Neuropathology II Flashcards
What is demyelination?
Preferential damage to the myelin sheath = relative preservation of axons
What are the causes of primary demyelination?
Multiple sclerosis, acute disseminated encephalomyelitis, acute haemorrhagic leukoencephalitis
What are the causes of secondary demyelination?
Viral = progressive mulitfocal leukoencephalopathy Metabolic = central pontine myelinosis Toxins = cyanide, carbon monoxide
What is the most common demyelinating disease?
Multiple sclerosis = 2x more common in women, peak incidence in 20-30s
What is multiple sclerosis?
Auto-immune demyelinating disorder characterised by distant episodes of neurological deficits separated in time and which correspond to spatially separated foci of neurological injury
How is multiple sclerosis diagnosed clinically?
Two distinct neurological defects occurring at different times Neurological deficit implicating one neuro-anatomical site and an MRI appreciated defect at another site Multiple distinct (usually white matter) lesions on MRI
How is multiple sclerosis diagnosed supportively?
Visual evoked potentials
IgG oligoclonal bands in CSF
What are the clinical features of multiple sclerosis with optic nerve lesions?
Optic neuritis = unilateral visual impairment
What are the features of multiple sclerosis with spinal cord lesions?
Motor/sensory deficit in trunk and limbs
Spasticity and bladder dysfunction
What are the features of MS with brainstem lesions?
Cranial nerve signs, ataxia, nystagmus, internuclear opthalmoplegia
What is the disease course like in multiple sclerosis?
Acute or insidious onset
Relapsing and remitting, later becoming progressive
What are the brain features of MS?
Principally white matter disease
Exterior surface of brain typically appears normal
Cut surface shows plaques
What are some features of plaques?
Well circumscribed and demarcated
Irregular shaped surface
Glossy almost translucent appearance
Vary from small to very large
What kind of distribution do plaques display?
Non-anatomical distribution
What are some common areas for plaques to develop?
Adjacent to lateral ventricles, corpus callosum, optic nerves and chiasm, brainstem, ascending and descending fibre tracts, cerebellum, spinal cord
What are shadow plaques?
May reflect degree of remyelination = demonstrate thinned-out myelin sheath at edge of lesion which results in less well defined lesion
What are some features of active (acute) plaques?
Perivascular inflammatory cells, microglia and ongoing demyelination
Demyelinating plaques are yellow/brown with and ill defined edge that blends into surrounding white matter
What are some features of inactive (chronic) plaques?
Gliosis, little remaining myeinated axons and oligodendrocytes and axons reduced in number
Well demarctaed grey/brown lesions in white matter
Classically situated around lateral ventricles
What are the environmental and genetic factors implicated in multiple sclerosis?
Environmental = associated with latitude and vitamin D deficiency, may have viral trigger Genetic = 15x risk if affected 1st degree relative, genetic linkage with HLA DRB1
What is the immune pathogenesis of multiple sclerosis?
Lymphocytic infiltration in histology
Oligoclonal IgG bands in CSF
T cell and humeral factors involved
Anti B cell therapies reduce relapses and frequency
What are some degenerative diseases that affect the cerebral cortex?
Alzheimer’s disease, Pick disease, CJD
What are some degenerative diseases that affect the basal ganglia and brainstem?
Parkinson disease, progressive supranuclear palsy, multiple system atrophy, Huntington’s disease
What is a degenerative disease that affects the spinocerebellar tract?
Spinocerebellar ataxia
What characterises the pathology of degenerative diseases?
Simple neuronal atrophy and subsequent gliosis
What is dementia?
Acquired and persistent generalised disturbance of higher mental functions in an otherwise fully alert person
What is the underlying pathology of dementia?
Progressive loss of neurons typically affecting functionally related neuronal groups
What are the primary dementias?
Alzheimer’s disease, Lewy body dementia, Pick’s disease (fronto-temporal dementia), Huntington’s disease
What are the secondary dementias?
Multi-infarct dementia, infection, trauma, metabolic causes
What are some general causes of dementia?
Drugs and toxins, vitamin B1 deficiency, paraneoplastic syndromes, intracranial space occupying lesions, chronic hydrocephalus
What is the most common cause of dementia in the elderly?
Alzheimer’s disease = more common in women
What are the genetic influences of Alzheimer’s disease?
Usually sporadic but familial in 1% = amyloid precursor protein (APP), presenillin 1 and 2
Increased incidence in trisomy 21
How does Alzheimer’s present?
Insidious impairment of higher intellectual function with alteration in mood and behaviour
What are the features of late Alzheimer’s disease?
Progressive disorientation
Memory loss and aphasia indicate severe cortical dysfunction
What is the prognosis of Alzheimer’s disease?
Can result in profound disability, muteness and immobility
Death usually occurs due to a secondary cause
What are the macroscopic features of Alzheimer’s disease?
Cortical atrophy = decreased brain weight and size
Widening of sulci and narrowing of gyri
Compensatory dilation of ventricles = secondary hydrocephalus ex vacuo
What parts of the brain are usually affected by Alzheimer’s disease?
Frontal, temporal and parietal lobes
Occipital lobe brainstem and cerebellum normal
What is the extensive neuronal loss that occurs on Alzheimer’s associated with?
Astrocyte proliferation = simple neuronal atrophy and gliosis
What are the microscopic features of Alzheimer’s disease?
Neurofibrillary tangles, neuritic plaques and amyloid angiopathy
What are some features of neurofibrillary tangles?
Intracytoplasmic = especially hippocampus and temporal lobe
TAU protein = associated with microtubules
Non-specific feature
Where are neuritic plaques found?
Surround astrocytes and microglia = also called Abeta amyloid plaques
What produces amyloid Abeta?
Cleavage of amyloid precursor protein = central element of neuritic plaques
Why is Alzheimer’s linked with Down’s syndrome?
Amyloid precursor protein gene is also located on chromosome 21
What do Abeta oligomers promote?
Hyperphosphorylation and mislocation of TAU
What are some features of amyloid angiopathy?
Extracellular eosinophilic accumulation
Polymerised beta pleated sheets formed by Abeta
Stains with congo red
What effect does amyloid angiopathy have on the BBB?
Disrupts the BBB = serum leaking, oedema and local hypoxia occur
How common is Lewy body dementia?
10-15% of dementias
What is Lewy body dementia?
Progressive dementia = hallucinations and fluctuating levels of attention/cognition, severity varies day to day
How can Lewy body dementia and Alzheimer’s be differentiated?
Memory is affected later in Lew body dementia than it is in Alzheimer’s
When do features of Parkinsonism present in Lewy body dementia?
Present at onset or develop soon after
What are the features of Parkinsonism?
Loss of facial expression, stooping, shiffling gait, slow initiation of movements, stiffness and pill rolling tremor
What is type of conditions display Parkinsonism?
Conditions that affect the nigrostriatal dopaminergic pathways
What are some conditions that cause Parkinsonisms?
Idiopathic Parkinsons, Lewy body dementia, drugs, trauma, multi-system atrophy, progressive supranuclear palsy, cortico-basal degeneration
What is the most common cause of Parkinsonism?
Idiopathic Parkinson’s = called Parkinson’s disease
What causes Parkinson’s disease?
Degeneration of the substantia nigra
What are the macroscopic features of Parkinson’s disease?
Pallor in the substantia nigra = this is where pigmented dopaminergic neurons run
What are the microscopic features of Parkinson’s?
Loss of pigmented neurons
Fewer cortical Lewy bodies
Reactive gliosis and microglial accumulation
Remaining neurons show Lewy bodies
How do Lewy bodies appear?
Single or multiple intracytoplasmic eosinophilic round/elongated bodies = have dense core and surrounding pale halo
What are Lewy bodies?
Aggregates of a-synuclein and ubiquitin
What is Huntington’s disease?
Relentlessly progressive neuropsychiatric disorder = onset usually between age 35-50 but can occur at any time, dementia occurs later in disease
What is the triad of Huntington’s disease?
Emotional, cognitive and motor disturbance
What are the symptoms of Huntington’s disease?
Chorea, myoclonus, clumsiness, slurred speech, depression, irritability, apathy
What is the inheritance of Huntington’s disease?
Autosomal dominant = Huntingtin gene on chromosome 4p
What does mutation of the Huntingtin gene cause?
Additional CAG repeats = disease occurs when >35 repeats occur
What are the macroscopic features of Huntington’s disease?
Atrophy of the basal ganglia in caudate nucleus and putamen
Cortical atrophy occurs later
What are the microscopic features of Huntington’s disease?
Simple neuronal atrophy of striatal neurons in basal ganglia
Pronounce astrocytic gliosis
What is Pick’s dementia?
Progressive dementia = characterised by progressive changes in character and social deterioration, onset usually between age 50-60
What are the symptoms of Pick’s dementia?
Personality and behaviour change, communication and speech problems, changes in eating patterns, reduced attention span
What is the prognosis of Pick’s dementia?
May last between 2-10 years = average is 7 years
leads to impairment of intellect, memory and language
What are the symptoms of Pick’s dementia related to?
Damage to the frontal and temporal lobes
What are the macroscopic features of Pick’s dementia?
Extreme atrophy of the cerebral cortex in frontal and temporal lobes = brain weight <1kg
Neuronal loss and gliosis
What are the histological hallmarks of Pick’s dementia?
Pick’s cells = swollen neurons
Pick’s bodies = intracytoplasmic filamentous inclusions
What is multi-infarct dementia?
Disorder involving deterioration in mental functioning due to cumulative damage to brain through hypoxia or anoxia
What causes multi-infarct dementia?
Result of multiple blood clots within the vessels supplying the brain
What do successive multiple cerebral infarctions cause?
Increasingly larger areas of cell death and damage = dementia results when sufficient area of brain is damaged
What is the epidemiology of multi-infarct dementia?
More common in men
Usually occurs after age 60
Also seen in middle aged hypertensives
What mental health issues are multi-infarct dementia patients prone to?
Depression and anxiety = they are aware of their mental deficits
How do you distinguish multi-infarct dementia form Alzheimer’s disease?
Multi-infarct dementia has abrupt onset, stepwise progression, history of hypertension or stroke and evidence of stoke on CT/MRI
What are some features of large vessel cerebral infarcts?
More common, scattered throughout hemispheres, atheroma of large cerebral arteries provoke thromboembolism
What are some features of small vessel (lacunar) cerebral infarcts?
Rarer, central with subcortical distribution, related to longstanding hypertension and arteriosclerosis of small vessels
