alcohol and dymyelination

Question 1

alcohol metabolism

Answer 1

predominantly in the liver but also in the brain
3 major pathways
- alcohol dehydrogenase-aldehyde dehydrogenase
- microsomal ethanol oxidising system
- catalase

Question 2

acute effects of alcohol

Answer 2

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

Question 3

chronic affects of alcohol

Answer 3

thiamine deficency 
- peripheral neuropathies 
- wernickle-korsakoff 
cerebral atrophy 
cerebellar degeneration 
optic neuropathy

Question 4

primary CNS effects

Answer 4

alcohol related brain damage ARBD
direct alcohol toxicity
intoxication
chronic toxicity

Question 5

secondary CNS effects

Answer 5

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

Question 6

other neurological effects of alcohol

Answer 6

skeletal muscle (type 2 fibre atrophy) 
peripheral nerve (polyneuropathy)

Question 7

major targets of alcohol in mature brains

Answer 7

supporting cells
glia - astrocytes, oligodendrocytes
and synaptic terminals

Question 8

alcohol in developing brains

Answer 8

neurotoxic and teratogenic effects

impairs neuronal and glial function, disrupts neuronal survival, neuronal migration, glial cell differentiation

Question 9

acute alcohol poisoning

Answer 9

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

Question 10

acute alcohol intoxication/poisoning at autopsy

Answer 10

cerebral oedema at autopsy, +- haemorrhages

Question 11

lethal levels of alcohol

Answer 11

> 450-500mg/dL potentiall lethal

1 glass wine blood level 20-30 mg/dL

Question 12

fetal alcohol spectrum disorder

Answer 12

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

Question 13

FASD and stage of exposure

Answer 13

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

Question 14

microcephaly

Answer 14

most common abnormality
other changes include - hydrocephalus, agenesis of corpus callosum, structural abnormalities hippocampus, neuronal migration disorders, disproportionate frontal lobe size reduction

Question 15

structural alcohol abnormalities of FAS

Answer 15

small palebral fissures 
low nasal bridge 
flat midface 
underdeveloped jaw 
microcephaly 
epicanthal folds 
smooth philtrum

Question 16

alcohol-related vitamin deficiencies

Answer 16

• thiamine B1
• niacin B3
• pyridoxine B6
• cobalamin B12

Question 17

niacin deificency

Answer 17

pelagra
dementia, dermatitis (in sun exposed areas), diarhhoea, depression
peripheral neuropathy
treatment - nicotinic acid suppliment

Question 18

thiamin deficiency

Answer 18

beri berii
poor nutritional intake
alcohol impairs absorption and utilisation of thiamine

Question 19

with alcohol, thiamine deficiency in the brain leads to

Answer 19

selective reduction in neurotransmitter levels 
selective neuronal loss 
white matter (myelin) degeneration 
microvascular damage predisposition to life threatening thalamic and brainstem haemorrhages

Question 20

wernickle-korsakoff syndrome

Answer 20

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

Question 21

wernicke syndrome

Answer 21

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

Question 22

acute wernicke encephalopathy

Answer 22

brain normal externally
vascular engorgement and haemorrhages in affected areas
micro changes depend on duration and severity

Question 23

micro changes in wernicke encephalopathy

Answer 23

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

Question 24

korsakoff psychosis

Answer 24

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

Question 25

symptoms of korsakoff syndrome

Answer 25

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

Question 26

alcoholic dementia

Answer 26

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

Question 27

reversibility of alcoholic dementia

Answer 27

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

Question 28

chronic toxicity - ARBD

Answer 28

``` 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 ```

Question 29

alcoholic cerebellar degeneration

Answer 29

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

Question 30

alcoholic cerebellar degeneration microscopically

Answer 30

loss of purkinje cells, variable loss of granular cells and associated reactve proliferation of bergmann astrocytes and gliosis of molecular layer

Question 31

neuromuscular complications of alcohol

Answer 31

alcohol-related peripheral neuropathy | alcoholic myopathy

Question 32

alcohol related peripheral neuropathy

Answer 32

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

Question 33

alcoholic myopathy

Answer 33

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

Question 34

demyelination

Answer 34

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

Question 35

demyelination result in

Answer 35

coordination failure or slowing of conduction

Question 36

role of myelin

Answer 36

electrical insulator - reduce axon capacitance - increases resistance across axolemma - slatatory conduction

Question 37

disorders of myelin

Answer 37

demyelination - autoimmune, viral, toxin, drugs - abnormal myelin formation, leukodystrophies, dysmyelinating diseases

Question 38

primary causes of demylinating diseases

Answer 38

parimary - MS, acute disseminated encephalomyelitis, acute heamorrhagic leukoencephalopathy

Question 39

secondary causes of demylinating diseases

Answer 39

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

Question 40

detecting demyelination

Answer 40

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

Question 41

excluding infacrction in detecting demyelination

Answer 41

loss of myelin alone s not diagnostic - need to demonstrate preserved axons (slver sstain or IHC) to distinguish from other process eg. infarction

Question 42

multiple sclerosis

Answer 42

autoimmune, episodic, activity separated in time, lesions separated in space commonest demylinating disease of the CNS autpommune response against components of the myeline sheath

Question 43

appearance of MS

Answer 43

well circumscribed foci of demyelination (plaques) are distributed throughout the CNS loss of apparently normal myelin sheaths with relative axonal sparing

Question 44

etiology of MS

Answer 44

1. genetic factors 2. environmental factors eg. highest prevalence at higher altitudes 3. viruses - exposure to childhood voral infections may act as a trigger 4. immunological factors - autoimmune disorder

Question 45

clinical features of MS

Answer 45

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

Question 46

prognosis of MS

Answer 46

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

Question 47

pathology of MS

Answer 47

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

Question 48

quality of plagues in MS

Answer 48

2-10mmoccur in grey matter but are difiicult to detect macroscopically

Question 49

CSF findings of MS

Answer 49

midly elevated protein increased immunoglobulin levels, esp IgG oligoclonal bands on protein electrophoresis possible increased cell count (lymphocytosis prossible breakdown products of myelin

Question 50

variants of MS

Answer 50

``` 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 ```

Question 51

3 types of plaques

Answer 51

acute plaques chronic (burnt out) plaques shadow plaques

Question 52

acute plaques

Answer 52

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

Question 53

post-viral autoimmune reactions to myelin

Answer 53

acute onset, monophasic 1. acute disseminated encephalomyelitis ADEM 2. acute necrotising haemorrhagic encephalomyelitis/leukoencephalitis AHL

Question 54

acute disseminated encephalomyelitis ADEM

Answer 54

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

Question 55

ADEM pathology

Answer 55

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

Question 56

acute haemorrhagic leukoencephalopathy AHL

Answer 56

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

Question 57

central pontine myellinolysis

Answer 57

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

Question 58

other causes of central pontine myelinolysis

Answer 58

- thiamine deficiency | - alcohol with drawal

Question 59

prognosis of central pontine myelinolysis

Answer 59

mortality +- 30% survivors often have severe motor dsabilities extrapontine myelinolysis - basal ganglia, thalamus, deep cortex, tips of cerebellar folia