What Disease Of The Cns Am I?

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autosomal recessive disorders with preference for myelin

generally no neuronal storage deficits

usually lysosomal/peroxosomal lack of enzyme

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leukodystrophies

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leukodystrophy due to absence of galactocerebroside beta galactosidase

presents by 3-6 months death by 2 years

Mutation of 14q31

Globosides

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Krabbe disease

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Leukodystrophy with lack of arylsulfatase A-> accumulation of sulfatides

Mutation on 22q

Infantile form quickly detrimental; Adult form starts with psychic episodes and progresses to motor deficits

demylination with resulting gliosis

metachromasia of CNS and PNS

metachromatic material in urine

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metachromatic leukodystrophy

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leukodystrophy with symptoms resulting from myelin loss in the CNS and PNS

Due to adrenal insufficiency

earlier the onset the quicker progressing the course

Mutation in ADL gene of Xq28

unable to catabolize VLCFA-> accumulate in urine

Sparing of subcortical U fibers, adrenal atrophy

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adrenoleukodystrophy

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X linked lethal leukodystrophy

Onset soon after birth

Progressive signs and symptoms due to mass white matter injury

Pendular eye movements, hypotonia, choreoathetosis, progresses to spacticity, ataxia, and dementia

Mutation on gene encoding for proteolipid protein

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Pelizaeus-Merzbacher Disease

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megalocephaly, severe mental deficits, blindness, and signs and symptoms of white matter injury in infancy-> death by 18 months
* Spongy degeneration of white matter particularly affecting subcortical U fibers; Alzheimer Type II astrocytes in grey matter
*Due to point mutation on gene for aspartylacylase on 17pter-p1

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Canavan Disease

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problems in oxidative phosphorylation-> due to mutations in mitochondrial genome

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mitochondrial encephalopathies

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characterized by lactic academia, extraoccular palsys, arrest in psychomotor development, seizures, weakness with hypotonia, problems feeding, and death before age 2.
* Particularly affects preventricular gray matter in midbrain, tegmentum in pons, preventricular regions in thalamus and hypothalamus
* Due to mitochondrial defect in complex IV (cytochome oxidase c)-> due to ability to make complex not the complex itself
* Maternal form due to point mutation on ATPase 6 subunit of complex 5; results in neuropathy, ataxia, and retinitis pigmentosum (NARP)

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Leigh syndrome

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due to defect in mtRNA; maternally transmitted disease; neuropathy reflective of defect in cerebellum (inferior olive etc. affected); myoclonus seizure disorder and cerebellar related ataxia

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MERRF

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due to defect in mtRNA; children have acute episodes of neurologic dysfunction including muscular involvement, cognitive changes, lactic acidosis
* Areas of infarction with vascular proliferation and focal calcification

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MELAS

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Opthalmoplegia; sporadic disorder involving mtDNA deletion/rearrangement; cerebellar ataxia with progressive opthalmoplegia, pigmentary retinopathy, and cardiac conduction disorders

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KSS

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Can present as Beri-Beri, or can present in certain individuals as Wernicke encephalopathy;
* If acute symptoms are unrecognized/ignored may develop irreversible syndrome-> Korsaroff syndrome; characterized by memory disturbances and confabulation
* Generally associated with alcoholism; may be associated with carcinoma, chronic gastritis, persistent vomiting
* Foci of hemorrhage and necrosis, particularly in mamillary bodies and adjacent to third and fourth ventricles
* Red cells leak from capillaries-> macrophages infiltrate-> makes cyst with hemosiderin ledin macrophages

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Vitamin B1 (Thiamine) deficiency

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often causes anemia
*Initially presents with slight numbness or tingling in lower extremities; rapidly progresses to spastic weakness of lower extremities; complete paraplegia may occur
*Leads to swelling of myelin-> vacuoles that begin segmentally at midthoracic level of spinal cord
* With time axons in ascending posterior cord and descending pyramidal tracts degenerate

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Vitamin B12 deficiency

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injury of pyramidal cells-> may lead to pseudolaminar necrosis, particularly regions III-V; may show dramatic loss of neurons in Sommer sector (CA1 of hippocampus)

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hypoglycemia

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usually due to uncontrolled diabetes (ketoacidosis, hyperosmolar coma); pt presents with dehydration, confusion, stupor-> leads to coma
* When correcting fluid depletion must do so slowly to prevent cranial edema

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hyperglycemia

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cellular response in CNS is predominantly glial-> Alzheimer type II changes

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hepatic encephalopathy

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symptoms due to hypoxia-> selective injury to layers III and V of cortex; Also injury to Sommer sector of hippocampus, perkinje cells
*Demyelination of white matter may be latter consequence

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carbon monoxide toxicity

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toxicity due to metabolite formate; path findings seen in retina-> degeneration of retinal ganglion cells (blindness); selective bilateral putamenal necrosis and white matter necrosis in severe cases

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methanol toxicity

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cerebellar disturbances in 1% of alcoholics-> truncal ataxia, unsteady gait, nystagmus
* Loss of perkinje cells and proliferation of adjacent astrocytes between depleted granular cells and molecular layer of cerebellum in severe cases (Bergmann gliosis)

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ethanol toxicity

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mimics intracranial mass/pressure-> headache, nausea, vomiting, papilledema
*May develop years after radiation
*White matter affected
*Proteinaceous spheroids may be seen; thickened blood vessel walls (fibrin-like material)
* Can lead to poorly differentiated sarcomas, gliomas, and menigiomas

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radiation toxicity

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drowsiness, ataxia, confusion-> may progress rapidly; may lead to coma
*Focal coagulative necrosis in white matter; often adjacent to ventricles
*Axons and cells bodies in vicinity undergo dystrophic mineralization with adjacent gliosis

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methotrexate toxicity

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-> usually found in cerebral hemispheres but can be found in cerebellum, spinal cord, etc.
- Presents with headache, seizures, focal neurological defect indicative of region of lesion
- Generally presents in 4th to 6th decade
- Lesions are poorly defined, gray, infiltrating, masses that expands/distorts normal CNS tissue
- Cut surface of tumor can be firm or gelatinous-> gliomas characterized by different consistency in different regions of tumor
- Radiology= mass effect and effects adjacent to tumor (edema, etc)
- High grade astrocytomas have leaky vessels-> can be visualized with contrast into venous system

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diffuse/fibrillary astrocytomas, gliomas

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astrocytoma with mild to moderate increase in glial cells, variable nuclear pleomorphism, intervening feltwork (GFAP + fibers that give background fibrillary appearance); transition between neoplastic cells and normal cells is indistinct

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well differentiated II/IV

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astrocytoma that is more cellularly dense, high nuclear pleomorphism, and some mitotically active centers may be evident

Gemistocytic: characterized by eosinophilic bodies with short emanating processes

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anaplastic astrocytoma III/IV

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similar to astrocytomas with addition of vascular proliferation and necrosis

hypercellularity with crowding of malignant tumor cells around necrotic regions-> pseudopalisading

hypervascularity that presents as tufts-> ball-like structure; caused by increased VEGF-> likely due to hypoxia

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glioblastoma IV/IV

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multiple gliomas throughout regions of brain

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Gliomatosis cerebri

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glioblastoma with inactive p53, overexpression of PDGF-A(and its receptors)

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low grade

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glioblastoinactive tumor suppressor genes, RB gene, p16/CDKNZA, and putative tumor suppressor genes on 19qma with

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high grade

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glioblastoma with amplification of EGFR, MDM2 overexpression, p16 deletion, PTEN mutation

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primary

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glioblastoma with PDGF-A amplification

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secondary

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distinguished from other astrocytomas by pathological appearance; generally found in children and young adults; usually located in cerebellum, can be in third ventricle, cerebral hemispheres, optic nerve
- Often cystic with mural body on wall of cyst
- May present with long, thin fibers (GFAP +), Rosenthal fibers, eosinophilic granular bodies, and microcysts
-Vascular proliferation with increased thickness of vessel walls
- Narrow infiltrative border with brain
- Cerebellar particularly easy to treat with resection
- Generally do not have p53/other genetic disruptions seen with astrocytomas

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pilocytic astrocytoma II/IV

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generally occurs in superficial temporal lobe in children and young adults with history of seizures
- Neoplastic, often bizarre astrocytes-> may be lipidized
- Necrosis/mitosis associated with more aggressive type (III/IV)
- 80% survival rate at 5 years

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pleomorphic xanthoastrocytomas

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usually in first 2 decades of life; make up 20% of primary CNS tumors in this age group
- Rare form of glioma found in adults-> generally involving pontine nuclei-> paraplegia
- Ranges from low-grade fibrillary astrocytomas to glioblastomas-> clinical course and survival expectations vary accordingly

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brainstem gliomas

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Usually diagnosed in 4th and 5th decades; lesions usually found in cerebral hemispheres white matter
- Macro: well circumscribed, gelatinous gray mass, often with cysts/focal hemorrhage
- Micro: sheets of normal appearing cells-> similar to normal cells; spherical chromatin dense nuclei surrounded by clear cytoplasmic halo

Most genetic abnormalities in 1p and 19q-> highly responsive to treatment
- Disruption in 9p, 10q, and CDKN2A-> anaplastic form, less responsive to treatment
- Absence of 1p/19q disruption= refractory to treatment
- Treatment= surgery, chemotherapy, radiation-> 5-10 survival

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oligodendrogliomas (II/IV)

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often arise in walls of ventricles; 4th ventricle is most common location in children, spinal cord is most common location in adults
- Solid or papillary masses spanning floor of ventricle-> proximity to pontine nuclei and medullary centers makes full removal virtually impossible.
- Cells with regular round to oval nuclei w/abundant chromatin-> dense fibrillary background between nuclei
- Perivascular pseudorosettes-> tumor cells arrange around vessel in intervening zone consisting of thin ependymal processes extending toward vessel

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ependymomas II/IV

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occur in filum terminale of spinal cord; contain papillary elements in myxoid background-> ependymoma like cells; contain neutral and acidic mucopolysaccharides; if tumor extended into subarachnoid space and surrounded roots of cauda equine-> recurrence is likely

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myxopapillary ependymomas

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solid, sometimes calcified nodules attached to ventricular lining, protruding into ventricle; may cause hydrocephalus; slow growing, difficult to remove

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Subependymomas

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can occur anywhere along choroid plexus; most common in children-> lateral ventricles; structure of normal choroid plexus; hydrocephalus due to obstruction or excess CSF

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Choroid plexus papillomas

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non-neoplastic lesion; found in roof of third ventricle in young adults; gradually obstructs both foramina of Monroe-> non-communicating hydrocephalus; thin, fibrous capsule, lining of low to flat cuboidal epithelium

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Colloid cysts of the third ventricle

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commonly exist as glial component and ganglion component= gangliogliomas; typically slow growing, although glial component may become frankly anaplastic= more aggressive lesion
- Typically presents as seizure disorder-> seizures well controlled with surgical resection
- Well circumscribed masses with focal calcification presenting on floor of third ventricle, hypothalamus, and temporal lobe
- Macro appearance similar to gliomas of comparable grade; found in temporal lobe, may have cystic component

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ganglion cell tumors

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low grade form of lesion in which glial cells form thin cell layer on vessel stalks, neuronal component form solid lesion

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Papillary glioneuronal tumor

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distinctive low-grade lesion that appears in childhood; often presents as seizure disorder; slow growth, good prognosis after surgical removal of tumor
- Typically located in superficial temporal lobe, although other cortical sites seen
- Characterized by specific glioneuronal element-> small, round cells with features of neurons that form columns around central processes= form multiple discrete intracortical nodules with myxoid background
- Floating neurons in mucopolysaccharide pools
- Binucleate/dysplastic neuronal forms not part of tumor
- Focal cortical dysplasia with misplacing of cortical layers of maloriented neurons
- Lesions with both specific element and glial component= mixed

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Dysembryoplastic neuroepithelial tumor (DNT)

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rare neoplasms, seen in childhood; particularly aggressive; Homer-Wright rosettes; found in cerebral hemispheres

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Cerebral neoblastomas

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low-grade neuronal neoplasm found w/in and adjacent to ventricular system (lateral and third particularly); even spaced, round, uniform, nuclei, and often islands of neuropil

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Central neurocytoma

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predominantly occurs in children, exclusively occurs in cerebellum, largely undifferentiated
- In children it occurs in the midline, in adults it may occur more laterally
- Tumor growth may restrict CSF flow-> may cause hydrocephalus
- Often well circumscribed; may extend to cerebellar folia and leptomeninges
- Sheets of anaplastic cells-> nuclei are hyperdense and may take on elongated crescent like shape
- Edges of main tumor may form chains of cells that traverse the cerebellar cortex to aggregate beneath the pia-> may break through pia to seed the subarachnoid space
- Metastasis to spinal cord= drop metastasis since it occurs directly through CSF
- May have neuronal (Homer-White rosettes) or glial (GFAP fibers) components
- Generally loss of material on short arm of chromosome 17-> p53 is on this chromosome but doesn’t appear to be relevant gene; people with increased neurotrophin crkC and receptors have better clinical course
- Aggressive tumor with poor clinical course for those that go untreated-> very radiosensitive and clinical course relative to degree of resection so those with high level of resection followed by radiation have good prognosis

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Medulloblastoma

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recently recognized, highly distinctive tumor of the young; occurs equally in posterior fossa and supratentorial compartment
- Well circumscribed gray mass with soft consistency-> able to spread over brain matter and into cortex
- Rhaboid cells= eosinophilic cytoplasm, sharply defined edges, and eccentrically arranged nuclei
- High levels of mitotic activity
- Actin/keratin present; desmin/myoglobin not
- Involvement of chromosome 22-> relevant gene= pSNF5/INI1
- Very aggressive tumor-> usually results in death within one year of diagnosis

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AT/RT

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most common tumor of CNS for immunosuppressant patients such as AIDS victims and recent organ donation recipients
- Occurance in non immunosuppressed population increases after age 60
- CNS involvement of non-Hodgkins Lymphoma presents in metastatic cells in the CSF; also may seed around intradural nerve endings
- Often multiple sites of tumor w/in brain parenchyma; bone, nodal, and extranodal involvement is rare and late complication
- Aggressive disease with poor response to chemotherapy compared to peripheral lymphomas
- Lesions frequently multiple in brain and involving deep gray matter, white matter, and cortex
- Extensive areas of necrosis and mitosis; nearly always high grade lymphomas
- Malignant cells infiltrate brain parenchyma and cortex
- “Hooping” pattern characteristic of CNS lymphomas (silver stain)
- Often benign mixture of T cells and B cells with plasmocytic component adjacent to lesions

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Primary CNS Lymphomas

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Generally occur in first two decades of life; histologically similar to gonadal counterparts
-Primarily occur in suprasellar region and pineal region
- Must rule out peripheral primary
- Can disseminate widely along CSF route

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Primary germ cell tumors

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arise from specialized cells of pineal gland; features of neuronal differentiation
-Low grade with neuropil (tumor cells with small, round nuclei that have no evidence of mitoses or necrosis) to high grade
- High grade spreads via CSF and is generally found in children or persons with retinoblastoma (RB gene)

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Pineal cell tumors

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generally benign tumors of adults derived from menigothelial cells of arachnoid
- Easy to separate from the brain
- Firm and fibrous to gritty and extremely calcified with psomoma bodies
-Several histologies-> scyntial= whorled appearance; fibroblastic= fibrous elongated cells; transitional= combo of scyntial and fibroblastic; psommomatic= many psomomma bodies; secretive= PAS + droplets in cytoplasm; microcystic= spongy appearance

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meningiomas

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Common sites of involvement= parasagital aspect of brain convexity, dura over lateral convexity, wing of sphenoid, olfactory groove, sella turcica, and foramen magnum
- May have progesterone receptors-> increased presentation during pregnancy

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menigiomas

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involve systemic immune response to tumor antigens that cross-react with antigens of CNS/PNS; often seen before metastatic neoplasm is recognized; most frequently occurs with small cell carcinoma of the lung

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paraneoplastic syndromes

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paraneoplastic syndrome with inflammation, gliosis, destruction of perkinje cells

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paraneoplastic cerebellar degeneration

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subacute dementia; involves temporal lobe; perivascular inflammatory cuffs, microglial nodules, some neuronal loss/gliosis

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limbic encephalitis

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paraneoplastic syndrome with loss of dorsal root ganglia; inflammation

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Subacute sensory neuropathy

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arise from peripheral nerve cells including Schwann cells, perineurial cells,and fibroblasts

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peripheral nerve sheath tumors

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arise from neural crest Schwann cells; benign tumors that are associated with neurofibroblastoma 2
- referred to compression of associated nerve or adjacent structures
- well- circumscribed encapsulated lesions attached to nerves-> can be removed from them; firm gray masses
- Antoni A histology-> elongated cells with processes that form fascicles in areas of moderate to high cellularity and low stromal matrix; verocay bodies
- Antoni B histology-> tumor is less dense; composed of meshwork of cells with myxoid stroma
- Silver/immunostains show that axons are largely excluded from tumor but may be trapped in capsule
- S-100 immunoreactive
- Degenerative changes= pleomorphism, xanthomatous change, and vascular hyalinization
- Most are found in cerebellopontine angle-> affect vestibular branch of 8th nerve-> acoustic neroma
- Sensory nerves preferred including trigeminal and dorsal roots

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schwannomas

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2 forms; not likely to metastasize (cosmetic concerns are predominant complaint); Plexiform associated with loss of wild copy NF1
- Cutaneous: well delineated, unencapsulated masses; composed of spindle cells; stroma is highly collagenized
-Plexiform: large nerve trunk is most common site-> cannot be separated from tumor; myxoid stroma, with low cellularity; “shredded carrot” appearance

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Neurofibromas

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highly malignant tumor often leading to reoccurance and sometimes metastasis; arise denovo or from transformation of a plexiform neurofibroma-> associated with NF1 mutations; also associated with p53 and p16
- Poorly defined tumor often involving nerve and adjacent soft tissue; necrosis, mitoses, and severe anaplasia common
- “Divergent” histological patterns
- Epithelioid malignant schwannoma= extremely aggressive variant derived from Schwann cells-> well defined borders and epithelial nests; immunoreactive for S-100 but not keratin

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Malignant peripheral nerve sheath tumors

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associated with fibromas, gliomas of the optic nerve, pigmented nodules of the iris, and cutaneous hyperpigmented macules
- NF1 on 17q11.2 identified to generate neurfibromin-> domain homologous with RAS family of GTPase activating proteins; thought to act in signal transmission regulation
-NF1= tumor suppressor gene

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neurofibromas type 1

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Patients develop variety of tumors, most commonly bilateral nerve VIII schwannomas and multiple meningiomas
- Less common than NF1
-Relevant gene= 22q12-> produces merlin; similar to cytoskeletal proteins

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neurofibromatosis 2

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autosomal dominant; results in hemartomas and benign neoplasms of brain and other tissues
- Lesions include renal angiomyolipomas, retinal glial hemartomas, pulmonary lesions, and cardiac rhabdymomas
- Obligate carriers of the gene sometimes have no symptoms
-TSC1 on 9q34-> produces hemartin, unknown function; TSC2 on 16p13.3 produces tuberin-> homology to GTPase activating protein; the two proteins interact directly to regulate cell proliferation
-Hemartomas of cortex are firm mass, in contrast to surrounding soft tissue, likened to potatoes
-Hemartomas= haphazardly arranged neurons; lack normal laminar organization
- Neuronal and Glial forms

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TB

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development of capillary hemangioblastomas within cerebellar hemispheres, retina, and less commonly the brainstem and spinal cord; cysts often develop in pancreas, liver, and kidney; patients have propensity for developing renal cell carcinoma of kidney
- Chromosome 3p25-26 affected-> produces pVHL-> targets hypoxia induced factor 1 which stimulates VEGF
- Highly vascular neoplasms occur as mural nodule associated with large, fluid-filled cyst
- Thin walled vessels with intervening stromal cells of uncertain histiogenesis; characterized by vacuolated, lightly PAS+, lipid rich cytoplasm and indefinite immunohistochemical phenotype
-Therapy= resection of cerebellar hemangioblastomas, and laser therapy

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Von Hippel Lau Disease