IUHS Student-2-Student USMLE Step 1 Recall

                                               Central Nervous System

                                     Demyelinating/Degenerative Disease

Multiple Sclerosis

its a demyelinating disorder characterized by distinct episodes of neurologic deficits, separated in time, attributable to white matter lesions that are separated in space...

prevalence of 1 per 1000 persons...

becomes clinically apparent at any age, although onset in childhood or after age 50 years is relatively rare...

women are affected twice as often as are men...

the clinical course of the illness evolves as relapsing and remitting flare-up episodes of neurologic deficit during variable intervals of time, followed by gradual, partial remission...

the frequency of relapses tends to decrease during the course of time, but there is a steady neurologic deterioration in a subset of patients...

mostly white matter of cervical region; random and asymmetric lesions...

optic nerves are most likely affected in the form of intranuclear opthalmoplegia...

immune mechanisms that underlie the destruction of myelin have been the focus of much investigation...

periventricular demyelination...linked to HLA-DR2...

inflammatory cell recruitment to MS lesions is associated with certain cytokines and with the up-regulation of various leukocyte adhesion molecules on endothelial cells...the infiltrate in plaques and surrounding regions of brain consist of both T cells (CD8+, CD4+) and macrophages...

both macrophages and T cells are thought to induce oligodendrocyte injury...injury by cytotoxic CD4+ T cells has been suggested to occur through the Fas/Fas ligand pathway: oligodendrocytes in MS lesions express Fas while Fas ligand is present on the infiltrating T cells...

from a variety of experiments, it is clear that development of MS-like lesions requires factors beyond cell-mediated immunity...increased CSF immunoglobulin is found in patients with MS, and there is evidence for a role of antibody-mediated damage involving myelin oligodendroglial protein...

marked by scattered plaques of demyelination...

periventricular demyelination....

lesions appear as multiple, well-circumscribed, somewhat depressed, glassy, gray-tan, irregularly shaped plaques, both on external examination and on section...

plaques commonly occur beside the lateral ventricles and may be demonstrated to follow the course of paraventricular veins...

they are frequent in optic nerves and chiasm, brain stem ascending and descending fiber tracts, cerebellum, and spinal cord...

lesions have sharply defined borders at the microscopic level...in an active plaque there is evidence of ongoing myelin breakdown with abundant macrophages containing lipid-rich, PAS positive debris...

inflammatory cells, including both lymphocytes and monocytes, are present, mostly as perivascular cuffs, especially at the outer edge of the lesion...

unilateral visual impairment during the course of a few days, due to involvement of the optic nerve (optic neuritis, retrobulbar neuritis), is a frequent initial manifestaiton of MS...however, only some patients (10-50%) with optic neuritis go on to develop MS...

involvement of the brain stem produces cranial nerve signs, ataxia, nystagmus, and

internuclear ophthalmoplegia from interruption of the fibers of the medial longitudinal fasciculus...

spinal cord lesions give rise to motor and sensory impairment of trunk and limbs, spasticity, and difficulties with the voluntary control of bladder function....

examination of the CSF in MS patients shows a mildly elevated protein level, and in one third of cases there is moderate pleocytosis...

the proportion of gamma globulin (IgG) is increased, and most MS patients show oligoclonal bands...

this increase in CSF immunoglobulin is the result of proliferation of B cells within the nervous system; the target epitopes of these antibodies are widely variable...

can be associated with trigeminal neuralgia...

Devic's Disease

Devic's disease is also known as neuromyelitis optica (NMO).

Manifestations may include an acute, severe ("transverse") myelitis and bilateral simultaneous or sequential optic neuritis occurring in close temporal succession and resulting in paraplegia and blindness.

The spectrum and natural history (frequency of attacks, mortality, and long-term morbidity) of NMO, particularly the relapsing form, remains undefined.

Characteristics associated with a relapsing course include female sex, older age at onset, longer time interval between index events, and the presence of systemic autoimmunity as evidenced by positive antinuclear antibody test.

Whether NMO is a subtype of MS or a distinct disease entity remains controversial.

By strict criteria, Devic's disease has bilateral optic neuritis and myelitis occurring within 2 years of one another without symptomatic disease outside of the optic nerve and spinal cord.

Cases not meeting strict criteria include unilateral optic neuritis or development of a second index event over a period greater than 2 years.

The brain, the brainstem, and cerebellum are not affected, even after several years of disease.

Oligoclonal bands are found in a few cases.

The pathological lesions in Devic's disease are mostly located along the optic tracts and the spinal cord and are microscopically characterized by areas of demyelination with inflammation and necrosis.

Alzheimer's Disease

Senile dementia of the Alzheimer's type, or Alzheimer's disease (AD) is becoming more common in developed nations.

There is no known cause for the disease. Familial cases with a defined inheritance pattern account for only 5 to 10% of Alzheimer's disease.

Genetic defects in familial cases have been identified on chromosomes 21, 19, 14, 12 and 1.

caregivers of AD have suppressed cellular immunity with a decreased ability to latent viruses...the percentage of T lymphocytes was lower, and the helper/suppressor ratio was smaller...

The so-called "early onset" cases of AD in persons in their 30's, 40's, and 50's may have a genetic basis.

Less than 1% of early onset AD cases are linked to a genetic defect on chromosome 21 (which may explain the appearance of Alzheimer's disease in persons with Down syndrome surviving to middle age) which affects amyloid precursor protein, resulting in fibrillar aggregates of beta-amyloid that are toxic to neurons.

amyloid precursor protein(APP) is overexpressed in down syndrome which leads to neurofibrillary tangles and neuritic plaques...

About half of early onset AD cases are linked to mutations in the presenilin 1 gene on chromosome 14.

A presenilin 2 gene has been discovered on chromosome 1, but this defect accounts for less than 1% of cases.

The more typical "late onset" cases of AD occurring after age 60 may have underlying genetic defects.

A genetic locus on chromosome 19 encodes for a cholesterol transporter called apolipoprotein E (apoE).

The E4 variant of apoE, which increases deposition of fibrillar beta-amyloid, can be found in 40% of AD cases.

However, the presence of apoE4 is neither necessary nor sufficient for development of AD.

A genetic locus on chromosome 12 that encodes for alpha-2-macroglobulin may be found in 30% of AD cases.

Mutations in the tau gene which codes for a protein that is associated with microtubules can be found in some AD cases.

The abnormal tau may account for helical filaments found in neurofibrillary tangles.

Grossly, there is cerebral atrophy, mainly in frontal, temporal, and parietal regions. As a consequence, there is ex vacuo ventricular dilation.

neuropathology presents in the cerebral cortex, large neurons in the basal nucleus of Meynert,

and hippocampus...

The confirmation of a diagnosis of AD is made at autopsy. The pathognomonic microscopic feature of AD is an increased number of neuritic plaques in the cerebral cortex.

These neuritic plaques are composed of tortuous neuritic processes surrounding a central amyloid core. Reactive astrocytes and microglia may appear at the periphery of these plaques.

Though plaques may easily be found in the hippocampus, their presence in increased numbers in neocortex is necessary for a diagnosis of AD.

The amyloid core consists primarily of a small peptide known as Aß which is derived from the larger amyloid precursor protein (APP).

Plaques that have the amyloid proteins but lack the neuritic processes are known as diffuse plaques, which do not count toward the diagnosis of AD.

Since the number of plaques increases with age, the number needed for diagnosis of AD is age-dependent. Other histologic features of AD include neurofibrillary tangles, amyloid angiopathy, and granulovacuolar degeneration.

Cerebral Amyloid Angiopathy (CAA): acumulation of ABeta amyloid within the media of small and medium size intracortical and leptomeningeal arteries...CAA may occur by itself and cause intracerebral hemorrhage...

Biochemical evidence points to a loss of choline acetyltransferase and acetylcholine in the cerebral cortex of patients with Alzheimer's disease.

However, the significance of this finding is not clear. There is loss of higher brain functions with AD leading to profound dementia.

The course is usually over 5 to 7 years. The immediate cause of death for most persons with Alzheimer's disease is pneumonia, typically aspiration pneumonia.

Nucleus Basalis projects to Memory and Cognition..Nucleus Basalis acetylcholie level 1% in Alzheheimer's Syndrome...

Pick Disease

This is an uncommon cause for dementia, but the clinical symptoms are similar to Alzheimer's disease.

Clinical manifestations reflect the distribution of cortical degeneration.

Personality deterioration and memory deficits are often more severe than visuospatial and apraxic disorders found commonly in Alzheimer's disease, but there is clinical overlap with other non-Alzheimer degenerative disorders.

The cerebral atrophy with Pick's disease is lobar and typically involves the  frontal and temporal lobes.

This atrophy is so striking that it is "knife-like" in appearance. The atrophy may be asymmetrical.

Microscopically, there is marked loss of cortical neurons with gliosis.

Ballooned neurons called Pick cells may be seen.

Pick bodies, rounded intracytoplasmic inclusions that are highlighted by silver stains, are seen in the cortex.

intracytoplasmic spherules composed of paired helical filaments...

Pick bodies mainly affect neurons in neocortical layers 2, 3, and 4, granular cells of the dentate gyrus, hippocampal pyramidal cells, subiculum, and entorhinal cortex.

Mutations in the tau gene which codes for tau, a protein that is associated with microtubules, can be found in Pick's disease.

The abnormal tau microtubule-associated protein is the main constituent of Pick bodies, which have partially degraded (called ubiquitinated, since they are positive with immunohistochemical staining for ubiquitin) tau fibrils.

Parkinsonism Disease

loss of pigmented cells in the substantia nigra, pars compacta...

the blood supply to the substantia nigra arise from the posterior circulation, specifically the posteromedial branches of the posterior cerebral artery and branches of the posterior communicating artery...

loss of dopamine...

Most cases are sporadic. This syndrome covers several diseases of different etiologies which affect primarily the pigmented neuronal groups including the substantia nigra, locus ceruleus, dorsal motor nucleus of cranial nerve X and the substantia innominata.

parkinson's disease has not been attributed to or associated with a specific gene mutation...

Patients usually present with movement problems such as a festinating gait, cogwheel rigidity of the limbs, poverty of voluntary movement, and a pill rolling type of tremor at rest.

In time the patient's facies will become mask-like. Usually mental deterioration does not occur but some patients may become demented as the disease  progresses.

Idiopathic Parkinson's disease commonly begins in late middle age and the course is slowly progressive.

The pigmented neurons are slowly lost as the disease progresses and melanin pigment can be seen within the background neuropil or within macrophages.

Astrocytosis occurs secondary to neuronal loss.

the loss of midbrain dopamine in this disease  is accompanied by an increase in both dopamine 1 and dopamine 2 receptor density...

Seborrheic dermatitis is well known to be related to neurologic diseases such as parkinson's disease...

Some patients with Parkinsonian symptoms also have dementia, and in these patients there are Lewy bodies in the cerebral cortex, as well as the substantia nigra.

lewy bodies contain alpha-synuclein....

This can be termed diffuse Lewy body disease (DLBD), or Lewy body dementia, and it is in the differential diagnosis for Alzheimer's disease.

Pathologically, Lewy bodies in association with Parkinson's disease are found within the cytoplasm of pigmented neurons.

For a diagnosis of DLBD, the Lewy bodies must be found in the neocortex. These are homogeneous pink bodies on H&E stains with a surrounding halo.

Immunohistochemical staining with antibody to alpha-synuclein or ubiquitin is positive in these Lewy bodies.

The rare familial forms of Parkinson's disease include an autosomal dominant form with mutations in the alpha-synuclein gene and an autosomal recessive form with mutations in the ubiquitin-protein ligase (parkin) gene.

Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP) is considered to be a sporadic disorder despite reports showing familial clustering.

The tau locus on chromosome 17q21 has been identified as a potential risk factor for developing the disease.

In addition to the highly penetrant mutations that are found in large families with FTDP-17, a common extended haplotype in the tau gene also appears to be a risk factor in the development of the sporadic PSP tauopathy.

Mitochondrial dysfunction and cellular oxidative stress are additional mechanisms that may increase the risk.

PSP clinically is marked by a supranuclear gaze palsy along with rigidity, but patients with this disorder may present with dementia that appears similar to Alzheimer's disease.

The initial presentation may be mistaken for Parkinson disease but can be clinically separated by the gaze palsy.

The diagnosis is made by the microscopic findings of globose neurofibrillary tangles and variable neuron loss with gliosis of the globus pallidus, subthalamic nucleus, periaqueductal grey matter, and substantia nigra.

Features associated with tau include neuropil threads, neuritic plaques, tufted astrocytes, glial inclusions, microglia and globose tangles.

In the PSP brain, there is a selective enrichment of tau isoforms containing four microtubule binding domains (4-repeat tau).

Huntington Disease

atrophy of Caudate nucleus...or the neostratium and cerebral cortex...

enlarged lateral ventricles...

loss of GABA neurotransmitter...

is inherited under the guiese of Anticipation...anticipation is severity of disease worsens or age of onset of disease is earlier insucceeding generations...

the essential neurochemical change is in the basal ganglia, where there is a significant reduction in the two transmitters ACh and GABA...in particular there are reduced levels of choline acetyltransferase, glutamic acid decarboxylase, and GABA...

Huntington's disease is seen worldwide but has the highest prevalence in Europe and North America.

It has an autosomal dominant pattern of inheritance, affecting males and females equally...50% chance of inheritance in offspring...

It affects about one in 10,000 individuals in North America. The genetic defect is localized to

IT15 located on chromosome 4p.

The abnormal gene, called HD, on chromosome 4 encodes a widely expressed 348 kDa cytoplasmic protein named huntingtin.

Patients with the disease usually present between the ages of 20 and 50 years, most commonly in the 3rd or 4th decade, with a course that averages 15-20 years to death.

Persons presenting at a younger age more typically progress to death in 7-10 years.

affects Caudate nucleus...

loss of GABA neurotransmitter...

Patients with HD may either present with

choreiform movements,  character change, or psychotic behavior.

Depression and manic-depressive behavior are common features.

Personality changes with irritability and apathy are often seen.

Disturbances in motor function affect both voluntary and involuntary movement.

The involuntary movements are choreiform with fast, uncontrolled movements of limbs and distal muscles.

Coordination of voluntary movements becomes progressively more difficult.

Cachexia is common, regardless of caloric intake.

The abnormal HD gene contains increased trinucleotide CAG repeat sequences.

The trinucleotide CAG codes for the amino acid glutamine and the expanded CAG repeats are translated into a series of uninterrupted glutamine residues (a polyglutamine tract, or polyGln).

The resulting extended polyglutamine stretch confers a deleterious gain-of-function to the huntingtin protein.

As a consequence of the presence of the expanded protein, the striatal medium-sized neurons undergo selective degeneration.

This CAG expansion has 6 to 39 units in normal individuals and 36 to 180 units in HD patients.

The greater the number of repeats, the earlier the onset of the disease. Individuals with 37 to 39 repeats can be unaffected.

Repeats above 100 can be associated with juvenile onset of disease. Spontaneous new mutations are uncommon.

On gross examination, 80% of HD brains show atrophy of the frontal lobes. A bilateral, symmetric atrophy of the striatum is observed in 95% of the HD brains.

Microscopically there is severe loss of small GABAergic spiny neurons in the caudate and putamen with subsequent astrocytosis. With the loss of cells, the caudate becomes shrunken and there is "ex vacuo" dilation of the anterior horns of the lateral ventricles.

The tail of the caudate nucleus shows more degeneration than the head. The caudate atrophy is associated with gradual atrophy and neuronal loss in other brain regions as the disease progresses, particularly the large pyramidal neurons of the cerebral neocortex.

The striatal and cerebral cortex projection neurons are much more susceptible to the disease than interneurons.

In the neostriatum, levels of GABA, dynorphin and substance P are decreased, while concentrations of somatostatin and neuropeptide Y are increased.

Friedreich Ataxia

Friedreich's ataxia is an autosomal recessive neurodegenerative disease.

The estimated incidence in Caucasians is 1 in 50,000. It is the most common type of inherited ataxia.

The disorder is usually manifest before adolescence and is generally characterized by incoordination of limb movements, dysarthria, nystagmus, diminished or absent tendon reflexes, Babinski sign, impairment of position and vibratory senses, scoliosis, pes cavus, and hammer toe.

The triad  is commonly hypoactive knee and ankle jerks, signs of progressive cerebellar dysfunction, and preadolescent onset is regarded as sufficient for diagnosis.

Friedreich's ataxia is a form of spinocerebellar degeneration.

The spinocerebellar tracts, dorsal columns, pyramidal tracts and, to a lesser extent, the cerebellum and medulla are involved by this disease.

The frataxin gene is also expressed in non-neuronal tissues, such as heart and pancreas, which may account for hypertrophic cardiomyopathy and the increased incidence of diabetes observed in these patients.

Hypertrophic cardiomyopathy from mitochondrial dysfunction is common, and half of the patients who die from Friedreich's ataxia succumb to heart failure, and nearly three-fourth of patients have evidence of cardiac dysfunction.

In Friedreich's ataxia, 94% of patients are homozygous for GAA trinucleotide repeat expansions, whereas the remaining 6% of cases are compound heterozygotes for a GAA expansion and a point mutation within the coding region of the gene.

The former are homozygous for an abnormal expansion of a polymorphic GAA triple repeat in the first intron of the X25 gene which is located on chromosome 9q13 and is composed of seven exons spanning 80 kb of genomic DNA.

This gene encodes a mitochondrial protein known as frataxin. There is an inverse correlation between triplet-repeat length and the age at onset of disease, the longer the repeat length the earlier the age of onset.

The GAA triplet repeat adopts an unusual DNA structure, demonstrated by hyperreactivity to osmium tetroxide, hydroxylamine, and diethyl pyrocarbonate.

These results raise the possibility that the GAA triplet-repeat expansion may result in an unusual yet stable DNA structure that interferes with transcription, ultimately leading to a cellular deficiency of frataxin.

Cellular degeneration in Friedreich's ataxia may be caused by mitochondrial dysfunction, possibly due to abnormal iron accumulation, as observed in yeast cells deficient for a frataxin homologue.

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of anterior motor neurons.

ventral horns and lateral columns of the spinal cord are involved also...

Patients with ALS typically present in middle age with weakness of the extremities, starting in either arms or legs.

They may go on to develop bulbar signs and symptoms, such as slurred speech and dysphagia.

Males are affected more commonly than females.

The course is usually 2 to 6 years after diagnosis, but patients presenting with bulbar signs and symptoms have a shorter life span because of swallowing difficulties and risk for aspiration.

involved both upper and lower motor neurons...

The genetic cause of familial amyotrophic lateral sclerosis (ALS) is known in a minority of cases.

Mutations in SOD1, the gene encoding a superoxide dismutase on chromosome 21, are found in 20% of familial ALS patients.

Almost all of the >90 SOD1 mutations found are dominant.

About 5% of sporadic ALS cases have SOD1 mutations.

In SOD1 mediated ALS, anterior motor neurons undergo apoptosis.

In rare cases, a mutation in NFH, the gene encoding the heavy subunit of neurofilament, is present.

Familial ALS has been linked to other loci but the genes involved remain to be identified.

Current data suggest that there are no significant environmental risk factors for sporadic ALS.

The pathologic hallmark of ALS is the degeneration and loss of motor neurons with gliosis in response to this loss.

Motor neuron loss is most striking in the anterior horn cells of spinal cord, but cranial motor nuclei of the brain stem (bulbar involvement) and Betz cells of the prefrontal motor cortex may also be lost.

Clinical features can be variable, depending on the location and rate of loss of motor neurons.

Degeneration of upper motor neurons leads to overactive tendon reflexes, Hoffman signs, Babinski signs, and clonus.

Degeneration of lower motor neurons leads to muscle atrophy, weakness, and fasciculations.