Demyelinating DiseaseDemyelinating DiseaseDr. BasuDr. Basu

Multiple sclerosis (MS)Multiple sclerosis (MS)

Sporadic chronic relapsing-remitting Sporadic chronic relapsing-remitting disease.disease.Demyelation of brain, Demyelation of brain, optic nerveoptic nerve and and spinal cord.spinal cord.

Pathogenesis: Multifactorial ?Pathogenesis: Multifactorial ?

Autoimmune disease. Autoimmune disease. Caused by CD4+ T cells mediated injury Caused by CD4+ T cells mediated injury to the to the oligodendrocytesoligodendrocytes..

Person living in temperate regionPerson living in temperate regionAge – 18 to 40 yearsAge – 18 to 40 yearsAssociation with HLA DR2 gene Association with HLA DR2 gene

ENVIRONMENTAL HEREDITARY

Morphology Morphology

Demyelinated plaque in a patient with Demyelinated plaque in a patient with multiple sclerosis in white matter.multiple sclerosis in white matter.Acute lesion: well demarcated plaque, Acute lesion: well demarcated plaque, inflammatory cells +.inflammatory cells +.

Chronic lesion: no inflammatory cells.Chronic lesion: no inflammatory cells.

Here is a (MS). Here is a (MS).

MRI: Abnormal increased signal in the periventricular white matter

Gross

LaboratoryLaboratory

1.1. CSF of increased protein [ IgG ] that CSF of increased protein [ IgG ] that demonstrates demonstrates oligoclonal bandsoligoclonal bands on on electrophoresis. electrophoresis.

2.2. Presence of Presence of Myelin Basic ProteinMyelin Basic Protein [ indicate the [ indicate the presence of active myelin breakdown] presence of active myelin breakdown]

Clinical FeaturesClinical FeaturesWaxing and waning of neurological sings over Waxing and waning of neurological sings over

few years.few years.Visual disturbance ( diplopia, blurred vision).Visual disturbance ( diplopia, blurred vision).Emotional disturbance.Emotional disturbance.Gait abnormality, Speech Gait abnormality, Speech

disturbance.disturbance.

Treatment:Treatment:Acute: steroidAcute: steroidOthers: interferon beta.Others: interferon beta.

Nutritional DisorderNutritional Disorder

Wernicke's disease.Wernicke's disease.Korsakoff psychosisKorsakoff psychosisSubacute combined degeneration of Subacute combined degeneration of spinal cord.spinal cord.

Wernicke's disease.Wernicke's disease.Etiology: chronic alcoholism Etiology: chronic alcoholism with with thiaminethiamine deficiency. deficiency.Present with ataxia. Present with ataxia. Peripheral neuropathyPeripheral neuropathyMorphology: small petechial Morphology: small petechial hemorrhages in the hemorrhages in the mammillary bodies.mammillary bodies.

Korsakoff psychosisKorsakoff psychosis

IfIf the Wernicke's encephalopathy is the Wernicke's encephalopathy is not not treatedtreated the patient may develop Korsakoff the patient may develop Korsakoff psychosis.psychosis.

Cannot remember Cannot remember newnew memories , or memories , or retrieve old memories.retrieve old memories.

Sub acute combined degeneration of spinal cordSub acute combined degeneration of spinal cord..Cause: Cause: Deficiency of Vitamin BDeficiency of Vitamin B12, 12, OCCUR IN A OCCUR IN A PATIENT OF PERNICIOUS ANAEMIA.PATIENT OF PERNICIOUS ANAEMIA.MorphologyMorphology: Spongy ( vacuolar) degeneration of : Spongy ( vacuolar) degeneration of posterior and lateral columns (posterior and lateral columns ( combined combined ) of spinal ) of spinal cord.cord.

Special stain reveal no

myelin ( pale areas)

Clinical FeaturesClinical Features

WWeaknesseakness, , Abnormal sensation on the limbs (insect Abnormal sensation on the limbs (insect crawling, pin pricking ) crawling, pin pricking ) , Mental problems. , Mental problems.

Loss of vibration sense is the Loss of vibration sense is the most most consistent signconsistent sign and is more pronounced and is more pronounced in legs than in the arms.in legs than in the arms.Late stage: increased deep tendon Late stage: increased deep tendon reflexes, clonus and Babinski sign. reflexes, clonus and Babinski sign.

Next topicsNext topics

d/d of dementiad/d of dementiaDegenerative disordersDegenerative disorders Alzheimer's diseaseAlzheimer's disease Idiopathic Parkinson's diseaseIdiopathic Parkinson's disease

Huntington's DiseaseHuntington's DiseaseAmyotrophic lateral sclerosisAmyotrophic lateral sclerosisFloppy baby syndromeFloppy baby syndromeGuillain Barré SyndromeGuillain Barré Syndrome

d/d of dementiad/d of dementia• Degenerative disordersDegenerative disorders• Multi-infarct DementiaMulti-infarct Dementia• Dementia with lewy bodyDementia with lewy body• Parkinson diseaseParkinson disease• Huntington diseaseHuntington disease• Nurosyphilis, Nurosyphilis, • AIDS-associated dementiaAIDS-associated dementia• Creutzfeldt-Jakob diseaseCreutzfeldt-Jakob disease• Chronic subdural hematomaChronic subdural hematoma• Demyelinating diseaseDemyelinating disease• and toxic-metabolic disorders.and toxic-metabolic disorders.

Degenerating disorderDegenerating disorder

Degenerative disease of the CNS Degenerative disease of the CNS characterized clinically by characterized clinically by progressive progressive cognitive impairment and memory losscognitive impairment and memory loss..

Disease of the grey matter.Disease of the grey matter.

Examples: Examples: Alzheimer's diseaseAlzheimer's disease

Alzheimer's diseaseAlzheimer's disease Dementia Dementia with with preservation of normal preservation of normal level of conscious level of conscious ness.ness.Age : 30% past age Age : 30% past age 85 years.85 years.Mostly sporadicMostly sporadic15% family history of 15% family history of Dementia.Dementia.

Pathogenesis: 15% case are familialPathogenesis: 15% case are familialGenetic factor ? Trisomy 21Perivascular deposition of A beta amyloid

Hyper phosphorylation of Protein tau

Expression of specific alleles of apoprotein E (E2, E3, E4: E4 increased risk)In familial case: Mutations in genes endoding the cellular proteins presenilin-1 and presenilin-2

PATHOGENESIS of early onsetPATHOGENESIS of early onset

Early onset:Early onset: Persons with trisomy 21 living to age of Persons with trisomy 21 living to age of

40y invariably develop Alzheimer's disease 40y invariably develop Alzheimer's disease (earlier than normal)(earlier than normal). .

Mutations in genes endoding the cellular proteins presenilin-1 and presenilin-2

Morphology Morphology GrossGrossA.A. Cerebral cortical atrophyCerebral cortical atrophyB.B. Dilatation of ventricle (Dilatation of ventricle (hydrocephalus ex vacuohydrocephalus ex vacuo))

Micro: Micro: A.A. *Neurofibrillary Tangle : composed of *Neurofibrillary Tangle : composed of Hyper

phosphorylated of Protein tau.B. *Neuritic (senile) plaques with amyloid core(AßAß)C. Amyloid angiopathyD. Lewy body

AtrophyAtrophy Compensatory dilation of the cerebral ventriclesCompensatory dilation of the cerebral ventricleshydrocephalus ex vacuohydrocephalus ex vacuo

MicroscopyMicroscopyAll microscopic

changes are commonly seen in hippocampus:

CA1 region

Neurofibrillary TanglesNeurofibrillary Tangles

Neuritic (senile) plaque stained for

tau protein( brown)

and beta-amyloid (red)

Clinical featuresClinical features

Insidious onset in very old ageInsidious onset in very old ageProgressive memory loss (Progressive memory loss (DementiaDementia))Change in mood and behaviorChange in mood and behaviorAphasia – become muteAphasia – become muteNo specific treatment yet.No specific treatment yet.

Multi-infarct Dementia Multi-infarct Dementia

The cumulative effect of multiple small areas of The cumulative effect of multiple small areas of infarction result in neuronal loss equivalent to infarction result in neuronal loss equivalent to Alzheimer's disease.Alzheimer's disease.

Multiple Multiple focal atrophy of cortexfocal atrophy of cortex. .

Dementia : otherDementia : otherDementia with lewy Dementia with lewy body:body:

Clinical: memory Clinical: memory loss, visual loss, visual hallucination, hallucination, parkinsonism.parkinsonism.

Presence of lewy body.Presence of lewy body.Involve limbic system and Involve limbic system and cingulate gyrus, substantia cingulate gyrus, substantia nigra, neocortex.nigra, neocortex.

Try: cholinesterase inhibitorTry: cholinesterase inhibitor..

Parkinson's Disease Parkinson's Disease

DefinitionDefinitionGenesGenesMorphologyMorphologyClinical featuresClinical features

Idiopathic Parkinson's diseaseIdiopathic Parkinson's disease

It is a degenerative disease commonly It is a degenerative disease commonly begins in late middle age and the course begins in late middle age and the course is slowly progressive. is slowly progressive.

Also know as: paralysis agitans.Also know as: paralysis agitans.

Pathogenesis Pathogenesis

1.1. An An autosomal dominantautosomal dominant form with form with mutations in the alpha-synuclein gene mutations in the alpha-synuclein gene

2.2. And, an And, an autosomal recessiveautosomal recessive form with form with mutations in the mutations in the ubiquitin-protein ubiquitin-protein ligase (Parkin) gene.ligase (Parkin) gene.

Morphology:Morphology:Loss of dopaminergic neurons (neuromelanin) in Loss of dopaminergic neurons (neuromelanin) in the pars compacta of the substantia nigra. the pars compacta of the substantia nigra.

NORMAL

A rounded pink cytoplasmic A rounded pink cytoplasmic Lewy bodyLewy body is seen ( cortical neuron) is seen ( cortical neuron) microscopically with H and E stain at the left. microscopically with H and E stain at the left.

Immunostain for Immunostain for alpha-synuclein on right.alpha-synuclein on right.

Clinical FeaturesClinical FeaturesFestinating gait, cogwheel Festinating gait, cogwheel rigidity of the limbs.rigidity of the limbs.Pill rolling type of tremor at Pill rolling type of tremor at rest.rest.In time the patient's facies will In time the patient's facies will become become mask-likemask-like..Treatment: Levodopa with Treatment: Levodopa with other drug combination.other drug combination.

Huntington's Disease : PathogenesisHuntington's Disease : Pathogenesis

Autosomal dominantAutosomal dominant disorder. disorder.Age: 20 and 50 years, with a course that Age: 20 and 50 years, with a course that averages 15 years to death. averages 15 years to death.

Involve extrapyramidal system.Involve extrapyramidal system.

Huntington's Disease : PathogenesisHuntington's Disease : Pathogenesis

Increased trinucleotide Increased trinucleotide CAG repeatCAG repeat sequencessequences occur in of HD gene that encodes occur in of HD gene that encodes for a protein, called for a protein, called huntingtinhuntingtin..

Loss of GABA nergic neurons… produce Loss of GABA nergic neurons… produce chorea. chorea.

Effect of mutant geneEffect of mutant gene

Severe atrophy of the caudate nuclei and Severe atrophy of the caudate nuclei and compensatory dilation of ventricles.compensatory dilation of ventricles.

Clinical FeaturesClinical Features

Involuntary movements ; choreiform Involuntary movements ; choreiform movements. Hyperkinetic with rigidity / movements. Hyperkinetic with rigidity / seizuresseizuresDepression and mood swingsDepression and mood swings

Huntington's Chorea

It is a also known as motor neuron It is a also known as motor neuron disease.disease.

DefinitionDefinition

Amyotrophic lateral sclerosis (ALS) or Amyotrophic lateral sclerosis (ALS) or Lou Gehrig disease, Lou Gehrig disease, is a degenerative is a degenerative disorderdisorder characterized by a characterized by a spontaneousspontaneous, , progressive lossprogressive loss of of both both

1.1. Upper motor neurons in the Upper motor neurons in the cerebral cerebral cortexcortex and and

2.2. Lower motor neurons in the Lower motor neurons in the anterior anterior horns of the spinal cordhorns of the spinal cord. .

Morphology Morphology loss of anterior horn loss of anterior horn cells of spinal cord: lead cells of spinal cord: lead to atrophy of the to atrophy of the skeletal muscle.skeletal muscle.

This is called “grouped This is called “grouped atrophy”.atrophy”.

Trichrome stainTrichrome stain..

Clinical signs- ALSClinical signs- ALS

Develop Develop bulbar signs ( difficulty in bulbar signs ( difficulty in deglutition) and symptoms.deglutition) and symptoms. Spasticity. Spasticity. Abnormally brisk deep tendon reflexes, Abnormally brisk deep tendon reflexes, and a Babinski sign.and a Babinski sign.

Friedreich ataxiaFriedreich ataxia

Autosomal recessive: early onsetAutosomal recessive: early onsetTriplet Nucleotide repeat of Triplet Nucleotide repeat of frataxin genefrataxin geneInvolveInvolve: dorsal coloum, Cranial nerve: VII, : dorsal coloum, Cranial nerve: VII, X, XIIX, XIIClinicalClinical: Gait ataxia, dysarthria, become : Gait ataxia, dysarthria, become wheel chair bound at age 5.wheel chair bound at age 5.

DISEASE OF THE PERIPHERAL DISEASE OF THE PERIPHERAL NERVOUS SYSTEM.NERVOUS SYSTEM.

Guillain Barré SyndromeGuillain Barré Syndrome

1.1. Most common life threatening disease of Most common life threatening disease of the Peripheral nerve.the Peripheral nerve.

2.2. Caused by Viral , Mycoplasmal Infection Caused by Viral , Mycoplasmal Infection 3.3. Or, May develop spontaneously.Or, May develop spontaneously.

acute ascending polyneuritis

C/FC/FRapid ascending motor weakness Rapid ascending motor weakness May lead to death leading to May lead to death leading to respiratory respiratory failure and Death.failure and Death.

MorphologyMorphologyPeripheral Nerves are infiltrated by Peripheral Nerves are infiltrated by macrophage and Reactive lymphocytes.macrophage and Reactive lymphocytes.CSF will show increase Protein CSF will show increase Protein

segmental myelin loss

Remember !!!!Remember !!!!

Since laboratory tests can not specifically Since laboratory tests can not specifically diagnose GBS, doctors must recognize diagnose GBS, doctors must recognize the disease form its pattern of symptoms the disease form its pattern of symptoms

George Charles Guillain : Jean-Alexander BarréGeorge Charles Guillain : Jean-Alexander Barré

Thank you