Pbl Exam 9 Case 8-2

Front 1

1. What are the biggest differences btwn CNS tumors in adulthood vs. childhood?

Back 1

The majority of adult primary tumors are supratentorial, while the majority of childhood primary tumors are infratentorial.

Note: half of adult brain tumors are metastases (well circumscribed; usually present at gray-white junction)

Front 2

2. What is the most common primary brain tumor?

Back 2

Glioblastomas

Pseudopalisading pleomorphic tumor cells. Found in cerebral hemispheres; can cross corpus callosum; stain astrocytes for GFAP.

Front 3

3. What is the second most common primary brain tumor?

Back 3

Meningiomas

Spindle cells concentrically arranged in a whorled patter; psammoma bodies (laminated calcifications).

Front 4

4. What is the third most common primary brain tumor?

Back 4

Schwannomas; usually found at cerebellopontine angle; S-100 positive.

Front 5

5. What is the only common childhood supratentorial tumor?

Back 5

Craniopharyngiomas

Derived from Rathke's pouch. Calcification is common

Front 6

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

Back 6

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

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

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

Front 7

7. Tumors of the CNS in children vs. adults

Back 7

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

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

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

Front 8

8. Fibrillary (diffuse) astrocytomas

Back 8

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

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

Front 9

9. Features of fibrillary (diffuse) astrocytomas

Back 9

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

These are WHO grade II/IV tumors.

Front 10

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

Back 10

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

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

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

4. Meningiomas
-includes atypical meningiomas and anaplastic meningiomas

Front 11

11. Anaplastic astrocytomas

Back 11

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

These are WHO grade III/IV tumors.

Front 12

12. Glioblastomas

Back 12

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

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

These are WHO grade IV/IV tumors.

Front 13

13. Low grade astrocytomas

Back 13

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

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

Front 14

14. Pilocytic astrocytomas

Back 14

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

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

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

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

Front 15

15. Pleomorphic xanthoastrocytomas

Back 15

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

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

Front 16

16. Brain stem gliomas

Back 16

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

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

Front 17

17. Molecular genetics of glioblastic tumors

Back 17

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

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

Front 18

18. Oligodendrogliomas

Back 18

Constitute about 5-15% of gliomas (relatively rare) and are most common in middle life in the cerebral white matter. They are slow growing; most often in frontal lobes. Look for chicken-wire capillary pattern.

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

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

Front 19

19. Morphology of oligodendrogliomas

Back 19

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

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

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

Front 20

20. Ependymomas

Back 20

Ependymomas arise from the ependymal lining of the ventricular system, including the central canal of the spinal cord. Most commonly found in 4th ventricle. Can cause hydrocephalus.

CSF dissemination is a common finding.

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

Front 21

21. Age of onset of ependymomas and location

Back 21

In the first 2 decades of life, ependymomas typically occur in the 4th ventricle; in middle life, the spinal cord is the most common location.

Front 22

22. Morphological characteristics of ependymomas

Back 22

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

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

Also, rod shaped blepharoplasts (basal ciliary bodies) found near nucleus.

Front 23

23. Myxopapillary ependymomas

Back 23

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

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

Myxoid areas contain neutral and acidic mucopolysaccharides.

Front 24

24. Subependymomas

Back 24

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

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

Front 25

25. Choroid plexus papillomas

Back 25

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

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

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

Front 26

26. Colloid cysts of the 3rd ventricle

Back 26

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

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

Front 27

27. Ganglion cell tumors

Back 27

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

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

Front 28

28. Gangliocytoma

Back 28

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

Front 29

29. Dysembryoplastic neuroepithelial tumor

Back 29

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

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

Front 30

30. Cerebral neuroblastomas

Back 30

This is a tumor with only neuronal elements.

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

Front 31

31.Neurocytomas

Back 31

This is another tumor with only neuronal elements.

This tumor is found adjacent to the foramen of Monro.

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

Front 32

32. Poorly differentiated neoplasms

Back 32

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

Front 33

33. Medulloblastomas

Back 33

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

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

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

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

Front 34

34. Morphological characteristics of medulloblastomas

Back 34

They are often well circumscribed, gray, and friable. Solid (gross), small blue cells (histology). They are usually extremely cellular, with sheets of anaplastic cells exhibiting hyperchromatic nuclei and abundant mitoses.

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

Rosettes or perivascular pseudorosette pattern of cells.

Front 35

35. Primary CNS lymphoma

Back 35

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

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

Front 36

36. Immunosuppressed patients and primary brain lymphoma

Back 36

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

Front 37

37. Clinical characteristics of primary brain lymphoma

Back 37

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

Nevertheless, it is initially responsive to radiotherapy and steroids.

Front 38

38. Morphological characteristics of primary brain lymphoma

Back 38

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

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

Front 39

39. Germ cell tumors

Back 39

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

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

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

Front 40

40. Meningiomas

Back 40

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

They show a moderate (3:2) female predominance within the cranial vault but a 10:1 female-male ratio within the spinal canal. Most often occurs in convexities of hemispherse and parasagittal region.

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

Front 41

41. Morphological characteristics of meningiomas

Back 41

Meningiomas tend to be rounded masses w/well-defined dural bases that compress the underlying brain but are easily separated from it. Lesions are usually firm to fibrous and lack evidence of necrosis or extensive hemorrhage.

***Spindle cells concentrically arranged in a whorled patter; psammoma bodies (laminated calcifications).***

Front 42

42. What are the histologic patterns of meningiomas?

Back 42

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

Front 43

43. Synctial meningiomas

Back 43

Clusters of cells in tight groups without visible cell membranes

Front 44

44.Fibroblastic meningiomas

Back 44

Elongated cells and abundant collagen deposition.

Front 45

45. Transitional meningiomas

Back 45

Feature of the syncytial and fibroblastic types.

Front 46

46. Psammomatous meningiomas

Back 46

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

Front 47

47. Papillary meningioma tumors

Back 47

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

Front 48

48. Anaplastic (malignant) meningiomas

Back 48

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

They have abundant mitoses w/atypical forms.

Front 49

49. Sarcomas of the meninges

Back 49

Uncommon but can include malignant fibrous histiocytomas and hemangiopericytomas.

Front 50

50. Atypical meningiomas

Back 50

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

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

Front 51

51. Molecular genetics of meningiomas

Back 51

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

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

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

Front 52

52. Meningiomas and neurofibromatosis type 2

Back 52

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

Front 53

53. Metastatic tumors

Back 53

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

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

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

Front 54

54. Morphology of intraparenchymal metastatic tumors

Back 54

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

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

Front 55

55. Paraneoplastic syndromes

Back 55

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

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

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

Front 56

56.Paraneoplastic cerebellar degeneration

Back 56

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

Front 57

57. Limbic encephalitis

Back 57

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

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

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

Front 58

58. Subacute sensory neuropathy

Back 58

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

Front 59

59. Eye movement disorders in paraneoplastic syndromes

Back 59

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

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

Front 60

60. Peripheral nerve sheath tumors

Back 60

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

Comparable tumors arise along the peripheral course of nerves.

Front 61

61. Schwannomas

Back 61

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

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

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

Front 62

62. Morphological characteristics of schwannomas

Back 62

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

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

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

S-100 positive

Front 63

63. Antoni A growth pattern in schwannomas

Back 63

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

Front 64

64. Antoni B growth pattern in schwannomas

Back 64

Less densely cellular tissue with microcysts and myxoid changes.

Front 65

65. Neurofibromas

Back 65

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

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

They arise sporadically or in association with neurofibromatosis Type 1.

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

Front 66

66. Cutaneous neurofibroma and solitary neurofibroma

Back 66

They occur sporadically an in association w/NF1.

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

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

Lesions within peripheral nerves are histologically similar.

Front 67

67. Plexiform neurofibromas

Back 67

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

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

Axons can be found within the tumor.

Front 68

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

Back 68

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

Front 69

69. Morphological characteristics of malignant Schwannomas

Back 69

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

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

Mitoses, necrosis, and nuclear anaplasia are common.

Front 70

70. Epitheliod malignant schwannomas

Back 70

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

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

Front 71

71. Familial tumor syndromes

Back 71

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

Front 72

72. Neurofibromatosis type 1 (NF1)

Back 72

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

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

Front 73

73. The NF1 gene

Back 73

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

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

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

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

Front 74

74.Molecular genetics of neurofibromatosis type 1 (NF1)

Back 74

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

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

Front 75

75. Neurofibromatosis type 2 (NF2)

Back 75

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

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

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

Front 76

76. Molecular genetics of neurofibromatosis type 2 (NF2)

Back 76

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

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

Front 77

77. Tuberous sclerosis

Back 77

Characterized by angiofibromas, seizures, and mental retardation.

Hamartomas within the CNS include cortical tubers and subependymal hamartomas.

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

Front 78

78. Cortical tubers

Back 78

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

Front 79

79. Subependymal hamartomas

Back 79

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

Front 80

80. Molecular genetics of tuberous sclerosis

Back 80

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

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

Front 81

81. What are the 4 characteristics of von Hippel-Lindau disease?

Back 81

Characterized by:

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

Front 82

82. Morphology of von-Hippel-Lindau disease

Back 82

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

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

Front 83

83. Clinical features of von-Hippel-Lindau disease

Back 83

They commonly are cystic lesions with a mural node.

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

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

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

Front 84

84. What are the inhibitors of serotonin storage?

Back 84

Amphetamine, methylphenidate, and modafinil.

Amphetamine and methylphenidate displace 5HT, DA, and NE from their storage vesicles in presynaptic nerve terminals

Front 85

85. Modafinil

Back 85

MOA: Interferes with the ability of synaptic vesicles to store monoamines; displaces 5HT, DA, and NE from their storage vesicles in presynaptic nerve terminals.

PURPOSE: Atypical depression, narcolepsy, obstructive sleep apnea.

ADVERSE: Cardiac arrhythmia, hypertension, dizziness, insomnia, agitation, rhinitis

CONTRA: Hypersensitivity to modafinil

NOTES: Useful as second line agent for atypical depression and for depression in the elderly. can induce psychosis in susceptible pts, especially those w/bipolar disorder.

Front 86

86. What are the inhibitors of serotonin degradation?

Back 86

These are MOAIs. The older MOAIs are nonselective and most older MAOIs, such as iproniazid, phenelzine, and isocarboxazid, are irreversible inhibitors.

Newer MAOIs, such as moclobemide, befloxatone, and brofaromine, are selective for MAO-A and bind reversibly, and are thus called reversible inhibitors of MOA.

Seleginine, a MAO-B inhibitor, also inhibits MAO-A at higher doses.

Front 87

87. MOA of Iproniazid, Phenelzine, Isocarboxyazid, Moclobemide, Befloxatone, Brofaromine, Selegiline

Back 87

MOA: Block deamination of monamines by inhibiting the functional flavin moiety of MAO; increases 5HT and NE available in the cytoplasm of presynpatic neurons, which lends to increased uptake and storage of 5HT and NE in synaptic vesicles and to some constitutive leakage of monoamines into the synaptic cleft.

Front 88

88. Iproniazid, Phenelzine, Isocarboxyazid

Back 88

MOA: Irreversible, nonselective MAOIs

PURPOSE: Depression

ADVERSE: Systemic tyramine toxicity; fever associated with increased muscle tone, leukopenia, hepatic failure, drug-induced lupus, worsening depression; dizziness, somnolence, orthostatic hypotension, weight gain, increased liver aminotransferase levels, orgasm disorder

CONTRA: Concomitant use of: sympathomimetic drugs, buprioron, buspirone, guanethidine, other MOAIs, serotonergic drugs, methyldopa, L-dopa, L-tryptophan, L-tyrosine, phenylanaine, CNS depressants, narcotics, DXM, excessive coffee or chocolate intake; foods with high levels of tyramine, Liver disease, pheochromocytoma, heart failure, general anesthesia, local anesthesia w/vasoconstrictors.

Front 89

89. 4 therapeutic considerations for Iproniazid, Phenelzine, Isocarboxyazid

Back 89

1. Due to the extensive effects of MAOIs on P450 enzymes, MAOIs can cause extensive drug-drug interactions; extreme caution must be sued when prescribing meds to pts concurrently taking a MAOI.
2. Iproniazid, Phenelzine, & Isocarboxyazid are irreversible, nonselective MAOIs
3. The most toxic effect of MAOI use is systemic tyramine toxicity; the older, nonselective MAOIs are no longer considered first line therapy for depression b/c of their significant potential for systemic tyramine toxicity
4. MAOIs can precipitate manic or hypomanic episodes in some bipolar pts.

Front 90

90. Moclobemide, Befloxatone, Brofaromine

Back 90

MOA: Reversible inhibitors of MAO-A (RIMAs)

PURPOSE: Depression

ADVERSE: Same as iponiazid, except less tyramine toxicity

CONTRA: Same as iproniazid

NOTES: These RIMAs are displaced by high concentrations of tyramine, resulting in significantly more tyramine metabolism and thus less tyramine toxicity.

Front 91

91. Selegiline

Back 91

MOA: Selegiline is a MAO-B inhibitor that also inhibits MAO-A at higher doses.

PURPOSE: Depression

ADVERSE: Same as iproniazid, except less tyramine toxicity

CONTRA: Same as iproniazid, except pts have greater freedom w/their diets

NOTES: Transdermal selegiline reduces the risk of a tyramine-induced hypertensive crisis, allowing pts greater freedom w/their diet.

Front 92

92. What are the tricyclic antidepressants?

Back 92

The TCAs inhibit the reuptake of 5HT and NE from the synaptic cleft by blocking 5HT and NE reuptake transporters, respectively.

They are:
1. Amitriptyline
2. Clomipramine
3. Desipramine
4. Doxepine
5. Imipramine
6. Nortriptyline
7. Protriptyline
8. Trimipramine

Front 93

93.

1. Amitriptyline
2. Clomipramine
3. Desipramine
4. Doxepine
5. Imipramine
6. Nortriptyline
7. Protriptyline
8. Trimipramine

Back 93

MOA: Inhibit reuptake of 5HT and NE from the synaptic cleft by respectively blocking 5HT and NE reuptake transporters, and thereby cause enhancement of postysynaptic responses.

PURPOSE: Depression; pain syndromes, such as migraines, chronic fatigue, Nocturnal enuresis (imipramine), OCD (clomipramine)

ADVERSE: Heart block, cardiac arrhythmias, orthostatic hypotension, MI, agranulocytosis, jaundice, seizure, worsening depression w/suicidal thoughts, bloating, constipation, xerostomia, dizziness, somnolence, blurred vision, urinary retention

CONTRA: Concomitant MAOI therapy, cardiac conduction system defects, use in pts during acute recovery after a MI.

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94. 5 therapeutic considerations for the TCAs...

Back 94

1. TCAs appear to affect cardiac sodium channels in a quinidine-like manner, leading to potentially lethal conduction delays; and ECG should be done to rule out conduction defects prior to starting TCAs.
2. Concurrent use of other agents that affect the cardiac conduction system requires careful monitoring
3. In pts taking TCAs, pressor response to IV epinephrine may be markedly enhanced
4. Orthostatic hypotension is a significant adverse effect for elderly pts
5. TCAs can precipitate mania in pts with bipolar disorder.

Front 95

95. What are the SSRIs?

Back 95

Although the effectiveness of the SSRIs is similar to that of the TCAs for the Tx of depression, their higher selectivity and reduced adverse effect profile has made them first line agents for the Tx of depression, as well as for anxiety and obsessive compulsive disorder.

These include:
1. Citalopram
2. Fluoxetine
3. Fluvoxamine
4. Paroxetine
5. Sertraline

Front 96

96. SSRIs:

1. Citalopram
2. Fluoxetine
3. Fluvoxamine
4. Paroxetine
5. Sertraline

Back 96

MOA: Selectively inhibit reuptake of serotonin and thereby increase synaptic serotonin levels; also cause increased 5HT receptor activation and enhanced postsynaptic responses. At high doses, also bind NE transporter.

PURPOSE: Depression, anxiety, obsessive compulsive disorder, post-traumatic stress disorder, pain syndromes

ADVERSE: Serotonin syndrome from concomitant admin of MAOI, may precipitate mania in a bipolar pt; sexual dysfunction, GI distress (sertraline = diarrhea; paroxetine = constipation); vasospasm, sweating, somnolence, anxiety

CONTRA: Concomitant use of MAOIs, pimozide, or thioridazine

Front 97

97. 3 therapeutic considerations for the SSRIs:

Back 97

1. SSRIs are the first line agent for the treatment of depression, anxiety, and OCD.
2. SSRIs are significantly more selective for 5HT transporters than TCAs, and therefore SSRIs have fewer adverse effects
3. SSRIs have a larger therapeutic index than the TCAs.

Front 98

98. What is serotonin syndrome?

Back 98

The clinical manifestations of serotonin syndrome include hyperthermia, muscle rigidity, myoclonus, and rapid fluctuations in mental status and vital signs.

Front 99

99. What are the SNRIs?

Back 99

Venlafexine and duloxetine

Front 100

100. Venlafexine and Duloxetine

Back 100

MOA: SNRIs block 5HT reuptake transporters and NE reuptake transporters in a concentration dependent manner.

PURPOSE: Depression, anxiety, panic disorder w/o or w/o agoraphobia, pain syndromes (duloxetine)

ADVERSE: Neuroleptic malignant syndrome, hepatitis, may exacerbate mania or depression in susceptible pts; hypertension, sweating, weight loss, GI distress, blurred vision, nervousness, sexual dysfunction

CONTRA: Concomitant use of MAOIs.

NOTES: *Venlafaxine at low concentrations acts as an SSRI but at high concentrations it also increases NE levels. *Duloxetine inhibits NE and 5HT reuptake and has been approved for Tx of neuropathic pain and other pain syndromes in addition to Tx of depression.

Front 101

101. What are the atypical antidepressants?

Back 101

Buproprion, Mirtazapine, Nefazodone, and Trazodone

Front 102

102. Buproprion

Back 102

MOA: Buproprion is an aminoketone antidepressant that weakly inhibits neuronal uptake of 5HT, dopamine, and NE.

PURPOSE: Depression, smoking cessation

ADVERSE: Tachyarrhythmia, hypertension, esp when combined with nicotine patch, seizure, may exacerbate mania in susceptible pts; pruritus, sweating, rash, dyspepsia, constipation, dizziness, tremor, blurred vision, agitation

CONTRA: Seizure, bulimia or anorexia, concomitant MAOI use; pts undergoing abrupt discontinuation of alcohol or sedatives (including benzos)

NOTES: Has the fewest sexual side effects among antidepressant agents; induces less mania than the other antidepressants.

Front 103

103. Mirtazapine

Back 103

MOA: Mirtazapine blocks 5HT2A, 5HT2C, and the α2-adrenergic autoreceptor, and presumably decreases neurotransmission at 5HT2 synapses while increase NE neurotransmission

PURPOSE: Depression

ADVERSE: Agranulocytosis, seizure, may exacerbate depression or mania in susceptible pts; somnolence, increased appetite, hyperlipidemia, constipation, dizziness

CONTRA: Concomitant MAO inhibitor use

NOTES: B/c mirtazapine is a potent somnorific as well as an appetite stimulant, it is useful in the elderly population in whom insomnia and weight loss are freq presentations.

Front 104

104. Nefazodone and Trazodone

Back 104

MOA: Nefazodone and trazodone block postsynaptic 5HT2 receptors. Trazadone is a prodrug that is converted into metachlorophenylpierazine (mCPP), a selective 5HT2A/2CR agonist.

PURPOSE: Depression, insomnia (trazodone)

ADVERSE: Priapism (trazodone), orthostatic hypotension (nefazodone), liver failure (nefazodone), seizure, may worsen depression or mania, sweating, weight change, dyspepsia, dizziness, somnolence, blurred vision.

CONTRA: Coadministration of MAOI, pimozide, triazolam, or carbamazepine; hypersensitivity

NOTES: Trazadone is used principally as a somnorific b/c the higher doses required for antidepressant effects are usually oversedating.

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105. What are the serotonin receptor agonists?

Back 105

These agents are primarily used to treat anxiety and migraine headaches. They are:

1. Buspirone
2. Sumatriptan
3. Rizatriptan
4. Almotriptan
5. Frovatriptan
6. Eletriptan
7. Zolmitriptan

Front 106

106. Buspirone

Back 106

MOA: Buspirone is a 5HT1AR selective agonist and does not bind to GABA receptors

PURPOSE: Anxiety

ADFVERSE: Myocardial ischemia or infarction, cerebrovascular accident; dizziness, confusion, headache, excitement, blurred vision, hostile feeling and behavior, nervousness

CONTRA: Hypersensitivity

NTOES: Buspirone is non-sedating w/moderate anxiolytic properties; although not as effective as benzos, it is attractive b/c of its non-additive properties.

Front 107

107. Sumatriptan and the rest of the triptans...

Back 107

MOA: The vasoconstrictive therapeutic effect of triptans is mediated by the 5HT1Rs (both 5HT1DR and 5HT1BR) expressed in the cerebral vasculature.

PURPOSE: Migraine headaches

ADVERSE: Coronary artery spasm, hypertensive crisis, myocardial ischemia or infarction, cerebrovascular accident, seizure, chest pain, flushing, nausea, dizziness

CONTRA: Ergot agent or serotonin 5HT1 agonist w/in 24 hours; concomitant MAOI therapy, ischemic cardiac, cerebrovascular, or peripheral vascular syndromes; uncontrolled hypertension

NOTES: Triptans are most useful for acute migraine attacks when taken at the onset of an episode rather than as prophylaxis

Front 108

108. What are the serotonin receptor antagonists?

Back 108

These drugs show varying degrees of receptor subtype selectivity and often cross react w/adrenergic, histamine, and muscarinic receptors. They are:

1. Ketanserin
2. Ondansetron
3. Tegaserod
4. Prucalopride
5. Alosetron

Front 109

109. Ketanserin

Back 109

MOA: 5HT2A/2CR antagonist

PURPOSE: Primarily used topically to reduce intraocular pressure in glaucoma; hypertension

ADVERSE: Orthostatic hypotension, ventricular tachycardia, flushing, rash, fluid retention, dyspepsia, dizziness, sedation

CONTRA: Hypersensitivity

Front 110

110. Ondansetron

Back 110

MOA: 5HT3R antagonist

PURPOSE: A potent anti-emetic that is freq used as an adjunct to cancer chemo or in cases of refractory nausea.

ADVERSE: Cardiac arrhythmias, bronchospasm, increased liver enzymes, constipation, diarrhea, fatigue, headache

CONTRA: Hypersensitivity

Front 111

111. Tegaserod and Prucalopride

Back 111

MOA: 5HT4R antagonists

PURPOSE: IBS w/constipation predominance

ADVERSE: Hypotension, syncope, diarrhea, dizziness, headache

CONTRA: Hx of bowel obstruction, abdominal adhesions or symptomatic gallbladder disease, moderate to severe hepatic impairment, severe renal impairment, suspected sphincter of Oddi dysfunction

NOTES: Enhance GI motility to treat constipation associated with IBS.

Front 112

112. Alosetron

Back 112

MOA: Alosetron is a 5HT3R antagonist

PURPOSE: IBS w/diarrhea predominance

ADVERSE: Severe constipation, acute ischemic colitis, abdominal pain, nausea, headache

CONTRA: Pre-existing constipation, concurrent use of fluvoxamine, Crohns disease, UC, diverticulitis, severe hepatic impairment, Hx of hypercoagulable state, Hx of impaired intestinal circulation, intestinal stricture, ischemic colitis, toxic megacolon

NOTES: Decreases serotonergic tone in intestinal cells, thus reducing intestinal motility.

Front 113

113. What are the three mood stabilizers?

Back 113

1. Carbamazepine
2. Valproic acid
3. Lamotrigine

Front 114

114. How does lithium work?

Back 114

Lithium can mimic other small monovalent cations and disrupt proteins and transporters that require cation cofactors.

Lithium enters cells via sodium channels. Lithium inhibits both the inositol phosphatase that dephosphorylates IP2 to inositol phosphate (IP1), and the inositol phosphatase that dephosphorylate IP1 to free inositol, thereby blocking the phosphatidylinositol signaling cascade in the brain.

*By blocking the regeneration of PIP2, lithium inhibits central adrenergic, muscarinic, and serotonergic neurotransmission.

Other MOA include increasing 5HT neurotransmission, decreasing NE and DA neurotransmission, inhibiting adenylyl cyclase by decoupling G proteins from neurotransmitter receptors, and altering electrochemical gradients across cell membranes by substituting for sodium and or blocking potassium channels.

Front 115

115. Lithium

Back 115

MOA: By blocking the regeneration of PIP2, lithium inhibits central adrenergic, muscarinic, and serotonergic neurotransmission

PURPOSE: Bipolar affective disorder

ADVERSE: Acute lithium intoxication; severe bradyarrhythmia, hypotension, sinus node dysfunction, hyperkalemia, pseudotumor cerebri, increased ICP and papilledema, seizure, polyuria; nephrogenic diabetes insipidus, hypothyroidism, goiter, ECG and EEG abnormalities, diarrhea, nausea, muscle weakness, transient visual field scotoma, renal impairment, acne.

CONTRA: Severe debilitation, dehydration, or sodium depletion; significant cardiovascular disease; significant renal impairment; lactation.

Front 116

116. 5 therapeutic considerations for lithium

Back 116

1. Lithium has a narrow therapeutic window and a wide range of adverse effects
2. Acute lithium toxicity is a medical emergency and may require dialysis for Tx.
3. NSAIDs or hyponatremia can lead to increased lithium reabsorption in the proximal tubules and elevation of plasma lithium concentrations
4. Lithium's inhibition of potassium entry into myocytes leads to abnormalities in myocyte repolarization, extracellular hyperkalemia, and intracellular hypokalemia.
5. Lithium has been shown to reduce the risk of suicide in pts with bipolar disorder.

Front 117

117. What is acute lithium intoxication?

Back 117

This is characterized by nausea, vomiting, diarrhea, renal failure, neuromuscular dysfunction, ataxia, tremor, confusion, delirium, and seizures.

Front 118

118. How does lithium cause nephrogenic diabetes insipidus and/or goiter?

Back 118

Antidiuretic hormone and TSH both activate adenylyl cyclase, which is inhibited by lithium.

By this mechanism, lithium treatment can also lead to nephrogenic diabetes insipidus and to hypothyroidism and/or goiter.

Front 119

119. DONE FOR THIS ROUND!!!

Back 119

WOO HOOO!!!