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iii. Meningomyelocele: defective formation of the bony arch with cystic outpouching of meninges, spina] cord, and spinal roots iv. Myelocele: defective bony arch with complete exposure of spinal cord v. Significant defects lead to paraplegia and urinary incontinence from birth

2. Arnold-Chiari malformations a. Type 1

i. Common, but mosdy asymptomatic ii. Downward displacement of cerebellar tonsils b. Type 2

i. Most often symptomatic ii. Faulty craniospinal junction, resulting in small posterior fossa, with

■ Downward displacement of cerebellar vermis and medulla

■ Compression of the fourth ventricle

• Obstructive hydrocephalus

• Frequent lumbar meningomyelocele iii. Frequent association with syringomyelia

3. Syringomyelia a. Ependymal-lined, CSF-filJed channel parallel to and connected with central canal (Hydromyelia: central canal is simply dilated)

b. Ninety percent of cases associated with Arnold-Chiari type 2

c. Remaining cases: post-traumatic or associated with intraspinal tumors d. Syrinx enlarges progressively and destroys the spinal parenchyma e. Symptomatology: paralysis and loss of sensory functions

4. Perinatal brain injury a. Injury to the brain during prenatal or immediately postnatal period b. Most common cause of cerebral palsy c. Most frequent in premature babies d. Germinal matrix hemorrhage: localized in the germinal matrix due to its fragile vessels e. Periventricular leukomalacia i. Infarcts in watershed areas (periventricular white matter in the fetus)

f. Multicystic encephalopathy, multiple brain infarcts occurring early in pregnancy Demyelinating Disorders

1. Multiple sclerosis a Definition: chronic relapsing-remitting disorder of probable autoimmune origin characterized by recurrent episodes of demyelination in the brain (including optic nerves) and spinal cord, which results in. progressive neurological deficits b. Epidemiology i. Overall prevalence: 1/1,000

ii. Prevalence higher in northern countries iii. Persons who emigrate after age 15 from areas of high prevalence to areas of low prevalence maintain original risk iv. Women have double the risk of men v. Clinical onset in the third or fourth decade c. Etiopathogenesis i. Multifactorial ii. Genetic factors

• Familial propensity

• Concordance rate in twins: 25% in monozygotic, 2% in dizygotic

■ Strong association with HLA-DR2

iii. Immune factors

• Oligoclonal CD4 lymphocytic infiltration

■ Experimental allergic encephalitis (EAE) obtained by injection of myelin basic protein (MBP)

• TH1 cytokines (IF-y and TNF) facilitate; Tm cytokines (IL-4 and IL-10) retard EAE

iv. Infectious agents (suspected, not proven): mumps, rubella, herpes simplex, measles, and JC virus d. Pathology i. Acute lesions: well circumscribed plaques, with loss of myelin

• Gross: well circumscribed, frequently periventricular, with same color as gray matter

• Histology: chronic inflammation with phagocytosis of myelin by macrophages; axons are initially preserved ii. Chronic lesions: no inflammation, with axons showing remyelination iii. Remyelination is defective because myelin sheaths are thinner with shorter intern odes .

e. Pathophysiology i. Acute attack: nerve conduction is entirely blocked, acute neurological deficits ii. Chronic plaque: slower nerve conduction, allowing for partial recovery iii. Recurrent attacks: progressive neurological deterioration f. Clinical course i. 85% cases: relapsing-remitting course ii. Minority: primary progressive (slow deterioration) or progressive-relapsing (slow progression punctuated by acute exacerbations) course iii. Recovery from each episode of demyelination occurs in weeks or months g. Symptomatology i. Blurred vision or loss of vision in one eye (optic nerve involvement)

ii. Diplopia and vertigo (brainstem involvement)

iii. Loss of sensation or weakness in one leg (spinal cord involvement)

iv. Hemiparesis or loss of sensation in half of the body (cerebral white matter , involvement) !

v. Many other symptoms, sometimes of neuropsychiatrie nature h. Treatment i. Acute attack: high-dose steroids facilitate recovery ii. Chronic treatment slows progression of disease iii. Interferon-P

iv. Copolymer 1 (Copaxone)

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2. Central pontine myelinolysis (CPM)

a. Focal demyelination of central area of basis pontis b. Patients at risk: severely malnourished, alcoholics, with liver disease c. Probably derives from rapid correction of hyponatremia d. Very often fatal Degenerative and Dementing Disorders 1. Parkinson disease and syndrome a. Definition i. Loss of dopaminergic neurons in the substantia nigra ii. Tremor, rigidity, and akinesia iii. Parkinson disease (PD) is the idiopathic form iv. Parkinson syndrome (PS) is secondary to known injuries to the substantia nigra (SN) (e.g., infections, vascular conditions, toxic insults)

b. Epidemiology i. Common disease: 2% of the population ii. PD arises in the fifth to eighth decade of life iii. No genetic-familial, sex, or race predisposition c. Etiopathogenesis i. Loss of dopaminergic neurons is unexplained in PD

ii. Theories emphasize oxidative stress iii. Accidental exposure to l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) causes death of dopaminergic neurons in SN

iv. MPTP is a by-product of illicit synthesis of meperidine analogue d. Pathology i. Gross: pallor of SN

ii. Histology: loss of pigmented (dopaminergic) neurons in SN

* Lewy bodies: intracytoplasmic round eosinophilic inclusions that contain a-synuclein; EM shows filaments most likely of cytoskeletal origin üi. Secondary degeneration of dopaminergic axons in the striatum e. Pathophysiology i. Loss of extrapyramidal nigra-striatal pathway ii. Inhibition of movement of proximal muscles and disruption of fine regulation of distal muscles iii. The pathophysiologic basis of PD-associated dementia is not clear f. Clinical manifestations i. Slowing of all voluntar)' movements ii. Tremor at rest that disappears during movement iii. Expressionless face iv. Rigidity of limbs and trunk and inability to initiate voluntary movement v. Increased incidence (20-40% of patients) of dementia and depression g. Treatment and prognosis: Levodopa treatment of choice usually combined with other drugs

2. Huntington disease (HD)

a. Autosomal dominant disorder characterized pathologically by degeneration of GABA-nergic neurons of caudate nucleus and clinically by chorea and dementia b. Epidemiology i. HD affects those of northwestern European descent ii. No cases are known due to new mutations iii. Incidence in high-prevalence regions is 1/12,000-20,000

c. Etiop at ho genesis i. HD gene is located on chromosome 4 coding for a protein called Huntington ii. Mutations are due to expansion of an unstable trinucleotide repeat iii. HD shows features of anticipation and genomic imprinting d. Pathology i. Gross: atrophy of the caudate nucleus with secondary ventricular dilatation ii. Histology: loss of small neurons in the caudate nucleus iii. Pathophysiology: loss of caudate nucleus GABA-nergic neurons removes inhibitory influences on extrapyramidal circuits, thus leading to chorea e. Cbnical manifestations i. The disease manifests between age 20 and 40.

ii. Chorea: sudden, unexpected, and purposeless contractions of proximal muscles iii. Changes in personality, marked tendency for suicide, and dementia f. Diagnosis: genetic diagnosis possible but controversial g. Treatment: antipsychotic drugs (e.g., haloperidol)

Table 29-4. The Dementias

Frequent Causes

Less Frequent Causes

Alzheimer disease

Pick disease

Dementia with Lewy bodies

Primary subcortical degenerations: Parkinson disease, multiple system atrophy, Huntington disease, progressive supranuclear palsy

Vascular dementia

Prion diseases (Creutzfeldt-Jacob)

Mixed Alzheimer and vascular

Normal pressure hydrocephalus dementia

3. Alzheimer disease (AD)

a. Epidemiology i. 60% of all cases of dementia ii. Incidence: 2% at 65 years, doubles every 5 years iii. Risk factors: aging, significant head trauma, and familiarity; aluminum: epiphenomenon, not a risk factor iv. Protective factors: high level of education, smoking b. Etiopathogenesis i. Genetic factors

■ 5-10% of AD cases are hereditary, early onset, and transmitted as an autosomal dominant trait.

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Table 29-5. Genetics of AD

Mutations known to cause AD:

Amyloid precursor protein (APP) gene (chromosome 21) Presenilin-1 gene (chromosome 14): majority of hereditary AD cases Mutations of presenilin-2 gene (chromosome 1) AD caused by all of the above mutations is early in onset Apolipoprotein E gene:

There are 3 allelelic forms of this gene, £2, £3, and £4 The allele £4 of apolipoprotein E (ApoE) increases the risk for AD: £4 allele is over represented in AD patients £2 is under rep resented; it confers relative protection AD associated with s4 ApoE allele is late in onset Trisomy 21:

Virtually all Down syndrome patients are destined to develop AD in their forties. Down patients have triple copies of the APP gene.

c. Pathology i. Accumulation of abnormal proteins intra- and extracellularly ii. Abnormal proteins

• AP amyloid: 42-residue peptide from a normal transmembrane protein, the amyloid precursor protein (APP)

• Abnormal tau (a microtubule-associated protein)

iii. Senile plaques: core of Ap amyloid surrounded by dystrophic neuritic/den-dritic processes and associated with microglia and astrocytes iv. Neurofibrillary tangles (NFT): intraneuronal aggregates of insoluble cytoskeletal elements, mainly composed of abnormally phosphorylated tau formingpaired helical filaments (PHF)

v. Cerebral amyloid angiopathy (CAA): accumulation of AP amyloid within the media of small and medium-size intracortical and lep to meningeal arteries. CAA may occur by itself and cause intracerebral hemorrhage.

vi. Additional changes

■ Gran ulovacuolar degeneration (GVD) and Hirano bodies (HBs)

• Develop in the hippocampus and are less significant diagnostically vii. Lesions involve neocortex, hippocampus, and several subcortical nuclei, including forebrain cholinergic nuclei (i.e., basal nucleus of Meynert).

■ Affected areas are involved in learning and memory

• The earliest and most severely affected are hippocampus and temporal lobe

• Small number of SP-NFT also form in intellectually normal aging persons viii. Macroscopic changes: atrophy of affected regions

• Brains are smaller (atrophic), with thinner gyri and wider sulci

• Hippocampi and temporal lobes are markedly atrophic d. Clinical manifestations i. Insidious onset beginning usually in the seventh or eighth decade ii. Progressive memory impairment, especially related to recent events iii. Alterations in mood and behavior iv. Progressive disorientation v. Aphasia (loss of language skills) and apraxia (loss of learned motor skills)

vi. Within 5—10 years, patients become mute and bedridden e. Treatment i. No effective treatment available ii. Mild improvement with inhibitors of acetylcholinesterase (e.g., tacrine)

4. Dementia with Lewy bodies a. Etiopathogenesis: obscure, no known risk factors b. Pathology i. The his to pathological hallmark is Lewy body (see Parkinson disease)

ii. Neuron loss accompanies Lewy body formation iii. Sites involved

• Neocortex, especially the limbic system and cingulate gyrus

* Subcortical nuclei: basal nucleus of Meynert, amygdala, and substantia nigra c. Pathophysiology i. Involvement of neocortex and substantia nigra responsible for cognitive deterioration and parkinsonism d. Treatment: possible benefit from cholinesterase inhibitors e. Clinical manifestations: memory loss, parkinsonism, and visual hallucinations

5. Amyotrophic lateral sclerosis a. Degeneration and loss of upper and/or lower motor neurons b. Usually manifests in middle age c. Loss of upper motor neurons i. Hyperreflexia ii. Spasticity d. Loss of lower motor neurons i. Weakness ii. Atrophy iii. Fasciculations e. In some cases, involvement of cranial nerve nuclei f. Clinical diagnosis supported by biopsy of muscles g. Etiopathogenesis is obscure, but i. 5—10% of cases are hereditary ii. A small number due to mutation of the gene encoding zinc-copper superoxide dismutase on chromosome 21

6. Friedreich ataxia a. Autosomal recessive disorder with onset in early childhood b. Due to expansion of an unstable triplet nucleotide repeat in the frataxin gene c. Degeneration involves the following groups of neurons i. Dorsal root ganglia ii. Clarke's column (origin of spinocerebellar tract)

iii. Neurons of posterior column of spinal cord iv. Cranial nerve nuclei of VII, X, and XII

v. Dentate nucleus and Parkinje cells of cerebellum vi. Betz neurons of primary motor cortex medical 287

d. Clinical manifestations: gait ataxia, dysarthria, hand clumsiness, loss of sense of position, impaired vibratory sensation, and loss of tendon reflexes. Patients become wheelchair bound by age 5. G. CNS TUmors

1. Epidemiology a. Half of all brain and spinal cord tumors are metastatic b. Most frequent primary CNS tumors: meningiomas and glioblastoma multiforme c. Primary malignant CNS tumors account for 2-3% of all cancer deaths in the United States.

2. Clinical manifestations a. Headache, often worse at night or early morning b. Seizures, with tumors involving cerebral cortex c Mental changes (e.g., deficits in memory, concentration, reasoning, etc.)

d. Focal neurological symptoms, related to involvement of specific brain regions e. Symptoms related to increased intracranial pressure i. Presence of a space-occupying mass within the cranial cavity ii. Blockage of CSF flow iii. Edema around the tumor (peritumoral edema)

3. Special features of brain tumors a. The concept of benign versus malignant neoplasm must be revised; consider i. Malignant CNS tumors do not metastasize outside the cranial cavity.

ii. Clinical consequences depend on infiltrative behavior and location.

Table 29-6. Differences Between Primary and Metastatic Tumors

Primary

Metastatic

Poorly circumscribed

Well circumscribed

Usually single

Often multiple

Location varies according to specific type

Usually located at the junction between gray and white matter

4. Astrocytomas a. Originate from astrocytes and exhibit i. Fibrillary background ii. Immunoreactivity for glial /ibriliary acidic protein (GFAP)

iii. Diffuse (ill-demarcated) pattern of growth b. Fibrillary astrocytomas i. Grading is important for both prognosis and treatment. Most frequent systems in the United States and Europe: Daumas-Duport and WHO

ii. Both systems identify four grades based on nuclear atypia (pleomorphism), mitoses, necrosis, and vascular endothelial hyperplasia (VEH)

iii. Grade 1-2 astrocytomas are well differentiated astrocytomas iv. Grade 3 astrocytomas are anaplastic astrocytomas v. Grade 4 astrocytomas are called glioblastoma multiforme (GBM) • GBM is the most common CNS primary malignancy

• Histology: marked nuclear atypia, mitoses, necrosis, and VEH

• Characteristic histopathological feature; areas of necrosis surrounded by rows of neoplastic cells (pseudopalisading necrosis)

• VEH is often florid, giving rise to glomeruloid formations vi. Most common location: white matter, commonly in the centrum semiovale vii. Well differentiated: affect younger patients and grow slowly viii. Anaplastic astrocytomas and GBM: aggressive, affect older patients c. Pilocytic astrocytoma i. Benign astrocytic tumor of children and young adults ii. Locations: posterior fossa (cerebellum) and diencephalon iii. Often presents as a cystic lesion with a mural nodule iv. Histology: spindly neoplastic astrocytes with long bipolar processes; tumors rich in Rosenthal fibers, thick corkscrew-like eosinophilic structures, which derive from hypertrophic processes of astrocytes v. Favorable prognosis for posterior fossa tumors

5. Oligodendroglioma a. Glioma of oligodendroglial origin b. Occurs in 30- to 50-year-old patients c. Location: white matter of cerebral hemispheres adjacent to neocortex d. Often manifests with seizures e. Characteristic histopathology i. Neoplastic cells are similar to oligodendroglia ii. Pronounced perinuclear halo: "fried-egg" appearance iii. Prominent capillary network in a chickenwire pattern f. Slow-growing tumors that allow long survival (average 5-10 years)

g. Recur after surgery and degenerate into high-grade gliomas over time

6. Ependymoma a. Glioma of ependymal origin b. Location i. Children: fourth ventricle ii. Adults: lateral ventricle or spinal canal c. Gross appearance: circumscribed tumors with papillary architecture d. Histology: neoplastic cells resemble ependymal cells. Characteristic features:

i. Ependymal rosettes: cells organized around a lumen ii. Perivascular pseudorosettes: cells arranged around small vessels e. Often presents with obstructive hydrocephalus, when present in the fourth ventricle f. Tend to recur after surgery and acquire more aggressive behavior

7. Meningioma a. Originates from meningothelial cells of the arachnoid b. Tumors of adulthood (women > men), rare in children c. Gross: attached to the dura, pushes underlying brain without invasion d. Microscopic i. Spindle-shaped cells with indistinct borders (syncytial)

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