CNS Pathology CNS Pathology

- Demyelinating Diseases- Demyelinating Diseases

- Neurodegenerative diseases- Neurodegenerative diseases

Associate Professor Dr. Alexey Podcheko

Spring 2015

Demyelinating diseasesDemyelinating diseasesConditions characterized by a preferential Conditions characterized by a preferential damage to myelin,damage to myelin, with relative preservation of with relative preservation of axonsaxons Diseases of oligodendrocyte / myelin sheath Diseases of oligodendrocyte / myelin sheath Clinical deficits are due to the effect of myelin Clinical deficits are due to the effect of myelin loss on the transmission of electrical impulses loss on the transmission of electrical impulses along axons along axons Examples include:Examples include:– LeukodystrophiesLeukodystrophies– Multiple Sclerosis (MS) Multiple Sclerosis (MS) – Acute Disseminated Encephalomyelitis Acute Disseminated Encephalomyelitis

(ADEM) (ADEM)

LeukodystrophiesLeukodystrophiesInherited mutations in enzymes necessary for Inherited mutations in enzymes necessary for

production or maintenance of myelinproduction or maintenance of myelin

The characteristics of leukodystrophies are:The characteristics of leukodystrophies are:

Age: infancy through adolescenceAge: infancy through adolescence

Lysosomal or peroxisomal enzyme defectsLysosomal or peroxisomal enzyme defects

Involve both the CNS and the PNSInvolve both the CNS and the PNS

Disease is progressive, resulting in death at an Disease is progressive, resulting in death at an early ageearly age

Metachromatic LeukodystrophyMetachromatic Leukodystrophy

• Most Common type of Most Common type of LeukodystrophyLeukodystrophy

• Genetic Deficiency of Genetic Deficiency of arylsulfatase enzymearylsulfatase enzyme

• Myelin can not be Myelin can not be degraded – accumulates in degraded – accumulates in lysosomeslysosomes

• Loss of myelin and gliosisLoss of myelin and gliosis• Macrophages containing Macrophages containing

sulfatides (when the sulfatides (when the sulfatides bind some types sulfatides bind some types of dyes, they change the of dyes, they change the absorbance spectrum, - absorbance spectrum, - called called metachromasiametachromasia

 Here the macrophages are clustered around a vessel, as well as scattered in the parenchyma.

Krabbe's Disease (Globoid Cell Krabbe's Disease (Globoid Cell Leukodystrophy)Leukodystrophy)

• Defect in galactocerebroside b-Defect in galactocerebroside b-galactosidasegalactosidase

• A breakdown product of A breakdown product of galactocerebroside is toxic galactocerebroside is toxic causing oligodendrocyte injurycausing oligodendrocyte injury

• Autosomal RecessiveAutosomal Recessive• Pathology characterized byPathology characterized by– loss of myelin and loss of myelin and

oligodendrocytes (and oligodendrocytes (and Schwann cells in the PNS)Schwann cells in the PNS)

– reactive astrogliosisreactive astrogliosis– multinucleated macrophages multinucleated macrophages

called globoid cells accumulate called globoid cells accumulate around blood vessels (blue around blood vessels (blue arrows)arrows)

•Severe sensory, motor and cognitive defects •Death within 1-2 years

AdrenoleukodystrophyAdrenoleukodystrophy• X-linked (Note: this is the disease that was the X-linked (Note: this is the disease that was the

topic of the film topic of the film Lorenzo's OilLorenzo's Oil))• Impaired addition coenzyme A to long-chain Impaired addition coenzyme A to long-chain

fatty acidsfatty acids• lack of catabolism of very long chain fatty acids lack of catabolism of very long chain fatty acids

(VLCFA's) in peroxisomes, and increased (VLCFA's) in peroxisomes, and increased levels of VLCFA's can be found in serumlevels of VLCFA's can be found in serum

• Atrophy of the Atrophy of the ADRENALADRENAL gland gland• CNS Pathology consists ofCNS Pathology consists of– myelin loss - myelin loss - LEUKODYSTROPHYLEUKODYSTROPHY– gliosisgliosis– lymphocytic inflammationlymphocytic inflammation

AdrenoleukodystrophyAdrenoleukodystrophy• Clinical Features:Clinical Features:• Children 3-10 years oldChildren 3-10 years old• Severe sensory, motor and cognitive

defects• Adrenal failure (Addison Disease)• Rx: Manipulation with dietary lipid

composition

Multiple SclerosisMultiple SclerosisAutoimmune destruction of CNS myelin and Autoimmune destruction of CNS myelin and oligodendrocytesoligodendrocytes

Most common demyelinating disorderMost common demyelinating disorder

More commonly seen in regions away from More commonly seen in regions away from equator equator

Prevalence ~ 1 per 1000 persons in USPrevalence ~ 1 per 1000 persons in US

Onset at any ageOnset at any age– Relatively rare in childhood or after age 50 Relatively rare in childhood or after age 50

Women > men 2:1Women > men 2:1

Multiple SclerosisMultiple Sclerosis

Etiology:Etiology:

– Not clearly establishedNot clearly established– Implicated factors:Implicated factors:

EnvironmentalEnvironmental

GeneticGenetic

Immune Factors: associated with HLA DR2Immune Factors: associated with HLA DR2

Multiple Sclerosis - Clinical featuresMultiple Sclerosis - Clinical featuresDemyelinating lesions can occur Demyelinating lesions can occur anywhere in the central nervous anywhere in the central nervous system and, as a consequence, system and, as a consequence, may induce a wide range of may induce a wide range of symptomssymptoms

Common clinical presentation:Common clinical presentation:

Blurred vision in one eye (optic Blurred vision in one eye (optic nerve)nerve)

VertigoVertigo

Scanning speech (brainstem)Scanning speech (brainstem)

Internuclear ophtalomoplegiaInternuclear ophtalomoplegia

(damage of medial longitudinal (damage of medial longitudinal fasciculus)fasciculus)

Multiple Sclerosis - Clinical featuresMultiple Sclerosis - Clinical features

Hemiparesis or unilateral loss of sensation Hemiparesis or unilateral loss of sensation (cerebral white matter injury)(cerebral white matter injury)Lower extremity loss of sensation or weakness Lower extremity loss of sensation or weakness (spinal cord)(spinal cord)Bowel, bladder and sexual dysfunction (ANS Bowel, bladder and sexual dysfunction (ANS injury)injury)Natural course of multiple sclerosis is variableNatural course of multiple sclerosis is variableEpisodes of neurologic deficits develop over Episodes of neurologic deficits develop over short periods of time (days to weeks) and show short periods of time (days to weeks) and show gradual partial remissiongradual partial remissionFrequency of relapses tends to decrease over Frequency of relapses tends to decrease over the course of timethe course of time

A 29-year-old Caucasian female complains of decreased A 29-year-old Caucasian female complains of decreased vision and pain around her eye, which is aggravated vision and pain around her eye, which is aggravated by eye movement. Several months later she is found by eye movement. Several months later she is found to have an intention tremor of her left arm. This to have an intention tremor of her left arm. This patient’s condition is most likely caused by:patient’s condition is most likely caused by:

A. Bacterial infection A. Bacterial infection

B. Vascular disease B. Vascular disease

C. Trauma C. Trauma

D. Autoimmune disease D. Autoimmune disease

E. Inherited metabolic disease E. Inherited metabolic disease

F. Intoxication F. Intoxication

Corr DCorr DExplanation:Explanation:

The patient’s complaints of pain with ocular movements and decreased vision are consistent with The patient’s complaints of pain with ocular movements and decreased vision are consistent with optic neuritis. Intention tremor is a sign of cerebellar dysfunction. Both of these symptoms are optic neuritis. Intention tremor is a sign of cerebellar dysfunction. Both of these symptoms are commonly seen in multiple sclerosis. Waxing and waning neurological deficits in a 20-30 year commonly seen in multiple sclerosis. Waxing and waning neurological deficits in a 20-30 year old patient are suggestive of this disorder. old patient are suggestive of this disorder.

The etiology of multiple sclerosis remains unknown. Currently, it is considered an autoimmune The etiology of multiple sclerosis remains unknown. Currently, it is considered an autoimmune disease, with viral and environmental factors also playing a role in its pathogenesis. The disease, with viral and environmental factors also playing a role in its pathogenesis. The autoimmune character of this disorder is supported by the following features: autoimmune character of this disorder is supported by the following features:

1. There is an elevated immunoglobulin G (lgG) level in the cerebrospinal fluid (CSE). It is seen as 1. There is an elevated immunoglobulin G (lgG) level in the cerebrospinal fluid (CSE). It is seen as an oligoclonal band on electrophoresis and suggests an activation of B cells in multiple an oligoclonal band on electrophoresis and suggests an activation of B cells in multiple sclerosis. sclerosis.

2. The incidence of multiple sclerosis is increased in people with certain HLA types. 2. The incidence of multiple sclerosis is increased in people with certain HLA types.

3. Immunomodulatory agents, such as interferon beta, have a positive impact on multiple sclerosis. 3. Immunomodulatory agents, such as interferon beta, have a positive impact on multiple sclerosis. Its mechanism is counteraction of the inflammatory action of immune cells. Its mechanism is counteraction of the inflammatory action of immune cells.

Environmental factors are also important in the pathogenesis of MS. This disease is much more Environmental factors are also important in the pathogenesis of MS. This disease is much more common in temperate latitudes. Its prevalence is 30-50 times as high in the USA, Canada and common in temperate latitudes. Its prevalence is 30-50 times as high in the USA, Canada and Northern Europe as it is in equatorial Africa. Northern Europe as it is in equatorial Africa.

The factors listed in the other choices do not participate in the development of multiple sclerosis. The factors listed in the other choices do not participate in the development of multiple sclerosis.

Educational Objective: Educational Objective:

Multiple sclerosis is viewed as an autoimmune condition. Viral and environmental factors are also Multiple sclerosis is viewed as an autoimmune condition. Viral and environmental factors are also considered to play a role in its development. Increased levels of lgG in the CSF, detected as an considered to play a role in its development. Increased levels of lgG in the CSF, detected as an oligoclonal band on electrophoresis, supports the immunologic theory. oligoclonal band on electrophoresis, supports the immunologic theory.

Diagnosis of MSDiagnosis of MS1.1. Lumbar puncture:Lumbar puncture:

a.a. elevated immunoglobulin G elevated immunoglobulin G (lgG) level in the (lgG) level in the cerebrospinal fluid seen as cerebrospinal fluid seen as oligoclonal band on oligoclonal band on electrophoresis (due to electrophoresis (due to activation of B cells)activation of B cells)

b.b. Increased level of Increased level of lymphocyteslymphocytes

c.c. Myelin basic proteinMyelin basic protein

2. MRI : reveals plaques2. MRI : reveals plaques

Multiple Sclerosis-MorphologyMultiple Sclerosis-MorphologyMS is a white matter diseaseMS is a white matter disease

Gross examination:Gross examination:Foci of demyelination appear as glassy, gray Foci of demyelination appear as glassy, gray lesions lesions

Microscopic examination:Microscopic examination:Characteristic multiple lesions scattered in white Characteristic multiple lesions scattered in white matter - Plaquesmatter - Plaques

Plaque!!!

Subacute Sclerosing PanecephalitisSubacute Sclerosing PanecephalitisProgressive debilitating encephalitis leading to Progressive debilitating encephalitis leading to

deathdeath

Result of slowly progressing infection of the brain Result of slowly progressing infection of the brain by measles virusby measles virus

Clinical signs develop several years after Clinical signs develop several years after measles, with extensive brain damage leading measles, with extensive brain damage leading to death usually within one to two years after to death usually within one to two years after onsetonset

Morphology –Morphology –

intranuclear, eosinophilic inclusion bodies with intranuclear, eosinophilic inclusion bodies with associated demyelination and gliosisassociated demyelination and gliosis

Subacute Sclerosing Panencephalitis (SSPE)Subacute Sclerosing Panencephalitis (SSPE)

Associated with measles (rubeola) virus either Associated with measles (rubeola) virus either as a primary infection or , rarely, as a as a primary infection or , rarely, as a complication of immunization against measles complication of immunization against measles since it is a live attenuated vaccine!!!!since it is a live attenuated vaccine!!!!

Progressive Multifocal Progressive Multifocal LeukoencephalopathyLeukoencephalopathy

• JC virus infection of oligodendrocytesJC virus infection of oligodendrocytes• Immunosuppression leads to reactivation of Immunosuppression leads to reactivation of

latent viruslatent virus• Prominent in the pathology of AIDS and Prominent in the pathology of AIDS and

patients who are immunocompromised patients who are immunocompromised (leukemia)(leukemia)

• Present with rapidly progressive neurological Present with rapidly progressive neurological signs leading to deathsigns leading to death

• Dementia, myoclonic fasciculations; normal funduscopic exam; no other focal neurologic signs

Central Pontine MyelinolysisCentral Pontine MyelinolysisFocal demyelination of ponsFocal demyelination of pons

Caused by rapid Intravenous correction of hypo Caused by rapid Intravenous correction of hypo Na emiaNa emia

Occurs in severely malnourished patientsOccurs in severely malnourished patients

Present as acute paralysis (“Locked in” Present as acute paralysis (“Locked in” syndrome)syndrome)

Locked-in syndrome is a condition in which a patient is aware and awake but cannot move or communicate verbally due to complete paralysis of nearly all voluntary muscles in the body except for the eyes

Degenerative DiseasesDegenerative Diseases

Are diseases of gray matter Are diseases of gray matter

Characterized principally by:Characterized principally by:– Progressive loss of neuronsProgressive loss of neurons with associated with associated

secondary changes in white matter tracts. secondary changes in white matter tracts. – Pattern of Pattern of neuronal loss is selectiveneuronal loss is selective, affecting one , affecting one

or more groups of neurons, while leaving others or more groups of neurons, while leaving others intact. intact.

– Disease Disease arises without any clear inciting eventarises without any clear inciting event in a in a patient without previous neurologic deficitspatient without previous neurologic deficits

Degenerative DiseasesDegenerative Diseases

Degenerative Diseases Affecting the Cerebral Degenerative Diseases Affecting the Cerebral Cortex – Cortex – lead to dementia!!!lead to dementia!!!– Alzheimer’s disease (AD)Alzheimer’s disease (AD)– Vascular dementiaVascular dementia– Pick’s diseasePick’s disease

Degenerative Diseases of Basal Ganglia and Degenerative Diseases of Basal Ganglia and Brain Stem – Brain Stem – lead to movement disorders!!!lead to movement disorders!!!

Spinocerebellar Degenerations Spinocerebellar Degenerations

Degenerative Diseases Affecting Motor Degenerative Diseases Affecting Motor Neurons Neurons

Degenerative Diseases Affecting the Cerebral Cortex

Major cortical degenerative diseases are – Alzheimer’s disease (AD) – MC cause of dementia!– Vascular Dementia– Pick’s disease– Levy body dementia– Vascular disease (multi-infarct dementia)– Creutzfeldt-Jakob disease– Neurosyphilis

Dementia is not part of normal aging and always represents a pathologic process.

Alzheimer’s Disease Insidious impairment of higher intellectual function, with alterations in mood and behavior, F:M=2:1

Later, progressive disorientation, memory loss, and aphasia indicate severe cortical dysfunction, and eventually, over 5 to 10 years, the patient becomes profoundly disabled, mute, and immobile

Down Syndrome patients become symptomatic before 50 years of age

Although pathologic examination of brain tissue remains necessary for the definitive diagnosis of AD, the combination of clinical assessment and modern radiologic methods allows for a diagnostic accuracy of 80 to 90%.

Alzheimer’s Disease (AD)-Morphology

Major microscopic abnormalities of AD are – Neurofibrillary tangles– Senile (neuritic) plaques– Amyloid angiopathy

Diagnosis of AD is based on a clinicopathologic correlation between the patient’s neurologic status and the frequency of plaques and tangles

Morphology1. Hydrocephalus ex

vacuo

2. Neuritic plaques (extracellular AB amyloid + Neuritic processes)

3. Neurofibrillary tangles are intracytoplasmic intraneuronal accumulations of polymerized hyperphosphorylated tau microtubular protein (arrows).

Alzheimer’s Disease

• DIFFUSE!!!! Cortical atrophy (right side meninges removed)

Pathogenesis of AD

1. hypothetical mechanism for the formation of senile plaques (SP) from soluble APP peptides produced inside cells and secreted into the extracellular space.

Conversion of normal tau protein overlying two microtubules into paired helical filaments.Overactive kinase(s) or hypoactive phosphatase(s) may contribute to this effect. Abnormally phosphorylated tau loses the ability to bind microtubules, thus causing their depolymerization, disruption of axonal transport and degeneration of neurons.

Clinical Features• Slow-onset of memory loss• Progressive disorientation• Loss of learned motor skills and language• Behavior and personality changes• Patients become mute and bedrdden• Focal neurologic deficits not seen early

Risk FactorsSporadic form of AD

a. Age

b. Presence of E4 allele of ApoE

(E2 allele decreases risk)

Early form of AD:

a. Presenillin 1 (MC) and 2

b. Down Syndrome due to APP is on the chromosome 21

Vascular Dementia• Due to multifocal infarction and injury• Due to Hypertension, Atherosclerosis or

Vasculitis• Second most common cause of dementia!!!!!• Better prognosis, partially reversible

Pick’s DiseasePick’s disease occurs far less frequently than Alzheimer’s disease but is also clinically manifested as profound dementia over a comparable time course.The brain in Pick’s disease invariably exhibits a pronounced atrophy of the frontal and temporal lobes with conspicuous sparing of the posterior two-thirds of the superior temporal gyrus The atrophy can be severe, reducing the gyri to a thin wafer (“knife-edge” appearance). Behavioral and language symptoms arise early; progress to dementia

Pick’s Disease

Microscopically:

Neuronal loss is most severe in the outer three layers of the cortex and may be severe enough to resemble superficially (pseudo)laminar necrosis

Round aggregates of Tau protein (not tangles as in AD!!!!) in neurons (Pick cells or Pick bodies)

Degenerative Diseases of Basal Ganglia and Brain Stem

Diseases affecting these regions of the brain frequently are associated with movement disorders, including rigidity, abnormal posturing, and chorea. In general, they can be categorized as manifesting either:– A reduction of voluntary movement – An abundance of involuntary movement.

The nigro-striatal pathway plays an important role in the system of positive and negative regulatory synaptic pathways that serve to modulate feedback from the thalamus to the motor cortex.– Parkinsonism – Idiopathic Parkinson’s Disease (IPD) – Progressive Supranuclear Palsy – Multiple System Atrophies – Huntington’s Disease

BG (STRIATUM)

Cortex

SN PcSubstantia Nigra parts compacta

D1Dopamine receptors increase stimulation

D2Dopamine receptorsDecrease inhibition

Normal interactions between nigra-striatal complex and cortex of the brain

Dopamine

ParkinsonismParkinsonism is a clinical syndrome characterized by – Tremor “Pill-rolling” tremor– Rigidity– Akinesia/Bradikynesia– Postural instability and shuffling gait– Diminished facial expression– Stooped posture– Slowness of voluntary movement– Festinating gait (progressively shortened, accelerated steps)

This type of motor disturbance is seen in a number of conditions that have in common damage to the nigrostriatal dopaminergic systemParkinsonism may also be induced by drugs that affect this system– Dopamine antagonists – Toxins (notably, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

[MPTP ])

The principal diseases that involve the nigrostriatal system are – Idiopathic Parkinson’s disease– Striatonigral degeneration– Lewy body dementia

Idiopathic Parkinson’s Disease (IPD)

Patients with progressive parkinsonism in the absence of a toxic or other known etiology.

As in Alzheimer’s disease, it is seen with increasing frequency in older age cohorts.

In addition to the movement disorder, there are other less well-characterized changes in mental function, and a few patients with the pathologic findings of idiopathic Parkinson’s disease present with a dementia clinically similar to that of Alzheimer’s disease.

Idiopathic Parkinson’s DiseaseThe dopaminergic neurons of the substantia nigra project to the striatum, and their degeneration in Parkinson’s disease is associated with a reduction in the striatal dopamine content. The severity of the motor syndrome is proportional to the dopamine deficiencyCan be partly corrected by replacement therapy with L-dopa (the immediate precursor of dopamine)Treatment does not, however, reverse the morphologic changes or arrest the progress of the disease, and with progression, drug therapy tends to become less effective, and symptoms become more difficult to manage.

Idiopathic Parkinson’s Disease

The most dramatic recent development in the treatment of IPD has been in the field of neural transplantation.

Stereotactic implants of fetal mesencephalic tissue into the striatum

Morphology

Pathologically, the typical gross findings are pallor of the substantia nigra and locus ceruleus

Microscopically

Loss of the pigmented, catecholaminergic neurons in these regions associated with gliosis

Lewy bodies may be found in some of the remaining neurons– These are intracytoplasmic, eosinophilic, round to

elongated inclusions that often have a dense core surrounded by a paler rim – contain alpha-synuclein protein!!!!

• Normal Substantia Nigra Depigmented Substantia Nigra

Lewy Body in Substantia Nigra

Dementia and Parkinson diseaseEarly-onset dementia suggests Lewy body

dementia disease:

A. Early dementia

B. Hallucinations!!!!!

C. Parkinsonism

D. Lewy bodies (filled with a-synuclein) in the cortex of brain!!!

Progressive Supranuclear Palsy

Usually present with loss of vertical gaze

Progressing to difficulty with all eye movements

Associated with – Truncal rigidity – Dysequilibrium– Loss of facial expression– Progressive dementia

Onset: fifth and seventh decades

Male: females = 2:1

Death occurs often within 5 to 7 years

Huntington’s DiseaseAppears between 20 and 50 years of age Degeneration of GABAergic neurons in caudate nucleus of basal gangliaAD, CaucasiansUncontrolled movements and progressive dementia Chorea– Jerky, hyperkinetic, sometimes dystonic movements

affecting all parts of the body – ATHETOSIS!!!!

May later develop parkinsonism with bradykinesia and rigidity.Early signs of higher cortical dysfunction – Forgetfulness and thought and affective disorders

DEPRESSION, SUICIDE high rate– An average course of about 15 years to death.

Morphology

Gross examination:

Brain is small

Striking atrophy of the caudate nucleus and putamen

Lateral and third ventricles are dilated

Microscopically:

Severe loss of striatal neurons

Huntington’s Disease

• Normal Cerebral Hemisphere (left)• Atrophy of Striatum and ventricular dilatation (Right)

Caudate Nucleus

Putamen Nucleus

Corpus StriatumGABA!!!

Hydrocephalus Ex vacuo

Internal capsule

Expanded trinucleotide repeats (CAG)

Huntingtin gene (Ch.4)

Future expansion occurs during spermatogenesis (meiosis)

Anticipation effect (grandfather, father and son – 60, 50 and 40 years manifestation of disease, respectively)

Huntington’s Disease

Normal Pressure Hydrocephalus• Increased CSF results in dilated

ventricles• Causes dementia in adults• Arachnoid granulations defect to

absorb excess of CSF• Stretching of corona radiataClinical: triad of Urinary

Incontinence, Gait Instability, Dementia

Lumbar Puncture improves symptoms

Treatment: Ventriculo-peritoneal shunting`

A 5-year-old boy is brought to the physician after he was hit in the head with a baseball The incident occurred about two hours ago He had no loss of consciousness, but was a little dazed after being hit However he seemed to improve after a short time About 30 minutes ago. the patient began to complain of a headache vomited twice, and is currently not acting nght according to his parents On examination, the child is sleepy and his left pupil is larger than his nght A CT scan of his head is shown below.

Which of the following is the most appropriate next step in management?

A Cerebral angiogram B MRI of the brain C Repeat CT in 24 hours D Dexamethasone E Emergent craniotomy

•PrP found in neurons (PrPc – normal protein)

•Role of PrP in the cell –it is platform for the assembly of signaling modules

•Conformational changes in the protein structure (misfolding) makes it resistant to action of proteases

•Misfolded PrP turns normal protein into misfolded PrP

Cause transmissable diseases -Transmissable spongioform encephalopathies:

•Kuru disease (cannibalism)

•Creutzfeldt-Jakob disease (from cattle to human)

•Fatal familial insomnia

•Way of infection: via blood products, organ transplant, surgery, meat products

PRIONS

Pathogenesis of Prion DiseasesPrion protein (PrP) is normally found in neurons

and has an a-helical structure. If the conversion of a-helix into beta- pleated sheet occurs the protein becomes resistant to proteases.

Accumulation of this abnormal protein in gray matter is most likely causing prion diseases

Prion Diseases, Common Features:1. They are associated with an abnormal prion protein (PrP).

This protein is normally present in host neurons. A change in its secondary structure renders it resistant to enzymatic digestion by proteases and leads to its accumulation

2. These diseases have long incubation periods. However they are rapidly progressive after the onset of clinical symptoms

3. Characteristic morphologic changes in brain are described as spongiform encephalopathy

4. Vacuoles form in the cytoplasm of the neutrophils and neurons. As the disease progresses, the vacuolated areas transform into cysts.

5. No inflammatory changes are present6. There is no treatment for prion diseases. These conditions

are invariably fatal

Bovine Spongiform Encephalitis, Creutsfeldt-Jakob Disease

Vacoulization (sponginess) of CNS tissue is the consistent diagnostic finding

Q: PrP is a normal cellular protein found in neurons that has an a-helical secondary structure. In some patients, this protein undergoes a conformational change to a β-pleated sheet isoform, making it highly resistant to proteases, thus causing intracellular accumulation. Which of the following best describes histological changes that may be seen in the brain of these patients?

A. Cytoplasmic inclusions in oligodendrocytes B. Neurofibrillary tangles and neocortical plaques C. Microglial nodules and multi nucleated giant cells D. Patches of white matter destruction E. Spongiform transformation of gray matter

Creutzfeldt-Jakob disease, Clinical Presentation

• Rapidly progressive dementia• Startle Myoclonus, Ataxia • Spike-wave complexes seen on EEG• Death in <1 year• May be history of transplant or usage extracts of Hypophysis

A 42-year-old Caucasian male treated for impaired vision develops rapidly progressive dementia and myoclonic jerks. He lapses into a coma and dies six months later. A sample of brain tissue shows gray matter changes with many uniform vacuoles between neuron cell bodies and in the perikaryon of neurons. No inflammatory changes are present. This patient most likely suffered from: A. Myastenia gravis B. Bacterial Meningitis C. Creutzfeldt-Jakob disease

D. Multiple sclerosis

Other Prion DiseasesVariant CJD – due to exposure to bovine

spongioform encephalopathy (beef meat) in young people

Familial fatal insomnia – inherited form of prion disease – insomnia + exaggerated startle response (The startle response or startle reaction is a response to sudden, startling stimuli, such as sudden noise or sharp involves flexion of most skeletal muscles and a variety of visceral reactions )

Spinocerebellar DegenerationsGroup of diseases affecting the cerebellar cortex, spinal cord, peripheral nervesPathologically: – Degeneration of the neurons in the affected areas

Clinically: – Combination of cerebellar and sensory ataxia– Spasticity– Peripheral motor and sensory defects

Types:Paraneoplastic cerebellar degeneration Alcoholic cerebellar degeneration also predominantly affects Purkinje cells, especially in the superior vermisFriedreich’s Ataxia (FA)Ataxia-Telangiectasia

Friedreich’s AtaxiaAutosomal recessive conditionFrataxin gene (iron and mitochondrial metabolism) accumulation of GAA repeats Male preponderanceAverage age at onset of about 11 yearsSymptoms– Gait ataxia– Hand clumsiness – Dysarthria– Deep tendon reflexes are absent– Extensor plantar reflex is typically present– Joint position and vibratory sense are impaired– Most patients become paralyzed over the course of about 20 years

There is a high incidence of concomitant diabetes and cardiac disease– Manifests as cardiac arrhythmias and Cardiomyopathy (congestive

heart failure)

Ataxia-TelangiectasiaAutosomal recessive disease Presents in childhood Loss of cerebellar function in the setting of recurrent infections. Neurologic signs appear before the appearance of the numerous telangiectatic lesions in conjunctiva and in other areas. Pathologic findings:Predominantly in the cerebellum– Loss of Purkinje and granule cells

Systemic findings:– Absence of a thymus as well as hypoplastic gonads.

Strong tendency for lymphoid malignancy

Degenerative Diseases Affecting Motor NeuronsAmyotrophic Lateral Sclerosis (ALS)ALS is a degenerative disease of upper and lower motor neurons of the brain and spinal cord, with progressive weakness and wasting of the extremities and tongue, a sometimes confusing combination of hyperreflexia and hyporeflexia and eventual impairment of respiratory muscles.Patients have loss of both – Lower motor neurons

Muscular atrophyFasciculationsWeakness

– Upper motor neurons HyperreflexiaSpasticityBabinski reflex

Men > women

Autosomal Dominant inheritance pattern in 5% cases

Mutation in SOD1 – free radical detoxifying enzyme

Intellectual capacities

preserved

Amyotrophic Lateral Sclerosis (ALS)