in plaques.

Front 120

120. How, exactly, do aggregates of Aβ and larger fibrils damage neurons?

Back 120

They are directly neurotoxic and can elicit various cellular responses, including oxidative damage and alterations in calcium homeostasis.

There is evidence that the inflammatory response that accompanies Aβ deposition may have both protective effects (through assisting clearance of the aggregated peptide) and injurious effects.

Front 121

121. What are the clinical features of AD?

Back 121

The progression of AD is slow but relentless, w/a symptomatic course often running more than 10 years. Initial symptoms are forgetfulness and other memory disturbances; with progression of the disease, other symptoms emerge, including language deficits, loss of mathematical skills, and loss of learned motor skills.

In the final stages of AD, pts may become incontinent, mute, and unable to walk. Intercurrent disease, often pneumonia, is usually the terminal event in these pts.

Front 122

122. What is frontotemporal dementia w/Parkinsonism linked to chromosome 17 (FTD(P)-17)?

Back 122

(FTD(P)-17) is a genetically determined disorder in which the clinical syndrome of a frontotemporal dementia is often accompanied by parkinsonian symptoms. In these families, the disease has been mapped to chromosome 17; in particular, it has been linked to a variety of mutations in the *tau gene.

Front 123

123. What is the significance of tau?

Back 123

Tau is a microtubule binding protein that has numerous sites of potential phosphorylation and exists in 6 splice forms as the result of alternative splicing of exons 2, 3, and 10.

The protein contains either 3 or 4 copies of the microtubule binding domain depending on whether exon 10 is included (4 repeat tau) or not (3 repeat tau).

Front 124

124. What is the morphology of (FTD(P)-17)?

Back 124

There is evidence of atrophy of frontal and temporal lobes in various combos and to various degrees. The pattern of atrophy can often be predicted in part by the clinical symptoms. The atrophic regions of cortex are marked by neuronal loss and gliosis as well as the presence of tau-contaning neurofibrillary tangles. These tangles may contain either 4 repeat tau or a mixture of 3 and 4 repeat tau, depending on the underlying genetic basis for the disease.

Nigral degeneration may also occur. Inclusions can also be found in glial cells in some forms of the disease.

Front 125

125. What causes (FTD(P)-17)?

Back 125

In some but not all pedigrees, there is linkage to mutations in the tau gene. The mutations fall into several categories; coding region mutations and intronic mutations that affect the splicing of exon 10.

The intronic mutations result in increased production of 4 repeat forms of tau. Coding region mutations appear to have several different consequences, including alterations in the interaction of tau w/microtubules (mutations in exon 10 will change this interaction only for 4 repeat tau) and altering the intrinsic tendency to aggregate.

Front 126

126. What is Pick disease (lobar atrophy)?

Back 126

Pick disease is a rare, distinct, progressive dementia characterized clinically by early onset of behavioral changes together w/alterations in personality (frontal lobe signs) and language disturbances (temporal lobe signs).

While most cases are sporadic, some familial forms identified are linked to mutations in tau.

Front 127

127. What is the morphology of the brain in a gross exam in Pick disease?

Back 127

The brain shows a pronounced, frequently asymmetric, atrophy of the frontal and temporal lobes w/conspicuous sparing of the posterior 2/3s of the superior temporal gyrus and only rare involvement of either the parietal or occipiatal lobe.

The atrophy can be severe, reducing the gyri to a thin wafer ("knife-edge" appearance).

Front 128

128. How can one distinguish the atrophy of a brain in AD from Pick disease?

Back 128

The pattern of lobar atrophy is often prominent enough to distinguish Pick disease from AD on macroscopic exam.

In addition to the localized cortical atrophy, there may also be bilateral atrophy of the caudate nucleus and putamen.

Front 129

129. What are the morphologic features of Pick disease on microscopic exam?

Back 129

On microscopic exam, neuronal loss is most severe in the outer 3 layers of the cortex.

***Some of the surviving neurons show a characteristic swelling (Pick cells) or contain Pick bodies, which are cytoplasmic, round to oval, filamentous inclusions that are only weakly basophilic but stain strongly with silver methods.

Front 130

130. What are these Pick bodies made of?

Back 130

Pick bodies are composed of straight filaments, vesiculated endoplasmic reticulum, and paired helical filaments that are immunocytochemically similar to those found in AD and contain 3 repeat tau.

Unlike the neurofibrillary tangles of AD, Pick bodies do not survive the death of their host neuron and do not remain as markers of the disease.

Front 131

131. What is progressive supranuclear palsy (PSP)?

Back 131

PSP is an illness characterized clinically by truncal rigidity w/dysequilibrium and nuchal dystonia; pseudobulbar palsy and abnormal speed; ocular disturbances, including vertical gaze palsy progressing to difficulty w/all eye movements; and mild progressive dementia in most pts.

The onset of the disease is usually btwn the 5ht and 7th decades, and males are affected approx 2x as freq as females. The disease is often fatal w/in 5-7 years of onset.

Front 132

132. What is the morphology of progressive supranuclear palsy?

Back 132

There is widespread neuronal loss in the globus pallidus, subthalamic nucleus, substantia nigra, colliculi, periaqueductal gray matter, and dentate nucleus of the cerebellum. Globose neurofibrillary tangles are found in these affected regions, in neurons as well as in glia.

*Ultrastructural analysis reveals 15-nm straight filaments that are composed of 4 repeat tau.

Front 133

133. Are mutations in tau responsible for PSP?

Back 133

Mutations in tau have not been found in PSP.

Analysis of the tau gene has shown that there is an extended haplotype. Of the two haplotypes, one of them is strongly overrepresented in PSP patients.

Front 134

134. What is corticobasal degeneration (CBD)?

Back 134

CBD is a disease of the elderly, and it is characterized by extrapyramidal rigidity, asymmetric motor disturbances (jerking movements of limbs: "alien hand"), and sensory cortical dysfunction (apraxias, disorders of language); cognitive decline occurs, and may be prominent in some cases.

*The same extended tau haplotype is linked to CBD as to PSP.

Front 135

135. What is the morphology of CBD?

Back 135

On macroscopic exam, there is cortical atrophy, mainly of the motor, premotor and anterior parietal lobes. *The regions of cortex show severe loss of neurons, gliosis, and "ballooned" neurons (neuronal achromasia).

Tau immunoreactivity has been found in astrocytes ("tufted astrocytes"), oligodendrocytes ("coiled bodies"), basal ganglionic neurons, and cortical neurons.

Front 136

136. What are the most specific pathologic findings of CBD?

Back 136

Clusters of tau-positive processes around an astrocytes ("astrocytic plaques") and the presence of tau-positive threads in gray and white matter may be the most specific findings of CBD.

Similar to PSP, the tau deposits in CBD contain predominantly 4 repeat tau.

Front 137

137. What is motor neuron disease inclusion dementia?

Back 137

Tau-negative, ubiquitin-positive inclusions can be found in superficial cortical layers in temporal and frontal lobe and in the dentate gyrus.

This pattern of path is termed motor neuron disease inclusion dementia. It has also been ascribed in the absence of ALS-like pathology.

Front 138

138. What types of vascular injury to the brain can result in dementia?

Back 138

Small areas of infarction (granular atrophy from cortical microinfarcts, multiple lacunar infarcts, cortical laminar necrosis associated w/reduced perfusion/oxygenation) and diffuse white matter injury (Binswanger disease, CADASIL).

Additional, dementia has been associated w/so called strategic infarcts, which are usually embolic and involve brain regions such as the hippocampus, dorsomedial thalamus, or frontal cortex including cingulate gyrus.

Front 139

139. What is the interaction between vascular injury and AD?

Back 139

It has been found that pts with vascular changes above a certain threshold have a lower burden of plaques and tangles for their level of cognitive impairment than do those w/o vascular base cerebral pathology.

Front 140

140. What is Parkinsonism?

Back 140

Parkinsonism is a clinical syndrome characterized by diminished facial expression, stooped posture, slowness of voluntary movement, festinating gait, rigidity, and a "pill-rolling" tremor.

This type of motor disturbance is seen in conditions that have in common damage to the nigrostriatal dopaminergic system.

Front 141

141. What are four main diseases that involve the nigrastriatal system?

Back 141

1. Parkinson disease
2. Multiple system atrophy
3. Postencephalitic parkonsonism
4. Progressive supranuclear palsy and corticobasal degeneration

Front 142

142. What are the typical morphologic findings in parkinsons?

Back 142

The typical macroscopic findings are pallor of the substantia nigra and locus ceruleus.

On microscopic exam, there is loss of the pigmented, catecholaminergic neurons in these regions associated w/gliosis. *Lewy bodies may be found in some of the remaining neurons.

Front 143

143. What are Lewy bodies?

Back 143

***Lewy bodies are single or multiple, cytoplasmic, eosinophilic, round to elongated inclusions that often have a dense core surrounded by a pale halo***

Front 144

144. What are Lewy bodies made of?

Back 144

Lewy bodies are composed of fine filaments, densely packed in the core but loose at the rim.

These filaments are composed of α-synuclein; neurofilament antigens, parkin, and ubiquitin are also present.

Front 145

145. What is the main malfunction in Parkinsons?

Back 145

The dopaminergic neurons of the substantia nigra project to the striatum, and their degeneration in Parkinson disease is associated w/a reduction int he striatal dopamine content. The severity of the motor syndrome is proportional to the dopamine deficiency, which can at least in part be corrected by replacement therapy with L-dopa.

Treatment does not, however, reverse the morphologic changes or arrest the progress of the disease; and w/progression, drug therapy tends to become less effective.

Front 146

146. What can cause an acute parkinsonian syndrome and destruction of neurons in the substantia nigra?

Back 146

Following exposure to MPTP, a contaminant in the illicit synthesis of psychoactive meperidine analogs. Action by MAO B is required for the toxicity of MPTP.

Also, pesticide exposure may increase the risk of PD, while caffeine and nicotine may be protective.

Front 147

147. A gene encoding _______ was identified as the basis for inherited autosomal dominant for of PD.

Back 147

α-synuclein, an abundant lipid-binding protein associated w/synapses.

However, only rare cases of PD have mutations in α-synuclein. Families w/autosomal dominant PD and genomic triplication of the region containing the gene for α-synuclein have been found.

***This suggests that gene dosage may also be related to PD, similar to the relationship btwn AD and trisomy 21.

Front 148

148. What about the gene encoding the protein parkin?

Back 148

A second gene, encoding the protein parkin, was linked w/a juvenile autosomal recessive form of PD. Alterations including deletions and nonsense and missense mutations resulting in loss of parkin functions have been found in various families.

***These mutations are most prevalent in the population of young-onset PD pts.

Front 149

149. What is the role of parkin?

Back 149

Parkin functions as an E3 ubiquitin ligase, with α-synuclein as one of its substrates.

Front 150

150. What are the clinical features of PD?

Back 150

About 10-15% of pts with PD develop dementia, w/increasing incidence w/advancing age.

Characteristic features of this disorder include a fluctuating course, hallucinations, and prominent frontal signs.

While many affected individuals also have pathologic evidence of AD, the dementia in others is attributed to widely disseminated Lewy bodies that are less distinct but still demonstrable by staining for ubiquitin and α-synuclein, particularly in the cerebral cortex but also involving the amygdala and brainstem neurons.

Front 151

151. What is dementia with Lewy bodies (DLB)?

Back 151

Similar pathology, with this distribution of cortical Lewy bodies, can also be found in individuals w/symptoms of dementia as their primary complaint 0 this is the disorder recognized as dementia with Lewy bodies (DLB).

Front 152

152. What is the treatment for PD?

Back 152

Sympatomatic resposne to L-dopa therapy is one of the features, in addition to clinincal sign and symptoms, that support a Dx of PD.

While L-dopa is often extremely effective in symptomatic treatment, it does not significantly alter the intrinsically progressive nature of the disease. Over time, L-dopa becomes less able to help the pt through symptomatic relief and begins to lead to fluctuations in motor function on its own.

Front 153

153. What is multiple system atrophy?

Back 153

MSA is now used to describe a group of disorders characterized by the presence of glial cytoplasmic inclusions (GCIs), typically w/in the cytoplasm of oligodendrocytes.

With recognition of GCIs, three entities of striatonigral degeneration, Shy-Drager syndrome, and olivopontocerebellar atrophy, were gathered into a single patholggic category.

*The identification of α-synuclein as the major component of the inclusions has resulted in this disorder being considered as a synucleinopathy. Unlike PD, no mutation sin the gene for this synaptic protein have been found in cases of MSA.

Front 154

154. What is the morphology of MSA?

Back 154

On macroscopic exam, there is typically atrophy of the cerebellum, including the cerebellar peduncles, pons, (especially the basis pontis), medulla (especially the inferior olive), substantia nigra, and striatum (especially putamen).

These brain regions show evidence of neuronal loss as well as variable numbers of neuronal cytoplasmic and nuclear inclusions.

Front 155

155. What are the diagnostic features of MSA?

Back 155

The cytoplasmic inclusion of MSA were originally demonstrated with silver impregnation methods and by immunostaining which stain α-synuclein as well as ubiquitin and αB-crystallin

***The inclusions are ultrastructurally distinct from those found in other neurodegenerative diseases and are composed primarily of 20-40 nm tubules. It appears the glial cytoplasmic inclusions can occur in the absence of neuronal loss, suggesting that they may represent a primary pathologic event.

Front 156

156. What are the clinical features of MSA?

Back 156

The two principal symptoms of MSA are parkinsonism and autonomic dysfunction, particularly orthostatic hypotension.

Parkinsonism can be related to the degree of cell loss from the substantia nigra and striatum; ataxia w/changes in the circuits involving the pons, cerebellum, and inferior olive; and autonomic symptoms with cell loss from the cetecholaminergic ncueli of the medulla and the IML column of the spinal cord.

Front 157

157. What is Huntington disease?

Back 157

HD is an inherited autosomal dominant disease characterized clinically by progressive movement disorders and dementia and histologically degeneration of striatal neurons.

The movement disorder chorea consists of jerky, hyperkinetic, sometimes dystonic movements affecting all parts of the body; pts may later develop parkinsonism w/bradykinesia and rigidity. The disease is relentlessly progressive, w/an average course of about 15 years to death.

Front 158

158. What are the macroscopic characteristics of the brain in HD?

Back 158

On macroscopic exam, the brain is small and shows ***striking atrophy of the caudate nucleus***, and less dramatically, the putamen. The globus pallidus may be atrophied secondarily, and the lateral and third ventricles are dilated.

Atrophy is freq also seen in the frontal lobe, less often in the parietal lobe, and occasionally in the entire cortex.

Front 159

159. What are the microscopic characteristics of the brain in HD?

Back 159

On microscopic exam, there is ***severe loss of striatal neurons; the most dramatic changes are found in the caudate nucleus, especially in the tail and portions nearer the ventricle.***

Pathologic abnormalities develop in a medial-to-lateral direction in the caudate and from dorsal to ventral in the putamen. The nucleus accumbens is the best preserved structure.

Front 160

160. Which neurons are affected first in HD?

Back 160

Both the large and small neurons are affected, but loss of the small neurons generally precedes that of the large. The medium-sized, spiny neurons that use GABA as their neurotransmitter, along w/enkephalin, dynorphin, and substance P, are especially affected.

Front 161

161. Which two populations of neurons are relatively spared in HD?

Back 161

1. The diaphorase-positive neurons that contain nitric oxide synthase
2. The large cholinesterase-positive neurons

Front 162

162. What is the functional significance of the loss of medium spiny striatal neurons in HD?

Back 162

The significance of the loss is to dysregulate the basal ganglia circuitry that modulates motor output.

The loss of the striatal inhibitory output to the external portion of the globus pallidus results in increased inhibitory input to the subthalamic nucleus. This inhibition of the subthalamic nucleus prevents it from exerting its regulatory effects on motor activity and thus leads to choreathetosis.

Front 163

163. What gene is involved in HD?

Back 163

The HD gene (genius!). It encodes a protein called huntintin. The coding region of the gene contains a polymorphic CAG trinucelotide repeat encoding a polyglutamine region of the protein.

Normal HD genes contain 6-35 copies of the repeat; in disease causing genes, the number of repeats is increased. Also, the larger the number of repeats, the earlier the onset of the disease.

Front 164

164. So, what's the significance of the CAG repeat in HD?

Back 164

The expanded polyglutamine repeat results in protein aggregation and formation of intranuclear inclusions.

Front 165

165. What are the clinical features of HD?

Back 165

The age at onset is most commonly in the 4th and 5th decades and is related to the length of the CAG repeat in the HD gene. Motor symptoms often precede the cognitive impairment. The movement disorder of HD is choreiform, w/increased and involuntary jerky movements of all parts of the body; writhing movements of the extremities are typical.

Early symptoms of higher cortical dysfunction include forgetfulness and thought and affective disorder, but there is progression to a severe dementia. HD pts have an increased risk of suicide, w/intercurrent infection being the most common natural cause of death.

Front 166

166. What are spinocerebellar ataxias?

Back 166

This is a group of genetically distinct diseases characterized by signs and symptoms referable to the cerebellum (progressive ataxia), brainstem, spinal cord, and peripheral nerves, as well as other brain regions in different subtypes.

Pathologically, they are characterized by neuronal loss from the affected areas w/secondary degeneration of white matter tracts.

Front 167

167. What is a common genetic feature in the spinocerebellar ataxias?

Back 167

Among dominantly inherited forms, there are many that are associated w/trinucleotide repeat expansion. In those forms in which there is expansion of a CAG repeat encoding polyglutamine tract (SCA1-3,6,7,17), neuronal intranuclear inclusions containing the abnormal protein can be found, similar to HD.

Front 168

168. What is the significance of SCA6?

Back 168

All but SCA6 show anticipation, w/expansion of the repeat length during gametogenesis. Curiously, SCA6 shares its genetic locus w/another cerebellar disorder - episodic ataxia type 2, which is associated w/point mutations.

Front 169

169. What is Friedreich ataxia?

Back 169

Friedreich ataxia is an autosomal recessive progressive illness, generally beginning in the first decade of life w/gait ataxia, followed by hand clumsiness and dysarthria.

DTRs are depressed or absent, but an extensor plantar reflex is typically present. Joint position and vibratory sense are impaired, and there is sometimes loss of pain and temp sensation and light tough.

Most pts develop pes cavus and kyphosciolosis. There is a high incence of cardiac disease w/arrhythmias and CHF. Most pts become wheelchair bound w/in 5 years of onset; the cause of death is intercurrent pulmonary infections and cardiac disease.

Front 170

170. What is the gene involved in Friedreich ataxia?

Back 170

The gene for Friedreich ataxia has been mapped to chromosome 9q13, and in most cases, there is a GAA trinucleotide repeat expansion in the first intron of a gene encoding a protein named frataxin.

*Affected individuals inherit abnormal forms of the frataxin gene from both parents and have extrememly low levels of the protein.*

Front 171

171. What is the role of frataxin?

Back 171

Frataxin undergoes processing and ends up in the inner mitochondrial membrane, where it has been suggested to play a role in regulation of iron levels.

B/c of the need for this metal in many of the complexes of the oxidative phosphorylation chain, mutations in frataxin have been suggested to result in generalized mitochondrial dysfunction.

Front 172

172. What is the morphology of Friedreich ataxia?

Back 172

The spinal cord shows loss of axons and gliosis in the posterior columns, the distal portions of the corticospinal tracts, and the spinocerebellar tracts. There is degeneration of neurons in the spinal cord, the brainstem (CN 8, 10, and 12), the cerebellum, and to some extent the Betz cells of the motor cortex.

Large dorsal root ganglion neurons are also decreased in number; their large myelinated axons, traveling first in the dorsal roots and then in dorsal columns, therefore undergo secondary degeneration. The heart is enlarged and may have pericardial adhesions.

Front 173

173. What is ataxia-telangiectasia?

Back 173

Ataxia-telangiectasia is an autosomal-recessive disorder characterized by an ataxic-dyskinetic syndrome beginning in early childhood, caused by neuronal degeneration predominantly in the cerebellum, the subsequent development of telangiectasias in the conjunctiva and skin, and immunodeficiency.

Front 174

174. What are the immune characteristics of ataxia-telangiectasia?

Back 174

Cells from pts w/the disease show increased sensitivity to x-ray induced chromosome abnormalities; these cells continue to replicate damaged DNA rather than stopping to allow repair or apoptosis.

Pts first come to medical attention b/c of recurrent sinopulmonary infections and unsteadiness in walking. Many affected individuals develops lymphoid malignant disease (T-cell leukemia, T-cell lymphoma); gliomas and CAs have been reported in some.

Front 175

175. What is the gene responsible for ataxia-telangiectasia?

Back 175

The ataxia-telangiectasia locus on chromosome 11q22-23 has been identified as a large gene, ATM, that encodes a protein w/a kinase domain. The protein orchestrates the cellular response to double-stranded DNA brakes.

As a result, the mutated ataxia-telangiectasia allele may underlie an increased risk of CA, specifically breast CA.

Front 176

176. What is the morphology of ataxia-telangiectasia?

Back 176

***The abnormalities are predominantly in the cerebellum, w/loss of Purkinje and granule cells; there is also degeneration of the dorsal columns, spinocerebellar tracts, and anterior horn cells and a peripheral neuropathy.***

The nuclei of cells in many organs show a bizarre enlargement of the cell nucleus to 2-5x normal size and are referred to as amphicytes. The lymph nodes, thymus, and gonads are hypoplastic.

Front 177

177. What are the clinical features of ataxia-telangiectasia?

Back 177

The disease relentlessly progresses to death early in teh second decade. Pts first come to medical attention b/c of recurrent sinopulmonary infectiosn and unsteadiness in walking.

Later on, speech is noted to become dysarthric, and eye movement abnormalities develop. Many affected individuals develop lymphoid malignant disease (T-cell leukemia, T-cell lymphoma); gliomas and CAs have been reported in some.

Front 178

178. What is amyotrophic lateral sclerosis (ALS)?

Back 178

ALS is characterized by neuronal muscle atrophy (amyotrophy) and hyperreflexia due to loss of lower motor neurons in the anterior horns of the spinal cord and upper motor neurons that project in corticospinal tracts, respectively.

The disease affects men slightly more freq than women and becomes clinically manifest in the 5th decade or later. 5-10% of cases are familial, mostly with autosomal dominant inheritance.

Front 179

179. What are the genes responsible for ALS?

Back 179

Fora subset of the familial cases, the genetic locus has been mapped to the copper-zinc superoxide dismutase gene (SOD1) on chromosome 21.

Also, an adverse gain of function phenotype caused by missense mutations have been identified. Among the mutations, the A4V mutation is the most common (50% of cases), and is associated w/a rapid course, and rarely has upper motor neuron signs.

Front 180

180. What are the morphologic findings in ALS?

1/2

Back 180

On macroscopic exam, the anterior roots of the spinal cord are thin; the precentral gyrus may be atrophic in especially severe cases. Microscopic exam demonstrates a reduction in the number of anterior horn neurons throughout the length of the spinal cord w/associated reactive gliosis and loss of anterior root myelinated fibers.

Remaining neurons often contain Bunina bodies: PAS positive cytoplasmic inclusions that appear to be remnant of autophagic vacuoles.

Front 181

181. What are the morphologic findings in ALS?

2/2

Back 181

Skeletal muscles innervated by the degenerated lower motor neurons show neurogenic atrophy.

Destruction of the upper motor neurons leads to degeneration of myelin the corticospinal tracts, resulting in pale staining that is particularly evident at the lower segmental levels but traceable throughout the corticospinal system w/special studies.

Front 182

182. What are the clinical features of ALS?

Back 182

Early symptoms include asymmetric weakness of the hands, manifested as dropping objects and difficulty in performing fine motor tasks, and cramping and spasticity of the arms and legs. As the disease progresses, muslce strength and bulk diminish, and involuntary contractions of individual motor units, called fasciculations, occur.

The disease eventually involves the respiratory muscles, leading to recurrent bouts of pulmonary infection.

Front 183

183. What is progressive musclular atrophy?

Back 183

The severity of involvement of the upper and lower motor neurons is variable; the term progressive muscular atrophy applies to those relatively uncommon cases in which lower motor neuron involvement predominates.

Front 184

184. What is progressive bulbar palsy or bulbar amyotrophic lateral sclerosis?

Back 184

In some pts, degeneration of the lower brainstem cranial motor nuclei occurs early and progresses rapidly, a pattern referred to as progressive bulbar palsy or bulbar amyotrophic lateral sclerosis.

**In these individuals, abnormalities of deglutition and phonation dominate, and the clinical course is relentless during a 1-2 year period.

Front 185

185. What is bulbospinal atrophy (Kennedy syndrome)?

Back 185

This X-linked adult onset disease is characterized by distal limb amyotrophy and bulbar signs such as atrophy and fasciculations of the tongue and dysphagia.

Affected individuals manifest androgen insensitivity w/gynecomastia, testicular atrophy, and oligospermia.

Front 186

186. Tell me more about Kennedy syndrome...

Back 186

On microscopic exam, there is degeneration of the lower motor neurons in the spinal cord and brainstem. The gene defect is expansion of a CAG/polyglutamine repeat in the androgen receptor (40-60 for affected individuals as opposed to 11-33 for the normal allele); nuclear inclusions containing aggregated androgen receptor can be found.

Front 187

187. What are neuronal storage diseases?

Back 187

Neuronal storage diseases are caused by a deficiency of a specific enzyme involved in the catabolism of sphingolipids, muopolysaccharides, or mucolipids.

They are often characterized by the accumulation of the substrate of the enzyme w/in the lysosomes of neurons, leading to neuronal death.

Front 188

188. What are leukodystrophies?

Back 188

Leukodystrophies show a selective involvement of myelin and generally exhibit no neuronal storage defects. Some of these disorders involve lysosomal enzymes; other affect peroxisomal enzymes.

Diffuse involvement of white matter leads to deterioration of motor skills, spasticity, hypotonia, or ataxia.

Front 189

189. What is Krabbe disease?

Back 189

Krabbe disease is an autosomal recessive leukodystrophy resulting from a deficiency of galactocerebroside β-galactosidase, the enzyme required for the catabolism of galactocerebroside to ceramide and galactose.

Front 190

190. Is it the accumulation of galactocerebroside that causes toxicity in Krabbe disease?

Back 190

While some accumulation of galactocerebroside may occur, this is not the direct toxic agent in Krabbe disease.

*Instead, it appears that an alternative catabolic pathway removes a fatty acid from this molecules, generating galactosylspingosine, which is a cytotoxic compound that could cause oligodendrocyte injury.

Front 191

191. What are the clinical features of Krabbe disease?

Back 191

The clinical course is rapidly progressive, with onset of symptoms often btwn the ages of 3 and 6 mos. Survival beyond 2 years is uncommon.

The clinical features are dominated by motor signs, including stiffness and weakness, w/gradually worsening difficulties in feeding. The brain shows loss of myelin and oligodendrocytes in the CNS and a similar process in peripheral nerves. Neurons and axons are relatively spared.

Front 192

192. What is one unique feature of Krabbe disease?

Back 192

The aggregation of macrophages filled w/cerebroside, forming multinucleated cells (globoid cells), around blood vessels.

Front 193

193. What is metachromatic leukodystrophy?

Back 193

Metachromatic leukodystrophy is an autosomal recessive disease that results from a deficiency of the lysosomal enzyme arylsulfatase A. This enzyme, present in a variety of tissues, cleaves the sulfate from sulfate-containing lipids, the first step in their degradation.

*Enzyme deficiency leads to an accumulation of the sulfatides, especially cerebroside sulfate which somehow breaks down myelin.

Front 194

194. What are the different forms of metachromatic leukodystrophy?

Back 194

Recognized clinical subtypes of the disorder include a late infantile form (the most common), a juvenile form, and an adult form.

The two forms w/childhood onset often present w/motor symptoms and progress gradually, leading to death w/in 5-10 years. In the adult form, psychiatric or cognitive symptoms are the usual initial complaint, w/motor symptoms coming later, and the disease has a slower course than in the infantile form.

Front 195

195. What is the most striking histologic finding in metachromic leukodystrophy?

Back 195

The most striking finding is demyelination w/resulting gliosis. Macrophages w/vacuolated cytoplasm are scattered throughout the white matter. The membrane bound vacuoles contain complex crystalloid structures composed of sulfatides. ***These sulfatides, when stained, shift the absorbance spectrum of the dye, a property called metachromasia.

The detection of metachromatic material in the urine is also a sensitive method for establishing Dx.

Front 196

196. What is adrenoleukodystrophy?

Back 196

Adrenoleukodystrophy is a progressive disease w/symptoms referable to myelin loss from the CNS and peripheral nerves as well as adrenal insufficiency. In general, forms w/early onset have a more rapid course. The X-linked form usually presents in the early school years w/neurologic symptoms and adrenal insufficiency and is rapidly progressive and fatal.

When it develops in adults, it is usually a slowly progressive disorder w/predominantly peripheral nerve involvement developing over a period of decades.

Front 197

197. What gene is responsible for adrenoleukodystrophy? If mutated, what is the consequence?

Back 197

The disease is associated w/mutations in the ALD gene, which encodes a member of the ATP-binding cassette transporter family of proteins.

*The disease is characterized by the inability to properly catabolize very-long chain fatty acids within peroxisomes, w/elevated levels of the long chain fatty acids in the serum.

Front 198

198. What is Pelizaeus-Merzbacher disease?

Back 198

Pelizaeus-Merzbacher disease is a fatal leukodystrophy beginning either early in childhood or just after birth, and is characterized by slowly progressive signs and symptoms resulting from widespread white matter dysfunction.

Pts present w/peduncular eye movements, hypotonia, choreoathetosis, and pyramidal signs early in the disease, followed later by spasticity, dementia, and ataxia.

Front 199

199. What gene is defective in Pelizaeus-Merzbacher disease?

Back 199

Pelizaeus-Merzbacher disease has been shown to arise in most cases from defects in a gene on the X chromosome that encodes proteolipid protein (PLP), a major protein of CNS myelin.

**Although myelin is nearly completely lost in the cerebral hemispheres, patches may remain, giving a "trigoid" appearance to tissue sections stained for myelin.

Front 200

200. What is Canavan disease?

Back 200

Canavan disease is characterized by megalocephaly, severe mental deficits, blindness, and signs and symptoms of white matter injury beginning in early infancy and relentlessly progressing to death by 18 mos of age.

Autopsy studies have shown spongy degeneration of the white matter, particularly affecting subcortical U fibers and Alzheimer type II astrocytes in the gray matter.

***Aspartoacylase activity is deficient in these pts, and point mutations and deletions in the gene for aspartylacylase underlie this autosomal-recessive disease.

Front 201

201. What is Leigh syndrome (subacute necrotizing encephalopathy)?

Back 201

Leigh syndrome is characterized in early childhood by lactic acidemia, arrest of psychomotor development, feeding problems, seizures, extraocular palsies, and weakness w/hypotonia. Death usually occurs w/in 1-2 years.

*Most cases show decreased activity of complex 4 (cytochrome c oxidase) of mitochondrial oxidative phosphorylation.

Front 202

202. What are the morphologic features of the brain in Leigh syndrome?

Back 202

On histologic exam, there are multifocal, moderately symmetric regions of destruction of brain tissue with a spongiform appearance and proliferation of blood vessels.

The areas that are most commonly affected include the periventricular gray matter of the midbrain, the tegmentum of the pons, and the periventricular regions of the thalamus and hypothalamus.

Front 203

203. What is myoclonic epilepsy and ragged red fibers (MERRF)?

Back 203

MERRF is a maternally transmitted disease in which pts have myoclonus, a seizure disorder, and evidence of a myopathy. Ataxia, associated w/evidence of neuronal loss from the cerebellar system, is also a common component.

MERRF is caused by mutations in mitochondrial tRNA, affecting protein synthesis w/in mitochondria.

Front 204

204. What is mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)?

Back 204

MELAS is a mitochondrial disease in which children have acute episodes of neurologic dysfunction, cognitive changes, and evidence of muscle involvement w/weakness and lactic acidosis.

*Pathologically, areas of infarction are observed, often w/vascular proliferation and focal calcification. This syndrome is associated with mutations involvement a different mitochondrial tRNA.

Front 205

205. What is Kearns-Sayre syndrome (KSS)?

Back 205

KSS AKA "ophthalmoplegia plus" is a sporadic disorder, associated w/a large mtDNA deletion/rearrangement.

This disorder may present w/cerebellar ataxia in addition to the progressive external ophthalmoplegia, pigmentary retinopathy, and cardiac conduction defects. Pathologically, there is spongiform change in gray and white matter, w/neuronal loss most evident in the cerebellum.

Front 206

206. What is Wernicke encephalopathy?

Back 206

Wernicke encephalopathy is due to thiamine deficiency which can lead to development of psychotic symptoms or ophthalmoplegia that begins abruptly.

Treatment with vitamin B1 may reverse manifestations of Wernicke syndrome.

Front 207

207. What is the morphology of the brain in Wernicke encephalopathy?

Back 207

Wernicke encephalopathy is characterized by foci of hemorrhage and necrosis, particularly in the mammillary bodies but also adjacent to the ventricle, especially the 3rd and 4th ventricles.

Early lesions show dilated capillaries w/prominent endothelial cells. Subsequently, the capillaries leak red cells into the interstitium, producing hemorrhagic areas that are easily detectable macroscopically.

Front 208

208. What is Korsakoff syndrome?

Back 208

The acute stages of Wernicke encephalopathy, if left untreated, may be followed by a prolonged and largely irreversible condition known as Korsakoff syndrome. This syndrome is characterized clinically by memory disturbances and confabulation.

The syndrome is particularly common in the setting of chronic alcoholism but it may also be encountered in pts w/thiamine deficiency resulting from gastric disorders.

Front 209

209. What are the morphologic findings in Korsakoff syndrome?

Back 209

The capillaries that leak red cells into the interstitium, producing hemorrhagic areas in Wernicke encephalopathy, can over time, develop into cystic space w/hemosiderin-laden macrophages which are permanent.

These chronic hemosiderin-laden lesions predominate in pts with Korsakoff syndrome.

Front 210

210. Which area of the brain appear to be best correlated with the neurologic symptoms in Korsakoff syndrome?

Back 210

Lesions in the medial dorsal nucleus of the thalamus appear to be the best correlate of the memory disturbance and confabulation in Korsakoff syndrome.

Front 211

211. Glucose deprivation in the brain initially leads to selective injury to which areas?

Back 211

Glucose deprivation in the brain initially leads to selective injury to large pyramidal neurons of the cerebral cortex, which if it is severely involved, may result in pseudolaminar necrosis of the cortex, *predominantly involving layers 3-5.

Front 212

212. What other areas of the brain are susceptible to hypoglycemic damage?

Back 212

The hippocampus is also vulnerable to glucose deprivation, as it is to hypoxia, and may show a dramatic loss of pyramidal neurons in Sommer sector (CA1 of the hippocampus).

Purkinje cells of the cerebellum are also vulnerable to hypoglycemia, although to a lesser extent than to hypoxia.

Front 213

213. What about carbon monoxide damage in the brain?

Back 213

In CO poisoning, selective injury of the neurons of layers 3 and 5 of the cerebral cortex, Sommer sector of the hippocampus, and Purkinje cells is a common consequence.

Bilateral necrosis of the globus pallidus may also occur, and is more common in CO-induced hypoxia than in hypoxia from other causes.

Front 214

214. What about methanol toxicity?

Back 214

The pathologic findings of methanol toxicity are seen in the retina, where degeneration of the retinal ganglion cells may cause blindness.

Selective bilateral putamenal necrosis and focal white matter necrosis also occur when the exposure is severe.

Front 215

215. Ethanol damage???

Back 215

Cerebellar dysfunction occurs in about 1% of chronic alcoholics, associated w/a clinical syndrome of truncal ataxia, unsteady gait, and nystagmus.

**The histologic changes are atrophy and loss of granule cells predominantly in the anterior vermis.

In advanced cases, there is loss of Purkinje cells and proliferation of the adjacent astrocytes (Bergmann gliosis) btwn the depleted granular cell layer and the molecular layer of the cerebellum.

Front 216

216. What are the CNS effects of radiation?

Back 216

Delayed effects of radiation present w/rapidly evolving symptoms of an intracranial mass, including headaches, nausea, vomiting, and papilledema that may develop months to years after irradiation.

The pathologic findings consist of large areas of coagulative necrosis w/adjacent edema. The typical lesion is restricted to white matter, and all elements w/in the area undergo necrosis, including astrocytes, axons, oligodendrocytes, and blood vessels.

Also, proteinaceous spheroids may be identified adjacent to the area of coagulative necrosis.

Front 217

217. What about MTX + radiation?

Back 217

MTX toxicity most commonly develops when the drugs has been administered in associated w/radiotherapy, either together or at separate times. Symptoms often begin w/drowsiness, ataxia, and confusion, and may progress rapidly. Other may become comatose.

The pathologic basis of the symptoms are focal areas of coagulative necrosis w/in white matter, often adjacent to the lateral ventricles but at times distributed throughout the white matter or in the brainstem. Surrounding axons are often dilated and form axonal spheroids.

Front 218

218. What are the two main dopamine receptors?

Back 218

D1 and D2

Activation of D1 class receptors leads to increased cAMP, while activation of D2 class receptors inhibits cAMP generation.

Front 219

219. What are the receptors in the D1 family?

Back 219

D1: Straitum and neocortex

D5: Hippocampus and hypothalamus

Front 220

220. What are the receptors in the D2 family?

Back 220

D2: Striatum, substantia nigra, and pituitary

D3: Olfactory tubercle, nucleus accumbens, hypothalamus

D4: Frontal cortex, medulla, midbrain

Front 221

221. What are the three main dopamine pathways in the brain?

Back 221

1. Nigrostriatal pathway
2. Ventral tegmental area
3. Tuber-infundibular pathway

Front 222

222. What is the nigrostriatal pathway?

Back 222

Nigrostriatal pathway contains about 80% of the brains dopamine. This tract projects rostrally from cell bodies in the pars compacta of the substantia nigra to terminals that richly innervate the caudate and putamen (aka the striatum).

Dopaminergic neurons the nigrostriatal system are involved in the stimulation of purposeful movement.

Front 223

223. What is the ventral tegemental area (VTA)?

Back 223

Medial to the substantia nigra is an area of dopaminergic cell bodies in the midbrain called the VTA. The VTA has widely divergent projections that innervate many forebrain areas, most notably the cerebral cortex, the nucleus accumbens, and other limbic structures.

These systems play an important role in motivation, goal-directed thinking, regulation of affect, and positive reinforcement (reward). Derangement of these pathways may be involved in the development of schizophrenia.

Front 224

224. What is the tubero-infundibular pathway?

Back 224

Dopamine containing cell bodies i the arcuate and periventricular nuclei of the hypothalamus project axons to the median eminence of the hypothalamus.

This system is known as the tubero-infundibular pathway. Dopamine is released by these neurons into the portal circulation connecting the median eminence w/the anterior pituitary gland, and tonically inhibits the release of prolactin by pituitary lactotrophs.

Front 225

225. Increased levels of dopamine in the straitum do what?

Back 225

Increased levels of dopamine in the striatum tend to activate the D1-expressing neurons the direct pathway, while inhibiting the D2 expressing neurons of the indirect pathway.

Front 226

226. What is levodopa?

Back 226

Levodopa is still the most effective treatment for Parkinsons. Dopamine itself is not suitable b/c it cannot cross the BBB. However, dopamine's immediate precursor, L-dopa, is readily transported across the BBB by the neutral AA transporter.. Once in the CNS, L-dopa is converted to dopamine by the enzyme aromatic AA decarboxylase (AADC).

Thus, L-dopa must compete w/other neutral AAs for transport across the BBB, and its availability in the CNS may be compromised by recent protein meals.

Front 227

227. Levodopa

Back 227

MOA: Provide substrate for increased dopamine synthesis; levodopa is transported across the BBB by the neutral AA transporter and then decarboxylated to dopamine by AADC.

PURPOSE: Parkinsons disease

ADVERSE: Dyskinesia, heart disease, orthostatic hypotension, psychotic disorder, loss of appetite, vomiting

CONTRA: History of melanoma, narrow-angle glaucoma, concomitant use of MAOI

Front 228

228. What are 3 therapeutic considerations for levodopa?

Back 228

1. Levodopa, when administered alone, has low availability in the CNS. ***Therefore, it is almost always administered in combo with carbidopa, and inhibitor of DPA decarboxylase***
2. Continued use results in both tolerance and sensitization; pts develop periods of increased rigidity alternating with periods of normal or dyskinetic movement.
3. Dyskinesias are nearly ubiquitous in pts w/in 5 years of stating levodopa. As the disease progresses, continued levodopa therapy leads to worsening of both the dyskinesias and the "on/off" phenomenon.

Front 229

229. What are the dopamine receptor agonists?

Back 229

Another strategy for enhancing dopaminergic enurotransmission is to target the postsynaptic dopamine receptor directly thru the use of agonists.

These include:
1. Bromocriptine (D2 agonist)
2. Pergolide (D1 and D2)
3. Pramipexole (D3>D2)
4. Ropinirole (D3>D2)

This class has several advantages in that they do not compete with levodopa or toher neutral AAs for transport across the BBB. Furthermore, they do not require enzymatic conversion by AADC, and thus they remain effective later in the course of Parkinsons. Also, they have a longer half life.

Front 230

230. Bromocriptine (MOA, PURPOSE, and ADVERSE)

Back 230

MOA: A synthetic dopamine receptor agonist (D2 agonist) that inhibits lactotroph cells growth (decreases prolactin levels)

PURPOSE: Amenorrhea and galactorrhea from hyperprolactinemia, acromegaly, Parkinson's disease, premenstrual syndrome, Cushing syndrome, hepatic encepaholopathy, neuroleptic malignant syndrome related to neuroleptic drug therapy

ADVERSE: Cerebral vascular accident, seizure, acute myocardial infarction, dizziness, hypotension, abdominal cramps, nausea

Front 231

231. Bromocriptine (CONTRA and NOTES)

Back 231

Bromocriptine

CONTRA: Hypersensitivity to ergot derivatives, uncontrolled hypertension, toxemia of pregnancy

NOTES:
1. Ergot alkaloid; dose 2x/day
2. Intravaginal administration may reduce GI side effects
3. Alcohol intolerance may occur
4. First dose phenomenon occurs in 1% of patients and may result in syncope
5. Coadministration w/amitriptyline, butryophenones, imipramine, methyldopa, phenothiazines, or reserpine causes increased prolactin levels
6. Coadministration w/antihypertensives potentiates hypotension

Front 232

232. Pergolide

Back 232

MOA: Dopamine receptor agonist at D1 and D2 that also decreases prolactin levels

PURPOSE: Parkinson's disease, hyperprolactinemia

ADVERSE: Arrhythmias, MI, heart failure, pulmonary fibrosis, nausea, dizziness, dyskinesia, dystonia, hallucinations, somnolence, orthostatic hypotension, rhinitis

CONTRA: Hypersensitivity to ergot derivatives and uncontrolled hypertension

NOTES:
1. Use cautiously in patients prone to arrhythmias and underlying psychiatric disorders
2. CNS depressants have additive effects

Front 233

233. Pramipexole and Ropinirole

Back 233

MOA: Non ergot agonists at dopamine receptors (D3>D2), bind to and activate postsynaptic dopamine receptors directly

PURPOSE: Parkinson's disease, Restless leg syndrome (ropinirole)

ADVERSE: Dyskinesia, otherostatic hypotension, extrapyramidal movements, somnolence, dizziness, hallucinations, dream disorder, asthenia, amnesia

CONTRA: Concomitant use of other sedating meds

NOTES: These non-ergot dopamine agonists have fewer adverse effects than the ergo derivatives

Front 234

234. Therapeutic considerations for dopamine agonists

Back 234

1. Dopamine agonists have longer half lives than that of levodopa, which allows for less freq dosing.
2. The non ergot agonists have fewer adverse effects that ergot agonists
3. Cognitive effects can include excessive sedation, vivid dreams, and hallucinations
4. Some studies suggest that use of dopamine agonists rather than levodopa as initial treatment for Parkinson's disease delays the onset of "off" periods and dyskinesias, esp in younger people.

Front 235

235. What are the inhibitors of dopamine metabolism?

Back 235

Rasagiline, selegiline, tocapone, and entacapone

Front 236

236. Rasagiline and Selegiline

Back 236

MOA: Inhibit breakdown of dopamine in the CNS by inhibiting MAO-B

PURPOSE: Parkinson's

ADVERSE: BBB, GI hemorrhage, Orthostatic hypotension, dyskinesia, rash, dyspepsia, arthralgia, headache, weight loss, insomnia, (selegiline), confusion (selegiline)

CONTRA: Concomitant use of: cyclobenzaprine, mirtazapine, St. John's wort, DXM, meperidine, methadone, propoxyphene, tramadol, MOAI's, cocaine; elective surgery requiring general anesthesia; pheochromocytoma

Front 237

237. Therapeutic considerations for rasagiline and selegiline

Back 237

1. Selegiline in low doses is selective for MAO-B, which predominates in the striatum; higher doses inhibit MOA-A as well as MAO-B, w/associated risks of toxicity
2. *Selegiline forms the potentially toxic metabolite amphetamine, which may lead to insomnia and confusion esp in the elderly
3. Rasagiline does not form toxic metabolites
4. Both rasagiline and selegiline improve motor function when used alone and can augment the effectiveness of levodopa

Front 238

238. Tolcapone and Entacapone

Back 238

MOA: Inhibit breakdown of dopamine in the CNS by inhibiting COMP (tolcapone); also inhibit the breakdown of levodopa by COMT in the periphery (entacapone and tolcapone)

PURPOSE: Parkinson's

ADVERSE: Dyskinesia, dystonia, hallucinations, orthostatic hypotension (tolcapone), hyperpyrexia (tolcapone), fulminant hepatic failure (tolcapone), rhabdomyolysis (tolcapone), dyspepsia, dream disorder, sleep disorder

CONTRA: History of rhabdomyolysis or hyperpyrexia related to tolcapone; liver disease

Front 239

239. Therapeutic considerations for tolcapone and entacapone

Back 239

1. Tolcapone is a highly lipid-soluble agent that can cross the BBB, while entacapone distributes only to the periphery
2. ***COMT inhibitors can be used in combo w/carbidopa to further enhance the plasma half-life of levodopa; COMT inhibitors have been shown in some trials to reduce the "off" periods that are associated w/decreasing plasma levodopa levels
3. Rare but fatal hepatic toxicity has been reported w/tolcapone use
4. Entacapone is the more widely used COMT inhibitor

Front 240

240. What about amantadine?

Back 240

MOA: Antagonism of excitatory NMDA receptors

PURPOSE: Parkinson's; influenza A

ADVERSE:* Neuroleptic malignant syndrome*, exacerbation of mental disorder, insomnia, dizziness, hallucinations, agitation, orthostatic hypotension, peripheral edema, dyspepsia, livedo reticularis

CONTRA: Hypersensitivity

NOTES: Amantadine is used to treat levodopa-induced dyskinesias that develop late in the course of the disease; may exacerbate mental illness in pts with psychiatric illness or substance abuse problems

Front 241

241. Trihexyphenidyl and Benztropine

Back 241

MOA: Muscarinic receptor antagonists that reduce cholinergic tone in the CNS by modifying the actions of striatal cholinergic interneurons

PURPOSE: Parkinson's

ADVERSE: Angle-closure glaucoma, increased intraocular pressure, psychosis, hyperpyrexia (bentropine), paralytic ileus (benztropine); dizziness, blurred vision, nervousness, nausea, xerostomia, urinary retention

CONTRA: Narrow angle glaucoma, younger than 3 years, tradice dyskinesias (trihexyphenidyl)

NOTES: Trihexyphenidyl and Benztropine reduce tremor more than bradykinesia and are therefore effective in treating pts for whom tremor is the major symptom; may worsen dementia and cognitive impairment int he elderly

Front 242

242. What does neuroleptic mean?

Back 242

"Neuroleptic" emphasizes the drugs neurological actions that are commonly manifested as adverse effects of treatment.

These include extrapyramidal effects, resulting from DA receptor blockage in the basal ganglia, and include the parkinsonian symptoms of slowness, stiffness, and tremor.

Front 243

243. What does antipsychotic mean?

Back 243

"Antipsychotic" means the ability of these drugs to abrogate psychosis and alleviate disordered thinking in schizophrenic pts. The antipsycotics may be further divided into typical and atypical antipsychotics.

Front 244

244. What are the 2 main categories of typical antipsychotics?

Give an example of the prototypical drug in each category.

Back 244

1. Phenothiazines (Chlorpromazine)

2. Butyrophenones (Haloperidol)

Front 245

245. What are the names of the phenothiazines?

Back 245

1. Chropromazine
2. Thioridazine
3. Mesoridazine
4. Perphenazine
5. Fluphenazine
6. Thiothixene
7. Trifluoperzine
8. Chlorprothixene

Front 246

256. Phenothiazines

Back 246

MOA: Antagonize mesolimbic, and possibly mesocortical, D2 receptors; adverse effects are likely mediated by binding to D2 receptors in basal ganglia and pituitary

PURPOSE: Psychotic disorder, nausea and vomiting (chlorpromazine, perphenazine)

ADVERSE: Parkinsonian symptoms, *neuroleptic malignant syndrome*, tardive dyskinesia, anticholinergic symptoms

CONTRA: Myelosuppression, severe toxic CNS depression or comatose states, concomitant admin of drugs that prolong QT interval (thioridazine and mesoridazine), Parkinson's disease

NOTES: Fluphenazine is available as decanoate ester, deliver IM every 3-4 weeks

Front 247

257. What are the therapeutic considerations for the phenothiazines?

Back 247

In general, aliphatic phenothiazines are less potent antagonists at D2 receptors than butyrophenones, thioxanthenes, or phenothiazines functionalized w/a piperazine derivatives
3. Administration of typical antipsychotics to pts with Parkinson's disease often leads to marked worsening of parkinsonian symptoms
4. Typical antipsychotics potentiate the sedative effects of benzos and antihistamines

Front 248

258. What is neuroleptic malignant syndrome?

Back 248

NMS is a rare, but life-threatening syndrome characterized by catatonia, stupor, fever, and autonomic instability; myoglobinemia and death occur in about 10% of these cases.

NMS is most commonly associated w/the typical antipsychotic drugs that have a high affinity for D2 receptors, such as haloperidol.

NMS is thought to arise at least in part from the actions of the antipsychotics on the dopaminergic system in the hypothalamus, which are essential for the body's ability to control temperature.

Front 249

259. What is the relationship between potency and adverse effects with the typical antipsychotics?

Back 249

High-potency drugs tend to have fewer sedative adverse effects and cause less postural hypotension than drugs with lower potency (i.e., drugs that require high doses to achieve a therapeutic effect).

On the other hand, lower-potency typical antipsychotics tend to cause fewer extrapyramidal adverse effects.

Front 250

260. What are the butyrophenones?

Back 250

Haloperidol and droperidol.

These decanoate esters are highly lipophilic drugs and are injected via IM, where they are slowly hydrolyzed and released. The decanoate ester dosage forms provide a long-acting formulation that can be administered every 3-4 weeks.

These formulations are particularly useful for treating poorly compliant pts.

Front 251

261. Haloperidol and Droperidol

Back 251

MOA: Antagonize mesolimbic, and possibly mesocortical, D2 receptors; adverse effects are likely mediated by binding to D2 receptors in basal ganglia and pituitary gland

PURPOSE: Psychoses (haloperidol), Tourette's syndrome (haloperidol), Nausea and vomiting; anesthesia adjunct (droperidol)

ADVERSE: Same as phenothiazines

CONTRA: Parkinson's disease, severe toxic CNS depression or comatose states

NOTES: *Haloperidol is the most widely used butyrophenone. Decanoate ester formulation is great for treating poorly compliant pts due to its long acting delivery

Front 252

262. What are three other typical antipsychotics?

Back 252

1. Loxapine
2. Molindone
3. Pimozide

Front 253

263.

Loxapine
Molindone
Pimozide

Back 253

MOA: Antagonize D2 receptors.
Molindone exerts it antipsychotic effects on the ascending reticular activating system in the absence of muscle relaxation and incoordination effects; Pimozide has more specific dopamine receptor antagonism and less alpha adrenergic receptor blocking activity, which results in less potential for inducing sedation and hypotension

PURPOSE: Psychotic disorders, Tourette's syndrome (pimozide)

ADVERSE: Parkisonian symptoms, NMS, tardive dyskinesia, prolonged QT interval (pimozide), anticholinergic symptoms, sedation

CONTRA: Comatose or severe drug induced depressed states; Parkinson's; See next card!!!

Front 254

234. What are the contraindications unique to pimozide?

Back 254

1. Concomitant pemoline, methylphenidate, or amphetamines that may cause motor and phonic tics
2. Concomitant dofetilide, sotalol, and other class Ia and class III anti-arrhythmics, mesoridazine, thoridazine, chlorpromazine, or droperidol
3. Concomitant use of fluoroquinolone antibiotics, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron, mesylate, probucol, tacrolimus, ziprasidone, sertraline, or macrolide antibiotics
4. Concurrent administration w/drugs that have demonstrated QT prolongation and inhibitors of P450 3A4 (zileuton, fluvoxamine)
5. History of cardiac arrhythmias

Front 255

235. What are the atypical antipsychotics?

Back 255

1. Risperidone
2. Clozapine
3. Olanzapine
4. Quetiapine
5. Ziprasidone
6. Aripiprazole

*These atypical antipsychotics have efficacy and adverse effect profiles that differ from those of the typical ones. All of these drugs are more effective than typical antipsychotics at treating the "negative symptoms" of schizophrenia. In addition, risperidone is more effective at combating the positive symptoms of schizophrenia. These cause milder extrapyramidal effects as well.

Front 256

236. Risperidone

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MOA: Risperidone binds to and antagonizes D2, 5HT2, α1. α2. H1 receptors

PURPOSE: Psychotic disorders and bipolar disorder

ADVERSE: Mild extrapyramidal symptoms, QT prolongation, anticholinergic symptoms (dry mouth, constipation, urinary retention), sedation, weight gain

CONTRA: Hypersensitivity

NOTES: Atypicals are more effective than typicals at treating the negative symptoms of schizophrenia.

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237. Clozapine

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MOA: Clozapine binds to and antagonizes D1-D5, 5-HT2, α1, H1, muscarinic receptors

PURPOSE: Schizophrenia refractory to other antipsychotics

ADVERSE: Mild extrapyramidal symptoms, *agranulocytosis, anticholinergic symptoms (dry mouth, constipation, urinary retention), sedation, weight gain

CONTRA: History of clozapine-induced agranulocytosis or severe granulocytopenia; myeloproliferative disorders

NOTES: *Clozapine has not been used as a first-line agent b/c of a small but significant risk of agranulocytosis

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238. Olanzapine

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MOA: Olanzapine binds to and antagonizes D1-D4, 5-HT2, α1, H1, M1-M5 receptors

PURPOSE: Psychotic disorders; bipolar disorder

ADVERSE: Mild extrapyramidal symptoms, anticholinergic symptoms (dry mouth, constipation, urinary retention), sedation, weight gain

CONTRA: Hypersensitivity

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239. Quetiapine

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MOA: Quetiapine binds to and antagonizes D1, D2, 5-HT1, 5-HT2, α1, α2, H1 receptors

PURPOSE: Psychotic disorders, bipolar disorder

ADVERSE: Mild extrapyramidal symptoms, anticholinergic symptoms (dry mouth, constipation, urinary retention), sedation, weight gain

CONTRA: Hypersensitivity

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240. Ziprasidone

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MOA: Ziprasidone binds to and antagonizes D2, 5-HT1, 5-HT2, α1, H1 receptors

PURPOSE: Psychotic disorder, bipolar disorder

ADVERSE: Mild extrapyramidal symptoms, QT prolongation, anticholinergic symptoms (dry mouth, constipation, urinary retention), sedation, weight gain

CONTRA: Concomitant arsenic trioxide, chlorpromazine, class Ia and III antiarrhythmics , or other drugs that cause QT prolongation; QT prolongation history including congenital long QT syndrome; cardiac arrhythmias, recent acute MI, uncompensated heart failure

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241. Aripiprazole

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MOA: Aripiprazole is a D2 and 5HT1A partial agonist and a 5-HT2A antagonist

PURPOSE: Psychotic disorders and bipolar disorder

ADVERSE: Same as risperidone

CONTRA: Hypersensitivity