Pbl Exam 9 Case 8

Front 1

1. What are the CNS cells that are derived from the neuroectoderm?

Back 1

Astrocytes, ependymal cells, and oligodendrocytes derive from the neural tube (neuroectoderm)

Front 2

2. What is the only type of neural cell that is not derived from the neuroectoderm?

Back 2

Microglial cells are derived from the mesoderm layer

Front 3

3. What is the acute neuronal injury (red neuron)?

Back 3

Acute neuronal injury (red neuron) refers to a spectrum of changes that accompany acute CNS hypoxia/ischemia, or other acute insults that ultimately lead to death of the cell. Red neurons are evident w/H and E prep at about 12-24 hours after an irreversible hypoxic/ischemic insult.

*The morphologic features consist of shrinkage of the cell body, pyknosis of the nucleus, disappearance of the nucleolus, and loss of Nissl substance, w/intense eosinophilia of the cytoplasm.

Front 4

4. What is subacute and chronic neuronal injury (degeneration)?

Back 4

This refers to situations leading to neuronal death occurring as a result of a progressive disease process of some duration.

*The characteristic histologic feature is cell loss, often selectively involving functionally related systems of neurons, and reactive gliosis.

Front 5

5. What is axonal reaction?

Back 5

Axonal reaction refers to the reaction w/in the cell body that attends regeneration of the axon. This reparative process is associated w/increased protein synthesis, and its most important effect is axonal sprouting.

Morphologic changes visible in the perikaryon include enlargement and rounding up of the cell body, peripheral displacement of the nucleus, enlargement of the nucleolus, an dispersion of Nissl Substance from the center to the periphery of the cell (central chromatolysis).

Front 6

6. What is gliosis?

Back 6

Gliosis is the most important histopathologic indicator of CNS injury, regardless of etiology.

Astrocytes participate in this process by undergoing both hypertrophy and hyperplasia. The nucleus enlarges and becomes vesicular, and the nucleolus is prominent.

Staining for GFAP demonstrates the strout, ramifying processes (gemistocytic astrocyte). These stout processes, glial fibrils, are not true extracellular fibers.

Front 7

7. What is Bergmann gliosis?

Back 7

Proliferation of astrocytes residing btwn the molecular and granule cell layers of the cerebellum is a regular accompaniment of anoxic injury and other conditions associated w/death of Purkinje cells, termed Bergmann gliosis.

Front 8

8. What are Rosenthal fibers? Where are they usually found?

Back 8

Rosenthal fibers are thick, elongated, brightly eosinophilic structures that are somewhat irregular in contour and occur w/in astrocytic processes. Ultrastructrually they exhibit dense deposits that contain two heat shock proteins and ubiquitin.

***Rosenthal fibers are typically found in regions of long-standing gliosis; they are also characteristic of cerebellar pilocytic astrocytoma, as well as the reactive brain adjacent to craniopharyngioma or syrinx cavities.

Front 9

9. What is corpora amylacea?

Back 9

Corpora amylacea, or polyglucosan bodies, are round, faintly basophilic, PAS positive, concentrically lamellated structures ranging btwn 5 and 50 um in diameter and located where there are astrocytic end processes, especially in the subpial and perivascular zones.

*They represent degenerative change in the astrocyte, and they occur in increasing #'s w/advancing age and in a rare disease called adult polyglucosan body disease.

Front 10

10. What are glial cytoplasmic inclusions?

Back 10

Glial cytoplasmic inclusions consisting of silver positive meshes of 20-40 nm intermediate filaments that contain the protein alpha-synuclein, are characteristic of a number of CNS degenerative diseases, collectively known as multiple system atrophy.

Front 11

11. What is the Alzheimer type II astrocyte?

Back 11

The Alzheimer type II astrocyte is a gray matter astrocyte w/a large (2-3x normal) nucleus, pale-staining central chromatin, an intranuclear glycogen droplet, and a prominent nuclear membrane and nucleolus.

Front 12

12. Where is the Alzheimer type II astrocyte found?

Back 12

The Alzheimer type II astrocyte is a gray matter astrocyte.

It is unrelated to Alzheimers, rather; it occurs especially in pts with long standing hyperammonemia due to chronic liver disease, Wilson disease, or hereditary metabolic disorders of the urea cycle.

Front 13

13. What is vasogenic edema?

Back 13

Vasogenic edema occurs when the integrity of the normal BBB is disrupted and increased vascular permeability occurs, allowing fluid to escape from the intravascular compartment predominantly into the intercellular spaces of the brain.

The paucity of lymphatics and close apposition of cell processes of neurons and glia in the brain greatly impairs the resorption of excess extracellular fluid.

Front 14

14. What is cytotoxic edema?

Back 14

Cytotoxic edema, in contrast, implies an increase in intracellular fluid secondary to neuronal, glial, or endothelial cell membrane injury, as might be encountered in a pts w/a generalized hypoxic/ischemic insult or with some intoxications.

In practice, conditions associated w/generalized edema often have elements of both vasogenic and cytotoxic edema.

Front 15

15. What is hydrocephalic edema?

Back 15

Interstitial edema (hydrocephalic edema) occurs especially around the lateral ventricles when there is an abnormal flow of fluid from the intraventricular CSF across the ependymal lining to the periventricular white matter in a setting of increased intraventriclar pressure.

Front 16

16. What is the morphology of the edematous brain?

Back 16

The edematous brain is softer than normal and often appears to "overfill" the cranial vault.

In generalized edema, the gyri are flattened, the intervening sulci are narrowed, and the ventricular cavities are compressed. As the brain expands, herniation may occur.

Front 17

17. What is raised ICP mean?

Back 17

Raised ICP is an increase in mean CSF pressure above 200 mm water w/the pt recumbant.

Most cases are associated w/a mass effect, either diffuse, as in generalized brain edema, or focal, as with tumors, abscesses, or hemorrhages.

Front 18

18. What is a subfalcine (cingulate) herniation?

Back 18

A subfalcine herniation occurs when unilateral or asymmetric expansion of a cerebral hemisphere displaces the cingulate gyrus under the falx cerebri.

This may be associated w/compression of branches of the ACA.

Front 19

19. What is a transtentorial (uncinate) herniation?

Back 19

A transtentorial herniation occurs when the medial aspect of the temporal lobe is presed against the free margin of the tentorium cerebelli.

***W/increasing displacement of the temporal lobe, CN 3 is compromised, and the PCA may also be compressed.

Front 20

20. What is Kernohan's notch?

Back 20

When the extent of transtentorial herniation is large enough, the contralateral cerebral peduncle may be compressed, resulting in hemiparesis ipsilateral to the side of the herniation; the changes in the peduncle in this setting are known as Kernohan's notch.

Front 21

21. What is secondary brainstem or Duret hemorrhages?

Back 21

Progression of transtentorial herniation is often accompanied by hemorrhagic lesions in the midbrain and pons, termed secondary brainstem, or Duet, hemorrhages.

***These linear or flame-shaped lesions usually occur in the midline and paramedian regions and are believed to be due to tearing of penetrating veins and arteries supplying the upper brainstem.

Front 22

22. What is a tonsillar herniation?

Back 22

Tonsillar herniation refers to displacement of the cerebellar tonsils through the foramen magnum. This pattern of herniation is life-threatening b/c it causes brainstem compression and compromises vital respiratory and cardiac centers in the medulla oblongata.

Front 23

23. What is hydrocephalus?

Back 23

Hydrocephalus refers to the accumulation of excessive CSF w/in the ventricular system. Most cases occur as a consequence of impaired flow and resorption of CSF; in rare instances, (e.g., tumors of the choroid plexus), overproduction of CSF may be responsible.

Whatever the cause, an increased CSF volume w/in the ventricles expands them and can cause an elevation in ICP.

Front 24

24. What is the difference between hydrocephalus developing before closure of the cranial sutures and after?

Back 24

When hydrocephalus develops before closure, there is enlargement of the head, manifested by an increase in head circumference.

Hydrocephalus developing after fusion of the sutures, in contrast, is associated w/expansion of the ventricles and increased ICP, w/a change in head circumference.

Front 25

25. Communicating vs. noncommunicating hydrocephalus?

Back 25

If a portion of the ventricular system is enlarged b/c of excess CSF, as may occur b/c of a mass in the 3rd ventricle, the patter is called noncommunicating hydrocephalus.

In contrast, in communicating hydrocephalus, there is enlargement of the entire ventricular system.

Front 26

26. What is hydrocephalus ex vacuo?

Back 26

The term hydrocephalus ex vacuo refers to dilation of the ventricular system w/a compensatory increase in CSF volume secondary to a loss of brain parenchyma.

Front 27

27. What is anencephaly?

Back 27

Anencephaly is a malformation of the anterior end of the neural tube, w/absence of the brain and calvarium. It occurs in 1/1000 live births, more commonly in female, and is thought to develop at 28 days of gestation.

Front 28

28. What is the morphology of anencephaly?

Back 28

Forebrain development is disrupted and all that remains in its place is the area cerebrovasculosa, a flattened remnant of disorganized brain tissue w/admixed ependyma, choroid plexus, and meningothelial cells.

The posterior fossa structures may be spared, depending on the extent of the skull deficit; descending tracts associated w/disrupted structures are absent.

Front 29

29. What is an encephalocele?

Back 29

An encephalocele is a diverticulum of malformed CNS tissue extending through a defect in the cranium. It most often occurs in the occipital region or in the posterior fossa.

Front 30

30. Myelomeningocele vs. meningocele?

Back 30

Myelomeningocele refers to extension of CNS tissue through a defect in the vertebral column; the term meningocele applies when there is only a meningeal extrusion.

Front 31

31. What are the clinical features of myelomeningocele?

Back 31

Clinical neurologic dysfunction is most often related to the structural abnormality of the cord itself and to superimposed infection that extends from the thin, overlying skin.

Myelomeningoceles occur most commonly in the lumbosacral region, and the pt manifests clinical deficits referable to motor and sensory function in the lower extremities as well as disturbances of bowel and bladder control.

Front 32

32. What is polymicrogyria?

Back 32

Polymicrogyria is characterized by a loss of the normal contour of the cerebral convolutions, which appear small, unusually numerous, and irregularly formed.

The gray matter is composed of 4 or less layers, w/entrapment of apparent meningeal tissue at points of fusion of what would otherwise be a cortical surface.

Front 33

33. What is microencephaly and what causes it?

Back 33

The volume of the brain may be abnormally small or large. Microencephaly, the more common of the two, can occur in a wide range of settings, including chromosome abnormalities, fetal alcohol syndrome, and HIV-1 infection.

A reduction in the number of neurons that reach the neocortex is postulated, and this leads to a simplification of the gyral folding.

Front 34

34. What is Miller-Dieker syndrome?

Back 34

In the Miller-Dieker syndrome, (seizures, mental retardation, and agyria), about 90% of pts have a deletion in chromosome 17p13.3.

The involved gene has been termed LIS1, it is normally expressed in the CNS but is absent in this disorder.

Front 35

35. What is thanatophoric dwarfism?

Back 35

Abnormal gyral patterns are also found in chondrodysplasias; thanatophoric dwarfism is a lethal form characterized by abnormally large and hyperconvoluted temporal lobes and skeletal anomalies (micromelia, and chest and skull deformities).

Front 36

36. What is holoprosencephaly?

Back 36

Holoprosencephaly is a spectrum of malformations characterized by incomplete separation of the cerebral hemispheres across the midline. Severe forms manifest midline facial abnormalities, including cyclopia; less severe variants (arrhinecephaly) show absence of the olfactor cranial nerves and related structures.

***Related to trisomy 13 and 18, and caused by mutations in Sonic hedgehog gene.

Front 37

37. What is agenesis of the corpus callosum?

Back 37

In agenesis of the corpus callosum, a relatively common malformation, there is an absence of the white matter bundles that carry cortical projections from one hemisphere to the other. Radiologic imaging studies show misshapen lateral ventricles (*Bat wing deformity).

Pts with this malformation can be shown to have only minimal deficits even with neuropsychologic testing. The malformation may be complete or partial.

Front 38

38. What syndrome features agenesis of the corpus callosum?

Back 38

Agenesis of the corpus callosum is the major structural abnormality in Aicardi syndrome, an X-linked syndorme that is lethal in males, in which it is associated w/chorioretinal defects and seizures.

Front 39

39. What is the Arnold-Chiari malformation (type II)?

Back 39

The Arnold-Chiari malformation (type II) consists of a small posterior fossa, a misshapen midline cerebellum w/downward extension of vermis through the foramen magnum, and hydrocyephalus and a lumbar myelomeningocele.

Other associated changes may include caudal displacement of the medulla, malformation of the tectum, aqueductal stenosis, cerebral heterotopias, and hydromyelia.

Front 40

40. What is the Arnold-Chiari malformation (type I)?

Back 40

In the Chiari I malformation, low-lying cerebellar tonsils extend down into the vertebral canal and may cause symptoms referable to obstruction of the CSF flow and medullary compression that are amenable to neurosurgical intervention.

Front 41

41. What is the Dandy-Walker malformation?

Back 41

The Dandy-Walker malformation is characterized by an enlarged posterior fossa. The cerebellar vermis is absent or present in only rudimentary form in its anterior portion. In its place is a large midline cyst that is lined by ependyma and is contiguous w/leptomeninges on its outer surface. This cyst represents the expanded, roofless 4th ventricle in the absence of a normally formed vermis.

Dysplasias of brain stem nuclei are commonly found in association w/Dandy-Walker malformation.

Front 42

42. What is syringomyelia and hydromyelia?

Back 42

These are disorders characterized by a discontinuous multisegmental or confluent expansion of the ependyma-lined central canal of the cord (hydromyelia) or by the formation of a fluid-filled cleftlike cavity in the inner portion of the cord (syringomyelia).

These lesions are associated w/destruction of the adjacent gray and white matter and are surrounded by a dense feltwork of reactive gliosis. The cervical cord is most often affects, and the slit-like cavity may extend into the brainstem (syringobulbia).

Front 43

43. Syringomyelia may be associated with what disorder?

Back 43

Syringomyelia may be associated w/the Chiari I malformation. It may also occur in association with intraspinal tumors or following traumatic injury.

Front 44

44. What are the common clinical features in syringomyelia?

Back 44

The distinctive initial clinincal symptoms and signs of a syrinx are progressive evolution of dissociated sensory loss of pain and temp sensation in the upper extremities due to early involvement of the crossing anterior spinal commisural fibers, w/retention of position sense and absence of motor deficits.

Front 45

45. What does cerebral palsy mean?

Back 45

The term cerebral palsy refers to a nonprogressive neurologic motor deficit characterized by spasticity, dystonia, ataxia/athetosis, and paresis attributable to insults occurring during the prenatal and perinatal periods.

Signs and symptoms may not be apparent at birth and only later declare themselves as development proceeds.

Front 46

46. Who is at an increased risk of intraparenchymal hemorrhage?

Back 46

Premature infants. There is an increased risk of intraparenchymal hemorrhage w/in the germinal matrix, often near the junction btwn the thalamus and the caudate nucleus.

Hemorrhages may remain localized or extend into the ventricular system and thence to the subarachnoid space, sometimes leading to hydrocephalus.

Front 47

47. What is a periventricular leukomalacia?

Back 47

Infarcts may occur in the supratentorial periventricular white matter (periventricular leukomalacia), especially in premature babies. These are chalky yellow plaques consisting of discrete regions of white matter necrosis and mineralization.

Front 48

48. What is multicystic encephalopathy?

Back 48

When both gray and white matter are involved by extensive ischemic damage, large destructive cystic lesions develop throughout the hemispheres; this condition is termed multicystic encephalopathy.

Front 49

49. What is ulegyria?

Back 49

In perinatal ischemic lesions of the cerebral cortex, the depths of sulci bear the brunt of inury and result in thinned-out, gliotic gyri (ulegyria).

Front 50

50. What is status marmoratus?

Back 50

Later with the development of myelination, aberrant and irregular myelin formation gives rise to a marble-like appearance of the deep nuclei: "status marmoratus".

B/c the lesions are in the caudate, putamen, and thalamus, choreoathetosis and related movement disorders are important clinical sequelae.

Front 51

151. Where are skull fractures when an individual falls while awake vs. loss of consciousness?

Back 51

When an individual falls while awake, the site of impact is often in the occipital portion of the skull; in contrast, a fall that follows loss of consciousness, as might follow a syncopal attack, commonly result in frontal impact.

Front 52

152. When do basal skull fractures occur? What are the clinical features?

Back 52

Basal skull fractures typically follow an impact to the occiput or sides of the head rather than a blow to the vertex; these fractures are difficult to detect.

Symptoms referable to the lower cranial nerves or the cervicomedullary region, and the presence of orbital or mastoid hematomas distant from the point of impact, raise the clinical suspicion of a basal skull fracture.

CSF discharge from the nose or ear and infection (meningitis) may follow.

Front 53

153. What are the characteristic neurologic symptoms of a concussion?

Back 53

These symptoms include instantaneous onset of transient neurologic dysfunction, loss of consciousness, temporary respiratory arrest, and loss of reflexes. Although neurologic recovery is complete, amnesia for the event persists.

Biochemical and physiologic abnormalities occur, such as depolarization due to excitatory AA-mediated ionic fluxes across cell membranes, depletion of mitochondrial ATP, and alterations in vascular permeability.

Front 54

154. What are contusions and lacerations?

Back 54

Contusion and laceration are lesions associated w/direct parenchymal injury of the brain, either through transmission of kinetic energy to the brain and bruising analogous to what is seen in soft tissues (contusion) or by penetration of an object and tearing of tissue (laceration).

Front 55

155. What areas of the brain are most susceptible to injury?

Back 55

The crests of gyri are most susceptible, whereas the cerebral cortex along the sulci is less vulnerable.

The most common locations where contusions occur are the frontal lobes along the orbital gyri, and the temporal lobes. Contusions are less frequent over the occipital lobes, brainstem, and cerebellum.

Front 56

156. What is the morphology of contusions?

Back 56

Contusions, when seen on cross section, are wedge-shaped, with the broad base spanning the surface and centered on the point of impact.

The histologic appearance in the earliest stages is edema and hemorrhage which is often pericapillary. During the next few hours, the extravasation of blood extends throughout the involved tissue, across the width of the cerebral cortex, and into the white matter and subarachnoid space.

Front 57

157. Morphologic evidence of injury due to contusions happens when?

Back 57

Morphologic evidence of injury in the neuronal cell body (pyknosis of the nucleus, eosinophilia of the cytoplasm, disintegration of the cell) takes about 24 hours to appear, although functional brain injury occurs earlier.

The inflammatory response to injured tissue followed its usual course, with the appearance of neutrophils followed by macrophages.

Front 58

158. What do old lesions look like?

Back 58

Old traumatic lesions on the surface of the brain have a characteristic macroscopic appearance: they are depressed, retracted, yellowish brown patches involving the crests of gyri most commonly located at the sites of contrecoup lesions (inferior frontal cortex, temporal and occipital poles).

These are called "plaque jaune" (yellow plaque).

Front 59

159. What are the microscopic findings of diffuse axonal injury? How does this happen?

Back 59

The microscopic findings include axonal swelling, indicative of diffuse axonal injury, and focal hemorrhagic lesions.

The most widely accepted explanation for diffuse axonal injury is that mechanical forces damage the integrity of the axons at the node of Ranvier, with subsequent alterations in axoplasmic flow.

Front 60

160. What is the morphology of diffuse axonal injury?

Back 60

The histopathology of diffuse axonal injury is characterized by the wide but often asymmetric distribution of axonal swellings that appear w/in hours of the injury and may persist for much longer. These are best demonstrated w/silver stain or w/stains for Aβ protein. Later, there are increased numbers of microglia in related areas of cerebral cortex, and degeneration of the involved fiber tracts.

Front 61

61. What is an epidural hematoma?

Back 61

Vessels that course w/in the dura, most importantly the middle meningeal artery, are vulnerable to injury, particularly w/skull fractures. Trauma to the skull, esp in the region of the temporal bone, can lead to laceration of this artery if the fracture lines cross the course of the vessel.

The expanding hemtoma has a smooth inner contour that compresses the brain surface (subfalcine herniation). Clinically, pts can be lucid for several hours between the moment of trauma and the development of neurologic signs.

Front 62

62. What is a subdural hematoma?

Back 62

Bridging veins travel from the surface of the convexities of the cerebral hemispheres through the subarachnoid space and the subdural space to empty w/dural vessels into the superior saggital sinus. These vessels are particularly prone to tearing along their course through the subdural space; they are the source of bleeding in most cases of subdural hematoma.

Front 63

63. What is the morphology of an acute subdural hematoma?

Back 63

On macroscopic exam, the acute subdural hematoma appears as a collection of freshly clotted blood along the contour of the brain surface, w/o extension into the depths of sulci. Typically, venous bleeding is self limited; breakdown and organization of the hematoma take place in time.

Front 64

64. What is the typical sequence in the organization of subdural hematomas?

Back 64

1. Lysis of the clot (1 week)
2. Growth of fibroblasts from the dural surface into the hematoma (2 weeks)
3. Early development of hyalinized connective tissue (1-3 mos)

Front 65

65. What is a chronic subdural hematoma?

Back 65

A common finding in subdural hematomas, however, is the occurrence of multiple episodes of rebleeding (chronic subdural hematomas), presumably from the thin-walled vessels of the granulation tissue.

*The risk of rebleeding is greatest in the first few months after the initial hemorrhage.

Front 66

66. What are subarachnoid and intraparenchymal hemorrhages?

Back 66

Subarachnoid and intraparenchymal hemorrhages most often occur concomitantly in the setting of brain trauma with superficial contusions and lacerations.

Front 67

67. What is spat-apoplexie?

Back 67

Spat-apoplexie (delayed post traumatic hemorrhage) is a syndrome of sudden, deep intracerebral hemorrhage that follows even minor head trauma by an interval of 1-2 weeks.

Front 68

68. What are the clinical features of subdural hematomas?

Back 68

Subdural hematomas most often become manifest w/in the first 48 hours after injury. They are most common over the lateral aspects of the cerebral hemispheres and are bilateral in about 10% of cases.

Neurologic signs commonly observed are attributable to the pressure exerted on the adjacent brain. In time, there may be slowly progressive neurologic deterioration, but acute decompensation is rare.

Front 69

69. What is posttrauamtic dementia?

Back 69

Posttrauamtic dementia and the punch-drunk syndrome (dementia pugilistica) follow repeated head trauma during a protracted period; the neuropathologic findings include hdyrocephalus, thinning of the corpus callosum, diffuse axonal injury, neurofibrillary tangles, (mainly in the medial temporal areas), and diffuse Aβ positive plaques.

Front 70

70. What are the histologic changes of traumatic injury of the spinal cord?

Back 70

Similar to those found at other sites in the CNS. At the level of injury, the acute phase consists of hemorrhage, necrosis, and axonal swelling in the surrounding white matter. The lesion tapers above and below the level of injury.

In time, the central necrotic lesion becomes cystic and gliotic; cord sections above and below the lesion show secondary ascending and descending wallerian degeneration, respectively, involving the long white matter tracts affected at the site of trauma.

Front 71

71.What is the body's response to invasion of the CNS?

Back 71

CSF cell counts increase in response to infection

Front 72

72.What is aseptic meningitis?

Back 72

This is reflected by an increase in lymphocytes, mostly T cells, and monocytes in the CSF. A slight increase in protein also occurs, the CSF remaining clear. This is called aseptic meningitis.

Front 73

73. What is septic meningitis?

Back 73

The response to pyogenic bacteria shows a more spectacular and more rapid increase in polymorphonuclear leukocytes and proteins, so that the CSF becomes visibly turbid. This condition is termed septic meningitis.

Front 74

74. What is the preference of viruses for neural cells?

What about bacteria?

Back 74

Polio and rabies viruses, for instance, invade neurons, whereas JC virus invades olidodendrocytes.

B/c there is very little extracellular paces, spread is mostly direct from cell to cell along established nervous pathways.

Invading bacteria and protozoa generally induce more dramatic inflammatory events, which limit local spread so that infection is soon localized to form abscesses.

Front 75

75. What is postvaccinial encephalitis?

Back 75

Infiltrating B cells produce antibody to the invading microorganism, and T cells react with microbial antigens to release cytokines that attract and activate other T cells and macrophages.

The pathologic condition evolves over the course of several days and occasionally, when partly controlled by host defenses, over the course of years, e.g., subacute sclerosing panencephalitis (SSPE) caused by measles, which has both a virological and immunological pathogenesis.

Front 76

76. Does CNS invasion facilitate the spread of infection?

Back 76

Only rarely does CNS invasion assist in the transmission of infection.

The only time when it does are:
1. When dorsal root ganglion neurons are invaded as an essential step in establishing latency (HSV and VZV).
2. In the case of rabies,w here CNS invasion in the animal host is necessary.

Front 77

77. What are two reasons for why rabies requires CNS invasion in the animal host?

Back 77

1. It enables spread of the virus from the CNS down peripheral nerves to the salivary glands, from which transmission takes place.

2. Invasion of the limbic system of the brain causes a change in behavior of the infected animal so that it becomes less retiring, more aggressive, and more likely to bite, thus transmitting the infection. Invasion of the limbic system can be regarded as a fiendish strategy on the part of rabies virus to promote its own transmission and survival.

Front 78

78. What is acute (pyogenic) bacterial meningitis?

Back 78

Acute bacterial meningitis is a life-threatening infection, needing urgent specific treatment.

Bacterial meningitis is more severe but less common than viral meningitis. Prior to the '90's, H. influenzae type b (Hib) was responsible for most cases.

However, the intro of new vaccines into childhood immunization regimens has lowered overall Hib incidence in favor of N. meningitidis and S. pneumoniae, which are now responsible for most bacterial meningitis.

Front 79

79. What is meningococcal meningitis?

Back 79

Neisseria meningitidis is a Gram-negative diplococcus, which has an additional polysaccharide capsule that is antigenic and by which the serotype of N. meningitidis can be recognized.

The bacteria are carried asymptomatically in the population, up to 20% dependent on geographic location, and are attached by their pili to the epithelial cells in the nasopharynx.

Front 80

80. Who is susceptible to N. meningitidis infection?

Back 80

People possessing specific complement-dependent bacterial antibodies to capsular antigens are protected against invasion.

Those with C5-C9 complement deficiencies show increased susceptibility to bacteremia.

Young children who have lost the antibodies acquired from their mother, and adolescents who have not previously encountered the infecting serotype, and therefore have no type-specific immunity, are those most often infected.

Front 81

81.What serotypes of N. meningitidis dominate in more resource rich countries?

What serotypes are targeted by vaccines?

Back 81

Serotyeps B, C, and Y tend to predominate in more resource-rich countries, whereas serotypes A and W-135 are more common in less developed regions.

Available vaccines target serotypes A, C, Y, and W-135 but not B.

Front 82

82.What are the clinical features of meningococcal meningitis?

Back 82

After an incubation period of 1-3 days, the onset of emningococcal meningitis is sudden with a sore throat, headache, drowsiness, and signs of meningitis which include fever, irritability, neck stiffness and photophobia.

*There is often a hemorrhagic skin rash with petechiae, reflecting the associated septicemia.*

In about 35% of pts, this septicemia is fulminating, with complications due to DIC, endotoxemia and shock, and renal failure.

Mortality from meningococcal meningitis reaches 100% if untreated, but remains around 10% even if treated. In addition, serious sequelae such as permanent hearing loss may occur in some survivors.

Front 83

83. What is the Waterhouse-Friedrichsen syndrome?

Back 83

In the most severe cases of meningococcal meningitis, there is an acute Addisonian crisis, with bleeding into the brain and adrenal glands referred to as Waterhouse-Friedrichsen syndrome.

Front 84

84. What is haemophilus meningitis?

Back 84

Type b H. influenzae causes meningitis in infants and young children.

H. influenzae is a Gram-negative coccobacillus. There are six types (a-f), distinguishable by their capsular polysaccharides.

Front 85

85. What are the clinical signs and symptoms of acute H. influenza meningitis?

Back 85

The incubation period of H. influenzae meningitis is 5-6 days, and the onset is often more insidious than that of meningococcal or pneumococcal meningitis. The condition is less freq fatal, but, as with meningococcal infection, serious sequelae such as hearing loss, delayed language development, and mental retardation and seizures may occur.

General diagnostic features are the same as for meningococcal meningitis. It is important to note that the organisms may be difficult to see in Gram-stained smears of CSF, particularly if they are present in small numbers.

Front 86

86. What types of H. influenzae vaccines are effective?

Back 86

H. influenzae type b (Hib) vaccine is effective for children from 2 mos of age and upwards. Close contacts of pts are sometimes given rifampicin prophylaxis.

Front 87

87. What is pneumococcal meningitis?

Back 87

Streptococcus penumoniae is a common cause of bacterial meningitis, particularly in children and the elderly.

Strep. pneumonia is a capsulate Gram-positive coccus carried in the throats of many healthy individuals.

Little is known about its virulence attributes apart from its polysaccharide capsule, and the pneumococcus remains a major cause of morbidity and mortality.

Front 88

88. What type of people are infected with pneumococcal meningitis?

Back 88

Invasion of the blood and meninges is a rare event, but is more common in the very young (<2 years of age), in the elderly, in those with sickle cell disease, in debilitated or splenectomized pts and following head trauma.

Susceptibility to infection is associated with low levels of antibodies to capsular polysaccharide antigens: antibody opsonizes the organism and promotes phagocytosis, thereby protecting the host from invasion. However, this protection is type-specific and there are more than 85 different capsular types.

Front 89

89. What is listeria monocytogenes meningitis?

Back 89

Listeria monocytogenes is a Gram-positive coccobacillus and an important cause of meningitis in immunocompromised adults, especially in renal transplant and CA pts.

It also causes intrauterine infections and infections of the newborn.

L. monocytogenes is less susceptible than Strep. pneumoniae to penicillin, and the recommended Tx is with a combo of penicillin or ampicillin with gentamicin.

Front 90

90. What types of newborns are at risk of neonatal meningitis?

Back 90

In general, neonates, especially those with low birth weight, are at increased risk for meningitis b/c of their immature immunological status.

Although mortality rates due to neonatal meningitis in resource-rich countries are declining, the problem is still serious.

Front 91

91. What causes neonatal meningitis?

Back 91

Neonatal meningitis can be caused by a wide range of bacteria, but the most frequent are group B hemolytic streptococci, and E. coli.

This may occur by routes such as nosocomial infection. However, the infant may also be infected from the mother.

Front 92

92.What are the consequences of neonatal meningitis?

Back 92

Neonatal meningitis often leads to permanent neurologic sequelae such as cerebral or cranial nerve palsy, epilepsy, mental retardation or hydrocephalus. This is partly b/c the clinical Dx of meningitis in the neonate is difficult, perhaps with no more specific signs than fever, poor feeding, vomiting, respiratory distress or diarrhea.

In addition, due to the possible range of etiological agents, 'blind' antibiotic therapy in the absence of susceptibility tests may not be optimal, and adequate penetration of the antibiotic into the CSF is also an issue.

Front 93

93. What is the morphology of bacterial meningitis?

1/2

Back 93

The normally clear CSF is cloudy and sometimes frankly purulent. In acute meningitis, an exudate is evident within the leptomeninges over the surface of the brain. The meningeal vessels are engorged and stand out prominently. The location of the exudate varies depending on the microorganisms.

H. influenzae meningitis for example, is usually basal, whereas in pneumococcal meningitis, it is often densest over the cerebral convexities near the sagittal sinus. From the areas of greatest accumulation, tracts of pus can be followed along blood vessels on the surface of the brain. When the meningitis is fulminant, the inflammation may extend to the ventricles, producing ventriculitis

Front 94

94. What is the morphology of bacterial meningitis?

2/2

Back 94

On microscopic exam, neutrophils fill the entire subarachnoid space in severely affected areas and are found predominantly around the leptomeningeal blood vessels in less severe cases.

In untreated meningitis, Gram stain reveals varying numbers of the causative organism, although they are frequently not demonstrable in treated cases.

Front 95

95. What is the morphology of fulminant meningitis?

Back 95

In fulminant meningitis, the inflammatory cells infiltrate the walls of the leptomeningeal veins with potential extension of the inflammatory infiltrate into the substance of the brain (focal cerebritis). Phlebitis may also lead to venous occlusion and hemorrhagic infarction of the underlying brain.

Front 96

96. What may follow pyogenic meningitis?

What is chronic adhesive arachnoiditis?

Back 96

Leptomeningeal fibrosis and consequent hydrocephalus may follow pyogenic meningitis, although if it is treated early, there may be little remaining evidence of the infection.

In some infections, particularly in pneumococcal meningitis, large quantities of the capsular polysaccharide of the organism produce a particularly gelatinous exudate that encourages arachnoid fibrosis, called chronic adhesive arachnoiditis.

Front 97

97. What would the spinal tap reveal in septic meningitis?

Back 97

A spinal tap yields cloudy or frankly purulent CSF, under increased pressure, with as many as 90,000 neutrophils/mm^3, a raised protein level, and a markedly reduced glucose content.

Front 98

98. What is tuberculous meningitis?

Back 98

Pts with tuberculous meningitis always have a focus of infection elsewhere, but approximately 25% may have no clinical or historic evidence of such an infection.

In >50% of cases, meningitis is associated with acute miliary tuberculosis. In areas w/a high prevalence of tuberculosis, meningitis tends to be most commonly seen in children from 0-4 years of age. However, in areas where tuberculosis is less frequent, most meningitis cases are in adults.

Front 99

99. What are the signs and symptoms of tuberculous meningitis?

Back 99

Tuberculous meningitis usually presents with a gradual onset over a few weeks.

There is a gradual onset of generalized illness beginning with malaise, apathy and anorexia and proceeding within a few weeks to vomiting, photophobia, neck stiffness and impairment of consciousness.

Occasionally, the onset is more rapid and may be mistaken for a subarachnoid hemorrhage.

Front 100

100. What are the CSF findings in tuberculous meningitis?

Back 100

There is only a moderate CSF pleocytosis made up of mononuclear cells or a mixture of polymorphonuclear and mononuclear cells.

The protein level is elevated, often strikingly so, and the glucose content typically is moderately reduced or normal

Front 101

101. What is the morphology of tuberculous meningitis?

1/2

Back 101

On macroscopic exam, the subarachnoid space contains a gelatinous or fibrinous exudate, most often at the base of the brain, obliterating the cisterns and encasing cranial nerves. There may be discrete, white granules scattered over the leptomeninges.

*The most common pattern of involvement is a diffuse meningoencephalitis.

On microscopic exam, there are mixtures of lymphocytes, plasma cells, and macrophages. Florid cases show well-formed granulomas, often with caseous necrosis and giant cells.

Front 102

102. What is the morphology of tuberculous meningitis?

2/2

Back 102

Arteries running thru the subarachnoid space may show *obliterative endarteritis* with inflammatory infiltrates in their walls and marked intimal thickening.

Organisms can often be seen with acid-fast stains. The infectious process may spread to the choroid plexuses and ependymal surface, traveling thru the CSF.

Front 103

103. What is a tuberculoma?

Back 103

Another manifestation of tuberculous meningitis is the development of a single (or often multiple) well-circumscribed intraparenchymal mass (tuberculoma) which may be associated with meningitis.

A tuberculoma may be up to several cm in diameter, causing significant mass effect.

On microscopic exam, there is usually a central core of caseous necrosis surrounded by a typical tuberculous granulomatous reaction; calcification may occur in inactive lesions.

Front 104

104. What are the most serous complications of chronic tuberculous meningitis?

Back 104

The most serious complications are arachnoid fibrosis, which may produce hydrocephalus, and obliterative endarteritis, which may produce arterial occlusion and infarction of underlying brain. B/c the process involves the spinal cord subarachnoid space, spinal roots may also be affected.

Front 105

105. What about infection by mycobacterium tuberculosis in pts with AIDS?

Back 105

Tuberculous infection in pts with AIDS is often similar to those of non-AIDS pts, but there may be less host reaction.

HIV-positive pts are also at risk for infection by M. avium-intracellulare, usually in the setting of disseminated infection.

When this occurs, the lesions may consist of confluent sheets of macrophages filled with organisms, and minimal granulomatous reaction.

Front 106

106. What is fungal meningitis?

Back 106

Cryptococcus neoformans and Coccidiodes immitis can invade the blood from a primary site of infection in the lungs and thence to the brain to cause meningitis.

Cryptococcus has a marked tropism for the CNS and is the major cause of fungal meningitis. C. neoformans occurs as two varieties, each with two serotypes.

Front 107

107. What is cryptococcus neoformans meningitis?

Back 107

C. neoformans meningitis is seen in pts with depressed cell-mediated immunity. It therefore occurs in individuals with AIDS and other immunosuppressive conditions.

The onset is usually slow, over days or weeks. The capsulate yeasts can be seen in India-ink stained preparations of CSF and can be cultured.

The CSF may have few cells but a high concentration of protein.

Front 108

108. What is the morphology of cryptococcal meningitis?

Back 108

With cryptococcal infection, the brain shows a chronic meningitis affecting the basal leptomeninges, which are opaque and thickened by reactive connective tissue and may obstruct the outflow of CSF and give rise to hydrocephalus.

*Sections of the brain disclose a gelatinous material w/in the subarachnoid space and small cysts w/in the parenchyma ("soap bubbles"), which are essentially prominent in the basal ganglia in the distribution of the lenticulostriate arteries. Parenchyma lesions consist of aggregates of organisms w/in expanded perivascular (Virchow-Robin) spaces associated with minimal or absent inflammation or gliosis.

Front 109

109. What is coccidioides immitis meningitis?

Back 109

C. immitis infection is common in particular geographic locations. These locations are notably Southwest, USA, Mexico, and South America. CNS infection occurs in < 1% of infected individuals, but is fatal unless treated. It may be part of the generalized disease or may represent the only extrapulmonary site.

The organisms are rarely visible in the CSF, and cultures are positive in < 50% of cases, but the Dx can be made by demonstrating complement-fixing antibodies in the serum. Tx with amphotericin B, fluconazole, or miconzole is recommended.

Front 110

110. What are the three main patterns of fungal infection in the CNS?

Back 110

1. Chronic meningitis
2. Vasculitis
3. Parenchymal invasion

Front 111

111. Which fungi commonly produce vasculitis?

Back 111

Vasculitis is most frequently seen with Mucor and Aspergillus, both of which have a marked predilection for invasion of blood vessel walls, but it occasionally occurs with other organisms, such as Candida.

The resultant vascular thrombosis produces infarction that is often strikingly hemorrhagic and that subsequently becomes septic from ingrowth of the causative fungus.

Front 112

112. Which fungi commonly produce parenchymal invasion?

Back 112

Parenchymal invasion, usually in the form of granulomas or abscesses, can occur w/most of the fungi and often coexists with meningitis.

The most commonly encountered fungi invading the brain are Candida and Cryptococcus. Candida usually produces multiple microabscesses, with or without granuloma formation.

Front 113

113. What is viral meningitis?

Back 113

Viral meningitis is the most common type of meningitis. It is a milder disease than bacterial meningitis, with headache, fever and photophobia, but less neck stiffness.

The CSF is clear in the absence of bacteria, and the cells are mainly lymphocytes, although polymorphonuclear leukocytes may be present in the early stages.

Front 114

114. What viruses causes meningitis?

Back 114

There are five groups of human enteroviruses which include the echoviruses, coxsackie Group A and B viruses, and the three polioviruses.

Infection is commonly asymptomatic, and therefore and enterovirus isolated from the throat or stool of a child w/mild meningitis may be of no help.

However, the enteroviruses are common causes of seasonal aseptic meningitis. In contrast to bacterial meningitis, viral meningitis usually has a benign course, and complete recovery is the rule.

Front 115

115. What is acute aseptic viral meningitis?

Back 115

The clinical course is less fulminant than that of pyogenic meningitis, and the CSF findings also differ between the two conditions.

*In aseptic meningitis, there is a lymphocytic pleocytosis, the protein elevation is only moderate, and the sugar content is nearly always normal.

Front 116

116. What is drug-induced aseptic meningitis?

What about other causes of aseptic meningitis?

Back 116

A true noninfectious process has been associated with some classes of medications, including NSAIDs and antibiotics; this entity is has been termed drug-induced aseptic meningitis.

An aseptic meningitis-like picture may also develop subsequent to rupture of an epidermoid cyst into the subarachnoid space or the introduction of a chemical irritant.

In these cases, the CSF is sterile, there is pleocytosis with neutrophils and a raised protein level, but the sugar content is usually normal.

Front 117

117. What is encephalitis?

Back 117

Encephalitis is usually caused by viruses, but there are many cases where the infectious etiology is not identified. Characteristically, there are signs of cerebral dysfunction, as the substance of the brain is affected, unlike meningitis where the lining of the brain is inflamed.

Someone with encephalitic illness will present with abnormal behavior, seizures, and altered consciousness, often with nausea, vomiting, and fever.

Front 118

118. What are the non-viral causes of encephalitis?

Back 118

Toxoplasma gondii and C. neoformans can also cause life-threatening encephalitis or meningoencephalitis. This is particularly likely in those with defective cell-mediated immunity, and cerebral malaria as a complication of Plasmodium falciparum infection is frequently fatal.

Encephalitis may occur in Lyme disease and Legionnaire's disease, but the relative importance of bacterial invasion, bacterial toxins and immunopathology is unknown.

Front 119

119. What are the most characteristic histologic features of viral encephalitis?

Back 119

***The most characteristic histologic features of viral encephalitis are perivascular and parenchymal mononuclear cell infiltrates (lymphocytes, plasma cells, and macrophages), glial cell reactions (including the formation of microglial nodules), and neuronophagia.***

Direct indications of viral infection are the presence of viral inclusion bodies and, most important, the identification of viral pathogens by ultrastructural immunocytochemical, and molecular methods.

Front 120

120. What is HSV encephalitis (HSE)?

How are HSV infections of the CNS different from those in older children and adults?

Back 120

HSE is the most common form of severe sporadic acute focal encephalitis. It is thought that the incidence of HSE in the USA is about 1/250,000 - 1/500,000 per year.

A distinction is made between HSV infections of the CNS during the neonatal period and those in older children and adults. Neonates may acquire a primary and disseminated infection with diffuse encephalitis after vaginal delivery from a mother shedding HSV-2 in the genital tract.

***Most HSE seen in older children and adults is due to HSV-1, of which are due to virus reactivation in the trigeminal ganglia, the infection then passing back to the temporal lobes of the brain, and the minority are due to a primary infection.

Front 121

121. What is HSV-1 encephalitis?

Back 121

HSV-1 produces an encephalitis that occurs in any age group but is most common in children and young adults.

Only about 10% of the pts have a history of prior herpes. The most commonly observed clinical presenting symptoms in HSE are alterations in mood, memory, and behavior.

Herpetic skin or mucosal lesions may be present. The Dx is indicated by finding temporal lobe enhancement using CT and MRI scan. HSV DNA detection should be carried out on a CSF sample using PCR.

Front 122

122. What is the morphology of HSV-1 encephalitis?

Back 122

***HSV-1 encephalitis starts in, and most severely involves, the inferior and medial regions of the temporal lobes and the orbital gyri of the frontal lobes.*** The infection is necrotizing and often hemorrhagic in the most severely affected regions.

*Perivascular inflmmatory infiltrates are usually present, and Cowdry type A intranuclear viral inclusion bodies may be found in both neurons and glia.*

In pts with slowly evolving HSV-1 encephalitis, there is more diffuse involvement of the brain.

Front 123

123. What is the clinical course of HSV-1 encephalitis?

Back 123

The 70% mortality rate in untreated pts is greatly reduced by early and prolonged treatment with IV aciclovir. The 21 day treatment course is important as relapse can occur.

In some individuals, HSV-1 encephalitis follows a subacute course with clinical manifestations (weakness, lethargy, ataxia, seizures) that evolve during a more protracted period.

Front 124

124. What about HSV-2 encephalitis?

Back 124

HSV-2 also infects the nervous system and usually manifests in adults as a meningitis.

A generalized and severe encephalitis develops in as many as 50% of neonates born by vaginal delivery to women with active primary HSV genital infections. The dependence on route of delivery indicates that the infection is acquired during passage thru the birth canal rather than transplacentally.

In AIDS pts, HSV-2 may cause an acute, hemorrhagic, necrotizing encephalitis.

Front 125

125. What other herpesviruses less commonly cause encephalitis?

Back 125

With VZV, encephalitis generally occurs as a sequel to reactivation, and with CMV either during primary infection in utero or reactivation as a complication of immunodeficiency, for example in AIDS.

HHV6 encephalitis has also been reported in immunosuppressed pts.

Finally, B virus is a Cercopicthecine herpesvirus of macaque monkeys that does not really affect the animal but can cause a severe and fatal encephalitis in humans when bitten or scratched by an infected monkey. The wound should be cleaned immediately and antiviral prophylaxis is recommended.

Front 126

126. What are the features of VZV encephalitis?

Back 126

Herpes zoster reactivation is usually a self-limited process, but there may be a persistent postherpetic neuralgia syndrome n up to 10% of pts. Overt CNS involvement with herpes zoster is much rarer but can be more severe.

Herpes zoster has been associated with a granulomatous arteritis.

In immunosuppressed pts, it may cause an acute encephalittis with numerous sharply circumscribed lesions characterized by demyelination followed by necrosis. Inclusion bodies can be found in glia and neurons.

Front 127

127. What is the most common opportunistic viral pathogen in pts with AIDS, affecting the CNS in 15-20% of cases?

Back 127

CMV

Front 128

128. What is the morphology of CMV encephalitis?

Back 128

In the immunosuppressed individual, the most common pattern of involvement is that of a subacute encephalitis, which may be associated with CMV inclusion-bearing cells.

*Although any type of cell within the CNS (neurons, glia, ependyma, endothelium) can be infected by CMV, there is a tendency for the virus to localize in the paraventricular subependymal regions of the brain.*

This results in a severe hemorrhagic necrotizing ventriculoencephalitis and a choroid plexitis. The virus can also attack the lower spinal cord and roots, producing a painful radiculoneuritis.

Prominent cytomegalic cells with intranuclear and intracytoplasmic inclusion can be readily identified on microscopic exam.

Front 129

129. What is poliomyelitis?

Back 129

Poliovirus used to be a common cause of encephalitis. Poliovirus is a member of the picorna group of enteroviruses. In nonimmunized individuals, poliovirus infection causes a subclinical or mild gastroenteritis. In a small fraction of the vulnerable population, however, it secondarily invades the nervous system.

After an initial 1-4 days of fever, sore throat and malaise, meningeal signs and symptoms appear, followed by involvement of motor neurons and paralysis.

Front 130

130. What is the paralysis like in poliomyelitis?

Back 130

When the disease affects the spinal cord with loss of motor neurons, it produces a flaccid paralysis with muscle wasting and hyporeflexia in the corresponding region of the body- the permanent neurologic residue of poliomyelitis.

In the acute disease, death can occur from paralysis of the respiratory muscles, and a myocarditis sometimes complicates the clinical course.

Permanent cranial nerve (bulbar) weakness is rare, as is any evidence of encephalitis, but severe respiratory compromise and an important cause of long-term morbidity.

At least 75% of paralytic cases are due to type 1 polioviruses.

Front 131

131. What is postpolio syndrome?

Back 131

A late neurologic syndrome can develop in pts affected by poliomyelitis who had been stable during intervening years (postpolio syndrome).

This syndrome, which typically develops 25-35 years after the resolution of the initial illness, is characterized by progressive weakness associated with decreased muscle mass and pain, and has an unclear pathogenesis.

Front 132

132. What is the morphology of poliomyelitis?

Back 132

Acute cases show mononuclear cell perivascular cuffs and neuronophagia of the anterior horn motor neurons of the spinal cord. In situ reverse transcriptase PCR has shown poliovirus RNA in anterior horn cell motor neurons.

The inflammatory reaction is usually confined to the anterior horns but may extend into the posterior horns, and the damage is occasionally severe enough to produce cavitation. The motor cranial nuclei are sometimes involved.

Front 133

133. How is rabies virus spread?

Back 133

The virus is excreted in the saliva of infected dogs, foxes, jackals, wolves, skunks, racoons and vampire and other bats, and transmission to humans follows a bite or salivary contamination of other types of skin abrasions or wounds. Some species of animal, such as foxes, are more infectious than others, b/c larger amts of virus are present in their saliva.

The infection is eventually fatal, although the course of the disease varies considerably between species.

Front 134

134. How does the rabies virus infect humans?

Back 134

The incubation period in humans is generally 4-13 weeks, although it may occasionally be as long as 6 mos, possibly due to a delay in virus entry into peripheral nerves. The virus travels up peripheral nerves and, in general, the further the bite is from the CNS, the longer the incubation period.

While the virus is traveling up the axons of motor or sensory neurons, there is no detectable antibody or cell mediated immune response, possibly b/c antigen remains sequestered in infected muscle cells. Hence, passively administered Ig may be given during the incubation period.

Front 135

135. What are the clinical features of rabies?

Back 135

After developing a sore throat, headache, fever and discomfort at the site of the bite, the pt becomes excited, with muscle spasms and convulsions. Involvement of the muscles of swallowing when attempting to drink water gave the old name for rabies, hydrophobia, as the symptoms are sometimes precipitated by the mere site of water.

Once rabies have developed it is fatal, death occurring following cardiac or respiratory arrest. Paralysis is often a major feature of the disease. Periods of alternating mania and stupor progress to coma and death from respiratory center failure.

Front 136

136. What is the morphology of rabies?

Back 136

On macroscopic exam, the brain shows intense edema and vascular congestion. On microscopic exam, there is widespread neuronal degeneration and an inflammatory reaction that is most severe in the rhombencephalon (mid brain, particularly in the medulla). The basal ganglia, spinal cord, and dorsal root ganglia may also be involved.

***Negri bodies, the pathognomonic microscopic finding, are cytoplasmic, round to oval, eosinophilic inclusions that can be found in pyramidal neurons of the hippocampus and Purkinje cells of the cerebellum.***

Front 137

137. What about arthropod-borne togaviruses?

Back 137

Numberous arthropod-borne togaviruses can cause meningitis or encephalitis. In different parts of the world, different mammals, birds or even reptiles act as reservoirs and there are a variety of arthropod (mosquito and tick) vectors. Usually < 1% of humans infected develop neurologic disease. There may be a febrile illness, but asymptomatic infection is common.

Front 138

138. What are the most important types of arthropod-borne viruses?

Back 138

In the Western hemisphere, teh msot improtant yptes are Eastern and Western equine, Venezuelan, St. Louis, and La Cross.

Elsewhere in the world, pathogenic arboviruses include Japanese B (Far east), Murray Valley (austrialia and New Guinea), and tick-borne (Russia and Eastern Europe).

All have animal hosts and mosquito vectors, except for the tick born type.

Front 139

139. What is the CSF like in arthropod borne viral encephalitis?

Back 139

The CSF is usually colorless but with a slightly elevated pressure and, initially, a neutrophilic pleocytosis that rapidly converts to lymphocytes.

The protein level is elevated, but sugar content is normal.

Front 140

140. What is the morphology of arthropod-borne viral encephalitis?

Back 140

Characteristically, there is a lymphocytic meningoencephalitis (sometimes with neutrophils) with a tendency for inflammatory cells to accumulate perivascularly.

Multiple foci of necrosis of gray and white matter are found; in particular, there is evidence of single-cell neuronal necrosis with phagocytosis of the debris (neuronophagia).

Front 141

141. When does HIV aseptic meningitis occur?

Back 141

HIV aseptic meningitis occurs w/in 1-2 weeks of seroconversion in about 10% of pts; antibodies to HIV can be demonstrated, and the virus can be isolated from the CSF.

HIV invasion of the nervous system have shown a mild lymphocytic meningitis, perivascular inflammation, and some myelin loss in the hemispheres.

Front 142

142. What is AIDS-dementia complex (ADC)?

Back 142

The dementia begins insidiously, w/mental slowing, memory loss, and mood disturbances, such as apathy and depression. Motor abnormalities, ataxia, bladder and bowel incontinence, and seizures can also be present.

Radiologic imaging of the brain may be normal or may show some diffuse cortical atrophy, focal abnormalities of the cerebral white matter, and ventricular dilation.

Front 143

143. What is the morphology of HIV encephalitis?

Back 143

On macroscopic exam, the meninges are clear and there is some ventricular dilation w/sulcal widening but normal cortical thickness. This process is best described as a chronic inflammatory reaction with widely distributed infiltrates of microglial nodules, sometimes associated with foci of tissue necrosis and reactive gliosis.

The microglial nodules show abnormally prominent endothelial cells and perivascular foamy or pigment-laden macrophages.

*These changes occur especially in the subcortical white matter, diencephalon, and brainstem.*

Front 144

144. What is an important component of the microglial nodule?

Back 144

The macrophage-derived multinucleated giant cell.

Front 145

145. What is vacuolar myelopathy?

Back 145

This disorder of the spinal cord is found in 20-30% of pts with AIDS in the US. The histopathologic findings resemble those of subacute combined degeneration, though serum levels of vitamin B12 are normal.

The pathogenesis of the lesion is unknown; it does not appear to be caused directly by HIV, and the virus is not present within the lesions.

Front 146

146. What is tropic spastic paraparesis, or HTLV-1-associated myelopathy (HAM)?

Back 146

HAM occurs in several countries in the Caribbean, along the Indian Ocean, in Japan, and in South America.

Some cases show a severe lymphocytic meningomyelitis unlike that seen in vacuolar myelopathy. Virologic studies and polymerase chain reaction data have implicated another retrovirus: human T-cell lymphotrophic virus (HTLV-1).

Front 147

147. What is AIDS- associated myopathy?

Back 147

Inflammatory myopathy has been the most often described skeletal muscle disorder in pts with HIV infection. The disease is characterized by the subacute onset of proximal weakness, sometimes pain, and elevated levels of serum CK.

The histologic findings include muscle fiber necrosis and phagocytosis, interstitial infiltration with HIV-positive macrophages, and in a few cases, cytoplasmic bodies and nemaline rods.

Front 148

148. An acute, toxic, reversible myopathy with "ragged red" fibers and myoglobinuria may also develop in what condition...?

Back 148

*An acute, toxic, reversible myopathy with "ragged red" fibers and myoglobinuria may also develop in...

pts treated with zidovudine (AZT).

Front 149

149. What about AIDS in children?

Back 149

Neurologic disease was common in children with congenital AIDS, occurring in 15-30% of infants born to seropositive mothers; the incidence has decreased due to HAART.

*Clinical manifestations of neurologic dysfunction are evident by the first years of life and include microcephaly with mental retardation and motor developmental delay with spasticity of limbs.*

Front 150

150. What is the most frequent neural morphologic abnormality in children with AIDS?

Back 150

The most frequent morphologic abnormality is calcification of the large and small vessels and parenchyma within the basal ganglia and deep cerebral white matter.

There is also loss of hemispheric myelin or delay in myelination; multinucleated giant cells and microglial nodules are also observed in many cases. HIV is present in brain tissue.

Front 151

151. What is PML?

Back 151

Progressive multifocal leukocencephalopathy (PML) is a viral encephalitis caused by the JC polyomavirus; because the virus preferentially infects oligodendrocytes, demyelination is its principal pathologic effect.

The disease occurs almost invariably in immunocuppressed individuals in various clinical settings, including chronic lymphoproliferative or myeloproliferative diseases, immunosuppressive chemotherapy, granulomatous diseases, and AIDS.

Although the incidence of PML appears to be decreasing HIV-infected individuals w/the advent of HAART, there may be direct interaction btwn HIV and JC viruses w/in cells.

Front 152

152.What are the clinical symptoms of PML?

Back 152

No clinical disease has been associated with primary infection by the JC virus, but about 65% of normal people have serologic evidence of exposure to the virus by the age of 14 years. It is thought that PML results from the reactivation of virus as a result of immunosuppression.

*Clinically, pts develop focal and relentlessly progressive neurologic symptoms and signs, and both CT and MRI scans show extensive, often multifocal lesions in the hemispheric or cerebellar white matter.*

Front 153

153. What is the morphology of PML?

Back 153

The lesions consist of patches of irregular, ill-defined destruction of the white matter ranging in size from mm's to extensive involvement of an entire lobe of the brain. The cerebrum, brainstem, cerebellum, and occasionally the spinal cord can be involved.

*On microscopic exam, the typical lesion consists of a patchy of demyelination, most often in a subcortical location, in the center of which are scattered lipid-laden macrophages and a reduced number of axons.* At the edge of the lesion are greatly enlarged oligodendrocyte nuclei whose chromatin is replaced by glassy amphophilic viral inclusion.

Within the lesions, there may be bizarre giant astrocytes with irregular, hyperchromatic, sometimes multiple nuclei. Reactive fibrillary astrocytes are scattered among the bizarre forms.

Front 154

154. What is subacute sclerosing panencephalitis?

Back 154

SSPE is a rare progressive clinical syndrome characterized by cognitive decline, spasticity of limbs, and seizures.

It occurs in children or young adults, months or years after an initial, early-age acute infection with measles.

This disease is thought to represent persistent, but nonproductive, infection of the CNS by an altered measles virus; changes in several viral genes have been associated with the disease.

With widespread measles vaccination programs, the disease seems to have largely disappeared.

Front 155

155. What is the morphology of SSPE?

Back 155

On microscopic exam, there are widespread gliosis and myelin degeneration; viral inclusions, largely within the nuclei, or oligodendrocytes and neurons; variable inflammation of white and gray matter; and neurofibrillary tangles.

Ultrastructural study shows that the inclusions contain nucleocapsids characteristic of measles, and the measles virus antigen is positive.

Front 156

156. What are spongiform encephalopathies caused by scrapie-type agents?

Back 156

Scrapie-type agents are closely associated with host-coded prion protein. Scrapie type agents infect a variety of mammals, including humans, and are transmissible to lab rodents or primates.

Disease is characterized by the appearance of a spongiform appearance of nervous tissues, caused by vacuolation and plaque formation.

Infections in animals seem to have originated from sheep and goats with scrapie which has been present in Europe for 200-300 years. Affected animals itch and scrape themselves against posts for relief.

Front 157

157. What part of the body is an important target in toxoplasmosis?

Back 157

The CNS is an important target in toxoplasmosis. Although congenitally acquired T. gondii is initially generalized, it may become localized in the CNS. Damage to the eye is the most common consequence, but the brain may also be affected, with hydrocephalus and intracerebral calcification.

Before HAART, toxoplasmosis was an important cause of death in AIDS pts, with encephalitis and toxoplasma abscess due to necrosis as contributory causes. It is still one of the most common causes of neurologic symptoms and morbidity in pts with AIDS.

Front 158

158. The abscesses in toxoplasmosis in the CNS appear where?

Back 158

In toxoplasmosis of the CNS, the brain shows abscesses, frequently multiple, most involving the cerebral cortex (near the gray-white junction) and deep gray nuclei, less often the cerebellum and brainstem, and rarely the spinal cord.

The blood vessels in the vicinity of these lesions may show marked intimal proliferation or even frank vasculitis with fibrinoid necrosis and thrombosis.

Front 159

159. What is the morphology of toxoplasmosis in the CNS?

Back 159

Acute lesions consist of central foci of necrosis with variable petechiae surrounded by acute and chronic inflammation, macrophage infiltration, and vascular proliferation. *Both free tachyzoites and encysted bradyzoites may be found at the periphery of the necrotic foci.*

After treatment, the lesions consist of large, well-demarcated areas of coagulation necrosis surrounded by lipid-laden macrophages.

Front 160

160. What are the symptoms of toxopasmosis in the fetus?

Back 160

Primary maternal infection with toxoplasmosis, particularly if it occurs early in the pregnancy, may be followed by a cerebritis in the fetus, with the production of multifocal cerebral necrotizing lesions that may calcify, producing severe damage to the developing brain.

Front 161

161. What are brain abscesses?

Where do they come from?

Back 161

Brain abscesses are usually associated with predisposing factors. They may arise by direct implantation of organisms, local extension from adjacent foci (mastoidits, paranasal sinusitis), or hematogenous spread (usually from a primary site in the heart, lungs, or distal bones or after tooth extraction).

Predisposing conditions include acute bacterial endocarditis, which tends to produce multiple abscesses; cyanotic heart disease, in which there is a right-to-left shunt and loss of pulmonary filtration or organisms, and chronic pulmonary sepsis, as can be seen with bronchiectasis.

Acute abscesses are caused by various bacteria, generally of oropharyngeal origin, including anaerobes. Chronic abscesses may be due to M. tuberculosis or C. neoformans.

Front 162

162. What are the most common offending organisms in brain abscesses in the nonimmunosuppresed?

Back 162

Streptococci and staphylococci are the most common offending organisms identified in nonimmunosuppressed populations.

Front 163

163. What are the clinical features of cerebral abscesses?

Back 163

Cerebral abscesses are destructive lesions, and pts almost invariably presents clinically with progressive focal deficits in addition to the general signs of raised ICP.

***The CSF is under increased pressure; the white cell count and protein level are raised but the sugar content is normal***

The increased ICP and progressive herniation can be fatal, and abscess rupture can lead to ventriculitis, meningitis, and venous sinus thrombosis.

Front 164

164. What is the morphology of brain abscesses?

Back 164

On macroscopic exam, abscesses are discrete lesions with central liquefactive necrosis, a surrounding fibrous capsule, and edema.

On microscopic exam, there is exuberant granulation tissue with neovascularization around the necrosis that is responsible for the marked vasogenic edema. The collagen of the capsule is produced by fibroblasts. Outside the fibrous capsule is a zone of reactive gliosis with numerous gemistocytic astrocytes.

Front 165

165. What are the most common locations for cerebral abscesses, in descending order?

Back 165

In descending order:

1. Frontal lobe
2. Parietal lobe
3. Cerebellum

Front 166

166. What is a subdural empyema?

Back 166

Bacterial or occasionally fungal infection of the skull bones or air sinuses can spread to the subdural space and produce a subdural empyema. The underlying arachnoid and subarachnoid spaces are usually unaffected, but a large subdural empyema may develop in the bridging veins that cross the subdural space, resulting in venous occlusion and infarction of the brain.

Symptoms include those referable to the source of the infection. In addition, most pts are febrile, with headache and neck stiffness, and if untreated, may develop focal neurologic signs, lethargy, and coma.

Front 167

167. What is an extradural abscess?

Back 167

Extradural abscess, commonly associated with osteomyelitis, often arises from an adjacent focus of infection, such as sinusitis or a surgical procedure.

When the process occurs in the spinal epidural space, it may cause spinal cord compression and constitute a medical emergency.

Front 168

168. What is neurosyphilis? What are the three types?

Back 168

Neurosyphilis is the tertiary stage of syphilis and occurs in about only 10% of pts with untreated infection.

The major forms are meningovascular neurosyphilis, paretic neurosyphilis, and tabes dorsalis.

Front 169

169. What is meningovascular neurosyphilis?

Back 169

Meningovascular neurosyphilis is a chronic meningitis involving the base of the brain, and variably, also the cerebral convexities and the spinal leptomeninges. In addition, there may be an associated obliterative endarteritis (Heubner arteritis) accompanied by a distinctive perivascular inflammatory reaction rich in plasma cells and lymphocytes.

Cerebral gumma (plasma cell-rich mass lesions) may also occur in relation to meninges and extending into the cerebral hemispheres, diencephalon, or spinal cord.

Front 170

170. What is paretic neurosyphilis?

Back 170

Paretic neurosyphilis is caused by invasion fo teh brain by T. pallidum and is clinically manifested as insidious but progressive loss of mental and physical functions with mood alterations (including delusions of grandeur), terminating in severe dementia called general paresis of the insane.

Front 171

171. What is the morphology of paretic neurosyphilis?

Back 171

On microscopic exam, inflammatory lesions are associated with parenchymal damage in teh cerebral cortex (particuarly the frontal lobe but also affecting other areas of teh isocortex) chracterized by loss of neurons with proliferation so microglia (rod cells), gliosis, and iron depsoits demonstrable with the Prussian blue stain.

The spirochetes can be, at times, demonstrated in tissue sections. ***There is often an associated hydrocephalus w/damage to the ependymal lining and proliferation of subependymal glia, called granular ependymitis.***

Front 172

172. What is tabes dorsalis?

Back 172

Tabes dorsalis is the result of damage by the spirochete to the sensory nerves in the dorsal roots which produces impaired joint position sense and resultant ataxia (locomotor ataxia); loss of pain sensation leading to skin and joint damage (Charcot joints); other sensory disturbances, particularly the characteristic "lightning pains" ; and absence of deep tendon reflexes.

On microscopic exam, there is loss of both axons and myelin in the dorsal roots, with pallor and atrophy in the dorsal columns of the spinal cord.

Front 173

173. Who is at an increased risk for neurosyphilis?

Back 173

Patients with HIV infection are at an increased risk for neurosyphilis, and the rate of progression and severity of the disease appear to be accelerated, presumably related to the impaired cell-mediated immunity.

CNS involvement by T. pallidum in this setting may be manifested as asymptomatic infection, acute syphilitic meningitis, meningovascular syphilis, and rarely, direct parenchymal invasion of the brain.

Front 174

174.What is neuroborreliosis (lyme disease)?

Back 174

Lyme disease is caused by the spirochete Borrelia burgdorferi, transmitted by various species of Ixodes tick; invovlement of the nervous sytem is referred to as neuroborreliosis.

Neurologic symptoms are highly variable and include aseptic meningitis, facial nerve palsies, mild encephalopathy, and polyneuropathies. The rare cases that have come to autopsy have shown a focal proliferation of microglial cells in the brain as well as scattered organisms (identified by Dieterle stain) in the extracellular spaces.

Front 175

175. What are transmissible spongiform encephalopathies?

Back 175

These diseases are characterized by spongiform changes due to intracellular vacuoles in neural cells. These are associated with abnormal forms of a specific protein, termed prion protein (PrP). Diseases may be sporadic, infectious, and transmissible, and include:

1. Creutzfeldt-Jakob disease, kuru, Gerstmann-Straussler-Scheinker syndrome
2. Scrapie in sheep and goats
3. Mink transmissible encephalopathy
4. Bovine spongiform encephalopathy (mad cow disease)
5. Chronic wasting disease

Front 176

176. What is the pathogenesis of the prion diseases?

Back 176

PrP is a normal cellular protein; disease occurs when PrP changes from a native isoform to an abnormally folded isoform, termed PrP scrapie. The infectious nature of PrP scrapie molecules derives from its ability to induce misfolding of native PrP and thus corrupt the integrity of normal cellular PrP.

*Accumulation of PrP scrapie appears to be the cause of the pathologic changes in these diseases, but the pathways by which this material causes the development of cytoplasmic vacuoles and eventual neuronal death are unknown.

Front 177

177. What is protective against vCJD and CJD?

Back 177

Heterozygosity at codon 129 is protective against development of vCJD and sporadic CJD.

Front 178

178. What is the morphology of spongiform diseases?

1/2

Back 178

The progression of the dementia in CJD is usually so rapid that there is little if any macroscopic evidence of brain atrophy. ***The pathognomonic finding is a spongiform transformation of the cerebral cortex and, often, deep gray matter structures (caudate, putamen); this consists of a multifocal process that results in the uneven formation of small, apparently empty, microscopic vacuoles of varying sizes within the neuropil and sometimes in the perikaryon of neurons.***

Front 179

179. What is the morphology of spongiform diseases?

2/2

Back 179

In advanced cases, there is severe neuronal loss, reactive gliosis, and sometimes expansion of the vacuolated areas into cystlike spaces ("status spongiosus"). No inflammatory infiltrate is present.

Kuru plaques are extracellular deposits of aggregated abnormal protein; they are Congo-red positive as well as PAS positive and occur in the cerebellum in cases of GSS; they are present in abundance in the cerebral cortex in cases of variant CJD.

*In all forms of prion disease, immunohistochemical staining demonstrates the presence of proteinase-K-resistant PrP scrapie in tissues.

Front 180

180. What is CJD?

Back 180

CJD is a rare cause of rapidly progressive dementia. The clinical picture is usually typical, with the initial subtle changes in memory and behavior followed by a rapidly progressive dementia, often with pronounced involuntary jerking muscle contractions on sudden stimulation (startle myoclonus).

It is primarily sporadic but may be familial. There are well-established cases of iatrogenic transmission, notably by corneal transplantation, deep implantation electrodes, and contaminated preparations of human growth hormone.

The disease is uniformly fatal with an average duration of only 7 months. There is extensive atrophy of the involved gray matter.

Front 181

181. What are the inhibitors of GABA metabolism?

Back 181

These include tiagabine and vigabatrin.

The major clinical indication for tiagabine is in the Tx of epilepsy. By inhibiting GABA reuptake, tiagabine increases both synaptic and extrasynaptic GABA concentrations.

Vigabatrin is a suicide inhibitor of GABA transaminase (GABA-T). Administration of this drug blocks the conversion of GABA to succinic semialdehyde, resulting in increased synaptic GABA release. Also used in the Tx of epilepsy.

Front 182

182. Tiagabine

Back 182

MOA: Inhibit GAT-1, which enhances GABA activity by blocking GABA reuptake into presynaptic neurons.

PURPOSE: Partial and tonic-clonic seizures *adjunct therapy

ADVERSE: Unexplained sudden death; confusion, sedation, dizziness, depression, psychosis, GI irritation

CONTRA: Hypersensitivity

NOTES: Tiagabine potentiates the action of GABA-A receptor modulators such as ethanol, benzodiazepines, and barbiturates.

Front 183

183. Vigabatrin

Back 183

MOA: Suicide inhibitor of GABA transaminase (GABA-T); blocks the conversion of GABA to succinic semialdehyde, resulting in increased synaptic GABA release

PURPOSE: Partial and tonic-clonic seizures

ADVERSE: Retinal atrophy, angioedema; fatigue, headache, ataxia, weight gain

CONTRA: Hypersensitivity

NOTES: Transfer across the BBB is slow, and the drug is cleared mainly by renal excretion w/a half life of 5-6 hours.

Front 184

184. What are the names of the GABA-A receptor agonists and antagonists?

Back 184

AGONISTS:
1. Muscimol
2. Gaboxadol

--------------

ANTAGONISTS:
3. Bicuculline
4. Gabazine
5. Picrotoxin

Front 185

185. Muscimol and Gaboxadol

Back 185

Agonists such as muscimol and gaboxadol activate the GABAa receptor by binding directly to the GABA binding site.

Muscimol, first derived from hallucinogenic Amanita muscaria mushrooms, is a full agonist at many GABAa receptor subtypes and is used primary as a research tool.

Gaboxadol is an investigational agent for Tx of insomnia.

Front 186

186. Bicuculline, Gabazine, and Picrotoxin

Back 186

Bicuculline and gabazine are competitive antagonists that bind at the GABA sites on GABAa receptors.

Picrotoxin, derived from a poisonous plant, is a non-competitive inhibitor of GABAa receptors.

***All of these GABAa antagonists produce epileptic convulsions and are used exclusively for research.***

Front 187

187. What are the benzodiazepines?

Back 187

Benzodiapines have sedative, hypnotic, muscle relaxant, amnestic, and anxiolytic effects. At high doses, benzos can cause hypnosis and stupor. However, when used alone, these drugs rarely cause fatal CNS depression.

Front 188

188. Where exactly do benzo's bind?

Back 188

Benzos are high-affinity, highly selective drugs that bind at a single site on GABAa receptors containing α1, α2, α3, or α5 subunits and a γ subunit.

Benzos acts as a positive *weak* allosteric agonists of GABA by enhancing channel gating in the presence of GABA.

They increase the frequency of channel openings at low GABA concentrations. The resulting increased Cl- influx causes membrane hyperpolarization and decreases neuronal excitability.

Front 189

189. What is the relationship btwn GABA levels and benzos?

Back 189

Benzos shift the response curve to the left, increasing the apparent potency of GABA up to 3x. This is a smaller allosteric effect than that caused by other modulators such as general anesthetics.

The limited efficacy of benzos is therefore associated with a reduced potential for fatal overdose. However, this safety net is eliminated when benzos are combined with other sedative/hypnotics.

Front 190

190. How do benzo's achieve an anxiolytic effect?

Back 190

They inhibit synapses in the limbic system, a CNS region that controls emotional behavior and is characterized by a high density of GABAa receptors.

Front 191

191. Which 6 benzos are used for anxiety?

Back 191

Anxiolytics:

1. Clorazepate
2. Alprazolam
3. Lorazepam
4. Chlordiazepoxide
5. Conazepam
6. Diazepam

Front 192

192. Which 3 benzos are used for amnesia induction?

Back 192

Amnesia:

1. Midazolam
2. Lorazepam
3. Diazepam

Front 193

193. Which 7 benzos are used for insomnia treatment?

Back 193

SLEEP:

1. Triazolam
2. Zolpidem
3. Lorazepam
4. Estazolam
5. Temazepam
6. Flurazepam
7. Quazepam

Front 194

194. What are the 4 short acting benzos?

Back 194

SHORT ACTING:

1. Midazolam
2. Clorazepate
3. Triazolam
4. Zolpidem

Front 195

195. What are the 4 short intermediate acting benzos?

Back 195

INTERMEDIATE ACTING:

1. Alprazolam
2. Lorazepam
3. Estazolam
4. Temazepam

Front 196

196. What are the 5 long acting benzos?

Back 196

LONG ACTING:

1. Chlordiazepoxide
2. Clonazepam
3. Diazepam
4. Flurazepam
5. Quazepam

Front 197

197. Benzodiazepines

Back 197

MOA: Weak allosteric agonists of the GABAa receptor that act to increase the freq of receptor opening and potentiate effects of GABA.

PURPOSE: Partial and tonic-clonic seizures, absence seizures, status epilepticus, amnesia induction, anxiety, alcohol withdrawal, insomnia

ADVERSE: Respiratory depression, apnea, desaturation in pediatric pts, agitation; excessive somnolence, headache, fatigue

CONTRA: Acute narrow-angle glaucoma or untreated open-angle glaucoma

Front 198

198. Therapeutic considerations for benzos

Back 198

1. Benzos are metabolized by P450 3A4 and excreted in the urine as glucuronides or oxidized metabolites
2. Benzo levels are decreased by carbamazepine or phenobarbital
3. Pts w/impaired hepatic function, including the elderly and the very young, may experience prolonged effects from benzo administration
4. Zolpidem is not technically a benzo, but binds to the same site on GABAa receptors as benzos

Front 199

199. What is midazolam used for?

Back 199

In acute care settings, such as in preparation for invasive procedures, midazolam is freq used as a rapid-onset and short acting anxiolytic/sedative/amnestic.

Front 200

200. How do the benzos affect sleep.

Back 200

Benzos both facilitate sleep onset and increase the overall duration of sleep.

They also alter the proportion of the various sleep stages; they increase the length of stage 2 non-REM sleep (the light sleep), and decrease the lengths of REM sleep and slow-wave sleep.

Front 201

201. What is flurazepam used for?

Back 201

Flurazepam is a long acting benzo that facilitates sleep onset and maintenance and increases sleep duration.

Although it does not cause significant rebound insomnia, its long elimination half life (about 74 hours) and the accumulation of active metabolites may cause daytime sedation.

Front 202

202. What is triazolam used for?

Back 202

Triazolam is a fast-onset benzo that also decreases the time needed to fall asleep.

Intermittent rather than chronic administration of this drug is recommended to lessen the rebound insomnia associated with its discontinuation.

Front 203

203. How does zolpidem work?

Back 203

Zolpidem is unique among sedatives used for insomnia in selectively interacting with GABAa receptors containing α1 subunits.

This selectivity is associated with reduced muscle relaxant and axiolytic actions, but tolerance and amnesia remain as reported adverse effects.

Front 204

204. What is clonazepam used for?

Back 204

Clonazepam is freq used for its antiepileptic effects. It is commonly used for this indication, b/c the anticonvulsant effects are not accompanied by significant psychomotor impairment.

Front 205

205. Diazepam?

Back 205

Diazepam is used to alleviate muscle spasms caused by physical trauma as well as the muscle spasticity associated with neuromuscular degenerative disorders such as multiple sclerosis.

It works by enhancing the activity of inhibitory interneurons in the spinal cord.

Front 206

206. Flumazenil

Back 206

MOA: Antagonizes the effects of benzos by competing for occupancy of high affinity benzo sites on GABAa receptors.

PURPOSE: Reversal of benzo activity (overdose)

ADVERSE: Seizures, cardiac arrhythmias, dizziness, blurred vision, diaphoresis, agitation

CONTRA: Pt begin given a benzo for intracranial hypertension or status epilepticus; pt w/serious tricyclic antidepressant overdose

NOTES: ***In pts with benzo dependence, flumazenil can induce a severe withdrawal syndrome***

Front 207

207. Etomidate

Back 207

MOA: Modulation of ligand-gated ion channels on GABAa receptors

PURPOSE: Induction of anesthesia in hemodynamically unstable pts

ADVERSE: Cardiovascular and respiratory depression, injection site reaction, myoclunus

CONTRA: Hypersensitivity to etomidate

NOTES: Causes minimal cardiopulmonary depression, possibly due to lack of effect on the sympathetic nervous system.

Front 208

208. Propofol

Back 208

MOA: Modulation of ligand-gated ion channels on GABAa receptors

PURPOSE: Induction and maintenance of anesthesia; sedation of mechanically ventilated pts

ADVERSE: Cardiovascular and respiratory depression; injection site reaction

CONTRA: Hypersensitivity

NOTES: Useful esp in short day surgery procedures b/c of its rapid elimination; tolerance has been reported in pediatric pts receiving frequent anesthetics, possibly due to increased clearance.

Front 209

209. What is the one GABAb receptor agonist?

Back 209

Baclofen.

Front 210

210. Baclofen

Back 210

MOA: Activates metabotropic GABAb receptor

PURPOSE: Spasticity

ADVERSE: Coma, seizure, death after abrupt withdrawal, constipation, somnolence

CONTRA: Hypersensitivity

NOTES: Clearance is primarily renal in an unmodified form and about 15% of the drug is metabolized by the liver before excretion in bile

Withdrawal from baclofen, esp intrathecal infusion, can precipitate acute hyperspasticity, rhabdomyolysis, pruritus, delirium, and fever.

Front 211

211. What are barbiturates?

Back 211

Barbituates reduce neuronal excitability primarily by increasing GABA-mediated inhibition via GABAa receptors.

Barbiturate enhanced GABAergic transmission in the brainstem suppresses the reticular activating system, causing sedation, amnesia, and loss of consciousness. Heightened GABAergic transmission at motor neurons in the spinal cord relaxes muscles and suppresses reflexes.

Front 212

212. What is the major action of the barbiturates?

Back 212

The major action of the barbiturates is to enhance the efficacy of GABA by increasing the time that the Cl- channel stays open, permitting a much greater influx of Cl- ions for each activated channel.

This elads to a greater degree of hyperpolarizationa nd to decreased excitability of the target cell.

The GABA-enhancing action of barbiturates is greater than that of the benzodiazepines.

Front 213

213. What are the 3 lipid soluble barbiturates used to induce general anesthesia?

Back 213

1. Thiopental
2. Pentobarbital
3. Methohexital

Front 214

214. What are the 4 barbiturates used for insomnia?

Back 214

Secobarbital, amobarbital, pentobarbital, and thiopental.

Front 215

215. What is phenobarbital used for?

Back 215

Phenobarbital is used as an antiepileptic especially for partial and tonic clonic seizures that are refractory to other meds.

It is also used for insomnia.

Front 216

216. Methohexital, Pentobarbital, Thiopental, Secobarbital, Amobarbital

Back 216

MOA: Enhance GABA activity at GABAa receptors. At high concentrations, act as direct agonists at GABAa receptors. May also antagonize AMPA receptor.

PURPOSE: Induction and maintenance of anesthesia (methohexital, thiopental), insomnia (pentobarbital, thiopental); Status epilepticus (pentobarbital, amobarbital), Raised ICP (thiopental); insomnia (secobarbital and amobarbital)

ADVERSE: Stevens Johnson syndrome, bone marrow suppression, hepatotoxcity, osteopenia; sedation, ataxia, confusion, dizziness, decreased libido, depression

CONTRA: Porphyria, severe liver dysfunction, respiratory disease.

Front 217

217. What are some metabolic interactions with the barbiturates?

Back 217

Chronic use of P450 3A4 induces such as phenytoin and rifampicin enhances barbiturate metabolism.

Conversely, P450 3A4 inhibitors such as ketoconazole, erythromycin, cimetidine, and certain SSRIs may reduce barbiturate metabolism, increasing sedative effects.

*Also, administration of IV sodium bicarb increases clearance

Front 218

218. Phenobarbital

Back 218

MOOA: Enhance GABA activity at GABAa receptors. At high concentrations, act as direct agonists at GABAa receptors. May also antagonize AMPA receptor.

PURPOSE: Refractory epilepsy, especially tonic-clonic seizures; insomnia
ADVERSE: Stevens Johnson syndrome, bone marrow suppression, hepatotoxcity, osteopenia; sedation, ataxia, confusion, dizziness, decreased libido, depression

CONTRA: Porphyria, severe liver dysfunction, respiratory disease.

NOTES: ***Phenobarbital is one of the few barbiturates that undergoes both renal AND hepatic clearance***. Approx 25% of the dose is cleared as the unchanged drug in the urine, while the liver metabolizes the remaining 75%.

Front 219

219. How does ethanol exert its effects?

Back 219

Ethanol appears to exert its effects by acting on multiple targets, including GABAa and glutamate receptors.

Ethanol increases GABAa-mediated Cl- influx and inhibits the excitatory effects of glutamate at NMDA receptors.

Ethanol interacts synergistically with other sedatives, hypnotics, antidepressants, anxiolytics, anticonvulsants, and opioids.

Front 220

220. How does ethanol tolerance occur?

Back 220

Ethanol use is associated with changes in GABAa receptor function. Chronic EtOH use blunts the ethanol mediated potentiation of GABA-induced Cl- influx in the cerebral cortex and cerebellum.

Other changes may be post-translational modifications of GABAa receptors or changes in second messenger systems.

Front 221

221. How do you explain ethanol withdrawal seizures?

Back 221

The upregulation of NMDA receptor expression that occurs w/prolonged EtOH use may account for the hyperexcitability associated with ethanol withdrawal.

Benzos reduce the tremors, agitation, and other effects of acute EtOH withdrawal.

Front 222

222. What are the names of the NMDA receptor antagonists?

Back 222

1. Riluzole
2. Memantine
3. Amantadine
4. Lamotrigine
5. Felbamate

Front 223

223. Riluzole

Back 223

MOA: Riluzole is thought to both block voltage-gated sodium channels (thereby reducing sodium conductance) and decrease glutamate release by directly antagonizing NMDA receptors

PURPOSE: Prolongs survival and decreases disease progression in ALS

ADVERSE: Neutropenia, cardiac arrest, hepatotoxcity, respiratory depression, hypertension, tachycardia, arthralgias

CONTRA: Hypersensitivity

Front 224

224. Memantine

Back 224

MOA: Noncompetitive NMDA receptor antagonist

PURPOSE: Slows the rate of clinical progression of moderate to severe Alzheimers

ADVERSE: Hypertension, constipation, dizziness, headache

CONTRA: Hypersensitivity

Front 225

225. Amantadine

Back 225

MOA: Noncompetitive NMDA receptor antagonist

PURPOSE: Parkinson's disease and influenza A prophylaxis and infection

ADVERSE: Neuroleptic malignant syndrome, suicidal ideation, orthostatic hypotension, edema, insomnia, hallucinations

CONTRA: Hypersensitivity

Front 226

226. Lamotrigine

Back 226

MOA: Stabilizes the inactivated state of the voltage-gated Na+ channel, and thereby reduces membrane excitability, the # of action potentials in a burst, glutamate release, and glutamate receptor activation

PURPOSE: Partial and tonic-clonic seizures; atypical absence seizures; bipolar I disorder

ADVERSE: Stevens-Johnson syndrome, toxic epidermal necrolysis, bone marrow suppression, hepatic necrosis, amnesia, angioedema; rash, ataxia, somnolence, blurred vision

CONTRA: Hypersensitvity

NOTES: Lamotrigine is a useful alternative to phenytoin and carbamazepine as a Tx for partial and tonic-clonic seizures. It is also effective in treating atypical absence seizures. It is the third DOC for Tx of absence seizures, after ethosuximide and valproic acid.

Front 227

227. Felbamate

Back 227

MOA: Inhibition of NMDA receptors

PURPOSE: Refractory epilepsy, especially partial and tonic-clonic seizures

ADVERSE: ***Aplastic anemia, bone marrow depression, hepatic failure, Stevens Johnson syndrome, photosensitivity, GI irritation, abnormal gait, dizziness

CONTRA: Blood dyscrasia; liver disease

NOTES: Felbamate lacks the behavioral effects observed w/the other NMDA antagonists. It is an extremely potent antiepileptic drug and has the additional benefit of lacking sedative effects. It has been associated with a number of cases of fatal aplastic anemia and liver failure and its use is restricted to pts w/extremely refractory epilepsy.