alcohol and dymyelination Flashcards
alcohol metabolism
predominantly in the liver but also in the brain
3 major pathways
- alcohol dehydrogenase-aldehyde dehydrogenase
- microsomal ethanol oxidising system
- catalase
acute effects of alcohol
depressant
subcortical structures affected modulating cerebral activities
disordered cortical, motor, intellectual behaviour (including hippocampus - memory)
higher alcohol levels - cortical neurones then lower medullary centres depressed including respiratory centre - respiratory arrest
chronic affects of alcohol
thiamine deficency - peripheral neuropathies - wernickle-korsakoff cerebral atrophy cerebellar degeneration optic neuropathy
primary CNS effects
alcohol related brain damage ARBD
direct alcohol toxicity
intoxication
chronic toxicity
secondary CNS effects
nutritional deficiencies - thiamine
malnourishment - central pontine myelinolysis
liver disease (hepatic encephalopathy)
increased risk of infection
increased incidence trauma
exacerbates hypertension, diabetes mellitus
interferes with metabolism and therapeutic action of various medications
other neurological effects of alcohol
skeletal muscle (type 2 fibre atrophy) peripheral nerve (polyneuropathy)
major targets of alcohol in mature brains
supporting cells
glia - astrocytes, oligodendrocytes
and synaptic terminals
alcohol in developing brains
neurotoxic and teratogenic effects
impairs neuronal and glial function, disrupts neuronal survival, neuronal migration, glial cell differentiation
acute alcohol poisoning
ingestion of large quantities of alcohol can lead directly to death from cardiorespiratory paralysis
haemorrhage (thalamic, brainstem) due to systemic hypertension, altered cerebral arterial tone
acute neuronal necrosis (thalamus, seletcive cortex, cerebellum) due to neurotoxicity, hypoxic-ischaemic injury
acute alcohol intoxication/poisoning at autopsy
cerebral oedema at autopsy, +- haemorrhages
lethal levels of alcohol
> 450-500mg/dL potentiall lethal
1 glass wine blood level 20-30 mg/dL
fetal alcohol spectrum disorder
ethOH consumption in pregnancy can cause a variety of CMS abnormalities
ranges from gross morphological changes with intellectual delay (FAS) to more subtle cognitive and behavioral disorders (FAE - fetal alcohol effect), including ADHD spectrum and learning disorder
commonest toxin related malformation syndrome
probably more common cause of intellectual delay than down syndrome or fragile X syndrome
FASD and stage of exposure
early embryogenesis - miscarriage, affects survival and proliferation of progenitor cells = microcephaly
7-20 weeks GA - affects neuronal migration = reduces neuronal populations cortex, basal ganglia
3rd trimester - dissrupts the crucial late gestation brain growth spurt = apoptosis of brain cells throughout cerebrum, altered cerebellar development
microcephaly
most common abnormality
other changes include - hydrocephalus, agenesis of corpus callosum, structural abnormalities hippocampus, neuronal migration disorders, disproportionate frontal lobe size reduction
structural alcohol abnormalities of FAS
small palebral fissures low nasal bridge flat midface underdeveloped jaw microcephaly epicanthal folds smooth philtrum
alcohol-related vitamin deficiencies
- thiamine B1
- niacin B3
- pyridoxine B6
- cobalamin B12
niacin deificency
pelagra
dementia, dermatitis (in sun exposed areas), diarhhoea, depression
peripheral neuropathy
treatment - nicotinic acid suppliment
thiamin deficiency
beri berii
poor nutritional intake
alcohol impairs absorption and utilisation of thiamine
with alcohol, thiamine deficiency in the brain leads to
selective reduction in neurotransmitter levels selective neuronal loss white matter (myelin) degeneration microvascular damage predisposition to life threatening thalamic and brainstem haemorrhages
wernickle-korsakoff syndrome
thiamine deificiency
malnourished chronic alcoholics longstanding thiamin dificiency
excessive vomitng
malabsorbtion due to GIT disease
disseminated malignancy (esp. leukaemia and lymphoma)
acute - wernickle’
chronic - korsakoff psychosis pahses
wernicke syndrome
triad - confusion, ataxia, abnormal eye movements
affects mamillary bodies, walls of 3rd ventricle, anterior nucleus of thalamus, periaqueductal tissues of midbrain and floor of 4th ventricle
changes restricted to MB in less fulminant cases
acute wernicke encephalopathy
brain normal externally
vascular engorgement and haemorrhages in affected areas
micro changes depend on duration and severity
micro changes in wernicke encephalopathy
acute - rarefaction of neuropil and haemorrhage but preservation of neurons and axons
subacute - hyperplasia of capillary endothelial cells
chronic - loss of myelin in central portion of MB, gliosis, hemosiderin deposition
korsakoff psychosis
amnestic syndrome
usually secondary to wernicke encephalopathy
thought to be due to structural abnormalities in the dorsomedial nucleus of the thalamus
normal temporal sequence of established memory is disrupted patient beings to confabulate
high morbidity
symptoms of korsakoff syndrome
severe irreversible loss of short term memory
inability to learn and later new information
confabulation
no clouding of conscousness
no general impairment of other cognitive function
alcoholic dementia
more common in middle aged people
chronic alcoholics show neuropsychological impairment with imaging changes of atrophy
- spectrum from mild cognitive imapirment to dementia
- cerebral atrophy (periventricular, ventromedial) and ventricular enlargment at autopsy
- atrophy may be due to reduction in vlume of deep white matter rather than loss of gray matter
reversibility of alcoholic dementia
some reversibility with abstinence, less marked with increased chronicity of drinking
changes +- due to nutrtional deficiencies rather than direct ressult of alcohol - particularly thiamine deficiency
chronic toxicity - ARBD
alcohol related brain dysfunctioon cerebral atrophy - 70g mean reduction in brain wieght white matter reduction neuronal looss - superior frontal lobe subcortical loss in the region of the hypothalamus cerebellar atrophy
alcoholic cerebellar degeneration
about 1% of chronic alcohol exposure
truncal ataxia, unsteady gait, nystagmus
most common form of acquired ataxia in alcoholic patients
may be a sequel of wernicke syndrome
M > F
selectve atrophy of anteror portion of superior vermis of cerebellum
alcoholic cerebellar degeneration microscopically
loss of purkinje cells, variable loss of granular cells and associated reactve proliferation of bergmann astrocytes and gliosis of molecular layer
neuromuscular complications of alcohol
alcohol-related peripheral neuropathy
alcoholic myopathy
alcohol related peripheral neuropathy
initially sensory, later also motor and autonomic
distal-predominant polyneuropathy
axonal degeneration +- demyelination
exacerbated by Vit B1 (thiamine), B3 (niacin), B6 (pyridoxine), or B12
alcohol also causes attenuation of small ntraepithelial nerve fibres
alcoholic myopathy
most prevalent skeletal muscle disorder in western hemisphere
40-60% alcohol abusers
30% reduction in muscle mass, worse with duration and severity of alcohol exposure
pathology - selective type 2muscle fibre atrphy
occurs independant of nutritional state, vitamin defs
demyelination
selective loss of the myelin sheath of a nerve fibre with preservation of the axon
excludes - disorders of myelin formation during development (leukodystrophies), loss of both axon and myelin sheath eg. infarction
results in coordination failure or slowing of conduction
demyelination result in
coordination failure or slowing of conduction
role of myelin
electrical insulator
- reduce axon capacitance
- increases resistance across axolemma
- slatatory conduction
disorders of myelin
demyelination
- autoimmune, viral, toxin, drugs
- abnormal myelin formation, leukodystrophies, dysmyelinating diseases
primary causes of demylinating diseases
parimary - MS, acute disseminated encephalomyelitis, acute heamorrhagic leukoencephalopathy
secondary causes of demylinating diseases
viral - progressive multifocal leukoencephalopathy (PML) (JC virus), HTLV-1 associated myelopathy
metabolic/nutritional - central pontine myelinolysis, marchiafava-bignami disease, mitochondral disease, subacute combined degeneration of the spinal cord (vit B12 deficiency
toxc - methotrexate, carbon monoxide, solvent abuse
detecting demyelination
neuroimaging - MRI
visual evoked responses - demyelination slows conduction
macroscopic - white matter loses white appearance and becomes grey in colour
microscopic - luxol fast blue stain or immunohistochemistry for myelin proteins
excluding infacrction in detecting demyelination
loss of myelin alone s not diagnostic - need to demonstrate preserved axons (slver sstain or IHC) to distinguish from other process eg. infarction
multiple sclerosis
autoimmune, episodic, activity separated in time, lesions separated in space
commonest demylinating disease of the CNS
autpommune response against components of the myeline sheath
appearance of MS
well circumscribed foci of demyelination (plaques) are distributed throughout the CNS
loss of apparently normal myelin sheaths with relative axonal sparing
etiology of MS
- genetic factors
- environmental factors eg. highest prevalence at higher altitudes
- viruses - exposure to childhood voral infections may act as a trigger
- immunological factors - autoimmune disorder
clinical features of MS
focal lesions in CNS eg. optic neurits
peak onset 20-40 years, very uncommon n childhood or > 60 years
F > M
chronic disease with variable and unpredictable course
prognosis of MS
early years characterised by relapses followed by remission with recovery of function
later years often progressive deterioraton leading to irreversible disability
correlation between site of plaques and clinical signs and symptoms
pathology of MS
weel circumscribed areas of gray discolouration withn the white matter (plaques)
usually numerous and scattered throughout CNS
most common sites - periventricular, deep cerebral white matter, interface between cortex and white matter and optic nerves and chiasm
variable in size 2-10mm in diameter
plaques also occur in grey matter but are difficult to detect macroscopically - best seen with IHC
quality of plagues in MS
2-10mmoccur in grey matter but are difiicult to detect macroscopically
CSF findings of MS
midly elevated protein
increased immunoglobulin levels, esp IgG
oligoclonal bands on protein electrophoresis
possible increased cell count (lymphocytosis
prossible breakdown products of myelin
variants of MS
classiic or chronic MS (charcot type) - relapses and remissions in early years aften followed by progressive disability in later years acute M (marburg type) - rapidly progressive disease which is fatal within months
3 types of plaques
acute plaques
chronic (burnt out) plaques
shadow plaques
acute plaques
extensive active dymylination
less well demarcated
macrophages containing phagocytosed myelin sheath debris
some indirect axonal damage at plaque margin (axonal swellings on APP immunohistochemistry)
lymphocytes and plasma cells
abundant reactive astrocytes
post-viral autoimmune reactions to myelin
acute onset, monophasic
- acute disseminated encephalomyelitis ADEM
- acute necrotising haemorrhagic encephalomyelitis/leukoencephalitis AHL
acute disseminated encephalomyelitis ADEM
rare monophasic self limiting disorder
onset 7-10days after non-specific URTI or other viral infectoin eg. measles, mumps, varicella or rubella
rarely follows immunisation (older vaccines which contained CNS antigens in their preparation)
immune mediated demyelination due to production of Ab which cross react with CNS myelin proteins
fatal up to 20%, rest compete recovery
ADEM pathology
multifocal perivanous demyelination and inflammation scattered througout white matter
macro - oedema and vacular congestion n acute phase
micro - widespread cuffing of small blood vessels by lymphocytes and macrophages with a small perivascular region of oedema and demyelination
acute haemorrhagic leukoencephalopathy AHL
very rare, young adults and children
petechial haemorrhages througout white matter
+- fibrinoid necrosis of small bllood vesselss with perivascular haemorrhages
perivascular demyelination +- axonal damage
rapidly progressve and usually fatal
hyperacute variant of ADEM
central pontine myellinolysis
osmotic demyelination syndrome
symmetrical demyelinatng lesion in the centre of the pons
usually surrounding rim of preserved myelin
demyelination may extend through brainstem in a rostral or caudal direction
axons preserved (distinguishes from infarct)
due to metabolic derangement - specifically associated with rapid iatrogenic correction of hyponatreamia
monophasic disorder which is often fatal
other causes of central pontine myelinolysis
- thiamine deficiency
- alcohol with drawal
prognosis of central pontine myelinolysis
mortality +- 30%
survivors often have severe motor dsabilities
extrapontine myelinolysis
- basal ganglia, thalamus, deep cortex, tips of cerebellar folia
