TIS

Chapter 9

Infection and Neoplasia

A. INFLAMMATION

1. Meningitis or Leptomeningitis.

a. Causes

Bacteria, fungi (viruses generally cause a meningoencephalitis and are not limited to leptomeninges). Usually blood-borne from lung or other primary infection, increasingly common in immune deficiency diseases. Subdural/epidural abscess (empyema or pachymeningitis) usually a complication of infection in adjacent bone or sinus.

b. Macroscopic Appearance

Early, pus within sulci and along congested veins; later, white, thick, fibrotic, opaque leptomeninges; maximal at brain base in tuberculous and fungal meningitis. May spread retrograde via CSF up into ventricles (ventriculitis).

c. Microscopic Appearance

Polymorphonuclear leukocytes appear early in bacterial infection, later lymphocytes and plasma cells; with TB and fungi, granulomas develop with lymphocytes, epithelioid cells and multinucleated giant cells.

d. Lesion Distribution and Clinical Correlates

1. Meningitis usually means leptomeningitis; organisms and inflammatory cells are in the subarachnoid space enclosed by the leptomeninges (pia mater and arachnoid).

2. Leptomeningitis produces headache, stiff neck, and fever. Basal meningitis (TB, fungi, sarcoid) may inflame vessels and produce brainstem infarcts or inflame cranial nerves and paralyze muscles controlling ocular or facial movements. Spinal epidural abscess is a surgical emergency and produces extreme spinal tenderness and paraplegia.

3. Late residuals of meningitis, especially at the brain base, include hydrocephalus from obstruction of CSF flow.

2. Parenchymal lesions - unifocal or multifocal - brain abscess or granuloma

a. Causes

A complication of infection elsewhere; arrives via vein from leptomeninges, paranasal sinuses, mastoid, face or middle ear; or via artery from lungs and heart valves; may occur in immunologically compromised patients.

b. Macroscopic Appearance

1. Early: simply a small focus of necrosis and congestion that becomes infected.

2. Fully developed: central zone of necrosis and pus, capsule of congested, tough, fibrotic tissue, and a peripheral zone of edema.

c. Microscopic Appearance

Central zone of cellular debris and macrophages, capsule of capillaries and fibroblasts (granulation tissue) with increasing amounts of collagen, an outer rim of glial fibers and reactive fibrous astrocytes, and a peripheral edematous zone with vacuoles and palely stained myelin.

d. Lesion Distribution and Clinical Correlates

1. Abscesses complicating middle ear and mastoid infections often lie in the cerebellum or temporal lobe. May be associated with leptomeningitis, andsubdural or epidural abscess.

2. Blood-borne abscesses are often multiple and begin at the junction of cerebral gray and white matter, where arteries narrow abruptly. The abscess extends medially into the poorly vascularized white matter and may enter the ventricle because capsule formation is poor on the avascular medial surface of the abscess.

3. Focal neurologic symptoms are similar to those caused by vascular lesions with the addition of increased intracranial pressure signs.

3. Parenchymal lesions - diffuse or multifocal encephalitis

a. Causes

Blood-borne arboviruses from insect vectors and enteroviruses produce viremia; herpes viruses latent in peripheral or cranial nerve ganglia are activated by local factors, and enter CNS via centripetal spread along the nerve; cytomegalovirus and papova viruses attack the immunologically compromised patient; HIV probably is spread by blood-borne infected monocytes; prions ("slow viruses") enter CNS via blood stream, but the source of initial infection is unknown except for iatrogenic inoculation.

b. Macroscopic Appearance

Usually only brain congestion; Herpesvirus hominis infection often produces a hemorrhagic necrotizing lesion, chiefly in anterior temporal and inferior frontal cortex. Longstanding HIV encephalitis produces generalized gray and white matter atrophy. Prion ("slow virus") infections produce mild gray matter atrophy.

c. Microscopic Appearance

Most viruses induce perivascular infiltration of lymphocytes, microglia, and monocytes, neuronal death with neuronophagia, and clusters of macrophages and glial cells (glial nodules). HIV encephalitis produces a minor degree of these changes along with perivascular multinucleated giant cells, but the cause of major brain dysfunction is in dispute. Certain viruses cause characteristic intranuclear and/or intracytoplasmic inclusions. Prions produce only gray matter vacuolization, neuronal loss and intense gliosis without inflammation (spongiform encephalopathy) and rare PAS-positive plaques.

d. Lesion Distribution and Clinical Correlates

1. Diffuse blood-borne infections produce headache, fever, delirium and progressive obtundation.

2. Herpesvirus hominis encephalitis causes memory loss and signs of unilateral or bilateral temporal lobe mass.

3. Prion infection (Creutzfeldt-Jakob disease) produces dementia, myoclonus, and visual hallucinations over a course of several months.

B. NERVOUS SYSTEM NEOPLASMS

1. Extrinsic, with compression of CNS - meningioma, Schwannoma, pituitary adenoma, craniopharyngioma.

a. Macroscopic Appearance

1. Sharply demarcated from CNS if benign

2. Meningioma is firm and homogeneous; Schwannoma is firm but may have multi-colored, cystic, degenerated areas; pituitary adenoma is vascular and friable.

3. Meningiomas attach to dura, Schwannomas attach to nerve root (often acoustic nerve).

4. Cysts: craniopharyngioma

b. Microscopic Appearance

1. Cellular relationships: whorls of cells inmeningioma, palisades of nuclei in Schwannoma.

2. Compact glandular tissue in pituitary adenoma

3. Keratinizing squamous epithelium in craniopharyngioma

c. Lesion Distribution and Clinical Correlates

1. Meningioma: cerebral convexity - focal or generalized seizures; parasagittal - paraplegia; medial sphenoid wing -visual loss, oculomotor palsy, psychomotor seizures with olfactory aura; olfactory groove - ipsilateral anosmia.

2. Schwannoma: usually cranial nerve VIII dysfunction initially (tinnitus, hearing loss).

3. Pituitary adenoma: panhypopituitarism or signs of hormonal secretion (usually prolactin or growth hormone); later bitemporal hemianopsia.

4. Craniopharyngioma - hypopituitarism, bitemporal hemianopsia due to suprasellar location.

2. Intrinsic, but apparently sharply demarcated from surrounding brain - malignant glial neoplasm (anaplastic astrocytoma, glioblastoma multiforme), medulloblastoma, metastatic melanoma or carcinoma (most often lung or breast).

a. Macroscopic Appearance

Heterogeneous (multiforme) appearance due to hemorrhage, necrosis, and vascular proliferation. Central zone may be totally necrotic and resemble an abscess. Surrounding brain extremely edematous.

b. Microscopic Appearance

1. Anaplastic astrocytoma (grade 3) contains a few cells that are elongated and resemble mature astrocytes, but majority of cells are bizarre with pleomorphic nuclei and mitoses. Mean K(67 labelling index 20%.

2. Secondary vascular changes that characterize glioblastoma multiforme (grade 4 astrocytoma) include endothelial proliferation and small necrotic foci (pseudopalisades). Mean Ki67 labelling index 30%.

3. Medulloblastoma is a primitive neuroectodermal tumor (PNET) that is made up of small, round hyperchromatic nuclei in sheets or neuroblastic rosettes with many mitoses. Ki67 labelling index 15-55%.

c. Lesion Distribution and Clinical Correlates

1. Anaplastic astrocytomas usually lie in the cerebral white matter of adults and produce contralateral sensory and/or motor signs; seizures (focal or generalized), and signs of rapidly increasing intracranial pressure (see below).

2. Medulloblastoma arises in cerebellar vermis of young children, produces truncal ataxia and nystagmus, occludes 4th ventricle to produce hydrocephalus and morning vomiting, and spreads throughout subarachnoid space including the lumbar sac.

3. Metastatic carcinoma is usually blood-borne to the brain and begins growth at the junction between gray and white matter (as in blood-borne brain abscesses). Often multiple, centrally necrotic and surrounded by edema.

4. Majority of focal cerebral signs may be relieved rapidly but temporarily by treatment of peritumoral edema with intravenous mannitol and corticosteroids. Cannot be completely excised. Survive 6-12 months; longer with radiotherapy and chemotherapy.

3. Intrinsic neoplasm that blends with surrounding brain: well-differentiated astrocytoma (grades 1 or 2).

a. Macroscopic Appearance

Firm, pale, gray or white, resembles normal white matter that has hypertrophied (but is not edematous). Tumor blends with and infiltrates adjacent brain. May be cystic, especially in children.

b. Microscopic Appearance

Oval nuclei and long tapering cytoplasmic processes of tumor cells (resemble mature astrocytes). Microcysts. No pleomorphism, vascular changes or mitoses. Mean Ki67 labelling indices grade 1 5-7%, grade 2 10-12%.

c. Lesion Distribution and Clinical Correlates

1. In adults, usually in cerebral hemispheres and produce few symptoms (except perhaps seizures) for many years. Cannot be completely excised; survival 1-4 years.

2. In children, cerebellar astrocytomas usually are cystic, more sharply circumscribed, easily treated and carry hope for a long-term survival if the lesion lies laterally in the hemisphere.

3. Similar tumors in thalamus and pons are not easily treated.

4. Symptoms depend on location: cerebellum - ipsilateral ataxia; pons - cranial nerve palsies; thalamus and hypothalamus - sensory dysfunction, ataxia, inanition.

C. HYDROCEPHALUS

1. Definitions (many terms that are not quite synonymous)

a. Obstructive hydrocephalus: In almost all cases, internal hydrocephalus is caused by obstruction of CSF flow somewhere between its sites of production within ventricles and its sites of absorption over the cerebral convexities. Exception: overproduction of CSF by choroid plexus papilloma which produces hydrocephalus without obstruction.

b. Non-communicating hydrocephalus - CSF does not reach the subarachnoid space; obstruction is somewhere upstream from the fourth ventricle foramina.

c. Communicating hydrocephalus - CSF reaches the subarachnoid space but is blocked somewhere along the subarachnoid cisterns or over the cerebral convexities.

2. Usual Sites and Causes of Obstruction

a. Cerebral aqueduct

1. Congenital atresia or forking

2. Gliosis - due to infection, hemorrhage

b. Arnold-Chiari malformation (see Lecture 22)

c. Basilar adhesive arachnoiditis (CSF obstruction in subarachnoid space)

1. Infection

2. Hemorrhage

3. Both conditions may be complications of surgery.

d. Neoplasms anywhere along the CSF pathways including the subarachnoid space.

3. Secondary Effects on the Brain by Internal Hydrocephalus

a. Ventricular dilatation upstream from the point of obstruction

b. Destruction of cerebral mantle (portions of brain between ventricles and surface); leathery pebble finish on surface with multiple tiny gyri, loss of cerebral white matter, flattened basal ganglia, gliosis along the ventricles.

c. Herniation of medial temporal lobe down through tentorial opening, herniation of inferior cerebellum through foramen magnum; third ventricle floor balloons to fill sella turcica and compress optic chiasm.

d. Head enlargement if sutures open; sutures that have recently closed in early childhood may reopen under pressure from the enlarging cerebrum.

4. Clinical Correlates

a. Enlarging lateral ventricles stretch motor fibers passing from parasagittal cortical leg areas to enter the internal capsule, producing leg spasticity and paralysis.

b. Hydrocephalus is a treatable cause of dementia, akinetic mutism and ataxia.

c. Paralysis of upward gaze from midbrain compression by enlarged posterior third ventricle may be an early sign.

D. INCREASED INTRACRANIAL PRESSURE

1. Causes (may be multiple in a given patient)

a. Brain edema

1. Diffuse - anoxia, meningitis, encephalitis, toxic encephalopathies, trauma, subarachnoid hemorrhage

2. Focal - on periphery of malignant neoplasms, abscesses, and within infarcts

b. Intrinsic mass lesions

1. Neoplasm - especially if rapidly enlarging

2. Abscess

3. Hematoma (vascular or traumatic origin)

c. Extrinsic mass lesions

1. Neoplasm

2. Traumatic hematoma: subdural (usually chronic), epidural (acute)

d. Hydrocephalus

2. Effects

a. Brain: gyri flattened against dura, sulci obliterated; ventricles diffusely compressed if the entire brain is swollen; a focal mass lesion compresses, distorts and shifts the ventricle nearest the lesion.

b. Herniations of brain tissue:

1. transtentorial (downward): uncus and hippocampus (medial temporal lobe); compresses and shifts midbrain caudally and toward the opposite side; due to supratentorial mass.

2. subfalcial (side to side): cingulate gyrus herniates beneath falx cerebri; usually produces no additional clinical deficit.

3. transtentorial (upward): superior cerebellar vermis is forced upward through the tentorial notch and compresses midbrain; due to posterior fossa mass.

4. cerebellar tonsils: shift caudally through foramen magnum; this compresses medulla and stops respiration; can be precipitated by lumbar puncture when CSF pressure is high.

c. Secondary effects of increased intracranial pressure and transtentorial herniation

1. Hemorrhages in midbrain and pons; multiple, small, confluent, midline; cause coma and death; the herniated hippocampus shifts the brainstem caudally away from its vessels which remain tethered.

2. Compression of structures against the tentorium

a. ipsilateral oculomotor nerve (pupillary dilatation)

b. ipsilateral posterior cerebral artery (infarction of calcarine cortex)

c. necrosis of contralateral cerebral peduncle (crus phenomenon, Kernohan's notch): produces hemiparesis ipsilateral to the mass lesion; these signs are added to whatever local destructive effects are produced by the mass lesion and its surrounding edema.

3. Compression of cerebral aqueduct with secondary hydrocephalus

d. Clinical correlates of increased intracranial pressure

1. obtundation, confusion, lethargy, morning vomiting

2. elevated BP, slow pulse and respirations

3. papilledema, enlarged blind spot; later, optic atrophy, if pressure relieved

4. bilateral VI nerve (lateral rectus) palsy

5. pupils reflect herniation effects: one pupildilated ipsilateral to transtentorial herniation due to compression of oculomotor nerve pupillary constrictor fibers, both pupils dilated with midbrain hemorrhages (due to destruction of parasympathetic components in the oculomotor nuclei), both pupils constricted with pontine hemorrhages (due to loss of ocular sympathetic fibers).

6. Respiratory failure with cerebellar tonsillar herniation.

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