Transcript Lecture 11 Brain Damage & Recovery

Brain Damage & Recovery
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Causes of brain damage
Some examples of brain damage
Effects of brain damage
Recovery from brain damage
Myelination disorders
Causes of Brain Damage
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Genetic (not necessarily hereditary!)
Congenital
Environmental (toxins)
Neoplasms
Apoptosis (programmed cell death)
Cerebrovascular problems
Head impact injuries (closed head)
Infections
Hereditary Brain Damage
• Passed from parent to child through DNA.
• Several types:
– Faulty chromosome duplication
• Rare
– Dominant gene disorders
• Rare, tend to be self-limiting.
– Recessive gene disorders
• Not all children express the defect.
– Polygenetic disorders
• By far the most common.
Faulty Chromosome Duplication
• Trisomies
– Patau’s Syndrome (trisomy 13)
• Cleft lip, polydactyly, heart, stillborn or die young.
– Edward’s Syndrome (trisomy 18)
• Multiple major abnormalities & MR
– Down’s Syndrome (trisomy 21)
• MR, Alzheimer’s
• Others
– Turner’s Syndrome (X0)
– Klinefelter’s Syndrome (XXY)
Dominant Gene Disorders
• Normally the disorders prevent their own
reproduction, with two exceptions:
– Disorder limited to rare environmental conditions.
– Disorder manifests itself later in life.
• Pubertal changes required for gene expression
• Adult onset.
• Huntington’s disease (Huntingtin, 4p16.3)
• Early-onset Parkinson’s (pre-50, chr. 4 & 6)
– (not all Parkinson’s cases are genetic)
Recessive Gene Disorders
• Single defective gene is passed from parents to
children, but only ~25% of children express (or
know of) the disorder.
• Often affects myelination of cerebral neurons.
• Pelizaeus-Merzbacher brain sclerosis
– PLP (proteolipid protein), Xq21.3-q22.
• Adrenoleukodystrophy (ALD)
– Xq28 mutation causes peroxisomes to lose the ability to
breakdown very long chain fatty acids (VLCFAs).
VLCFAs degrade both myelin and the adrenal gland.
Polygenetic Disorders
• Requires the presence of
multiple defective genes,
along with environmental
influences.
• Most psychological disorders
& personality traits.
• Genetics can also protect
against disorders.
Congenital Brain Disorders
• In-womb damage
– Typically due to maternal toxin exposure
– Fetal Alcohol/Narcotic Syndrome (FAS/FNS)
– Prescription drugs
• Thalidomide – “seal limb”
• DES (synthetic estrogen) – 50% vaginal cancer by age 10
• Birth Trauma
– Hypoxia due to umbilical strangulation
– Forceps damage during delivery
– Gonorrhea and herpes infections
Environmental
• Toxins
– Ingested toxins (alcohol, drugs, etc.)
– Heavy metal (mercury, lead, etc.) poisoning
• Radiation (fallout, exposure, X-rays, etc.)
– Radiation can cause genetic mutations.
• Drugs
– Drugs of abuse
– Aspirin – Reye’s Syndrome
• Nutritional problems
Neoplasms (Cancers)
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Mass of new tissue (= “new growth”).
Physiologically useless.
Growth is usually not controlled.
Neoplasms account for a relatively high
proportion of neurological disease.
• Brain is 2nd only to uterus as tumor area.
• Brain tumors typically not from nerves.
– Gliomas account for 45% of brain neoplasms
Neoplasms
• Two types of tumors
– Benign (-omas)
• Regular, well-defined shape.
• Does not intrude into surrounding tissue.
• Effects only by pressure on the brain.
– Malignant (-carcinomas)
• Irregularly shaped.
• Intrudes (infiltrates) into surrounding tissue.
• Tend to be recurrent.
Neoplasms
• Astrocytomas
– 40%, slow growing, good
prognosis
• Glioblastomas
– 30%, M, >30, highly malignant,
< 1 year.
• Meduloblastomas
– 11%, children only, 1.5-2 years
• Meningioma
– Most benign of brain tumors,
well encapsulated.
Glioblastoma
Neoplasms
• Metastatic Tumors
– Cancerous cells migrate from other parts of the
body, normally the lung or breast.
– It is not uncommon for lung cancers to first be
noticed in the brain.
– Normally multiple implant sites.
– All malignant.
– Very hard to treat.
Cell Death
• Necrosis
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Externally caused
Death by injury
Cells swell and rupture
Death is swift, < 1 hour
Surrounding area
becomes inflamed
– Nucleus not affected
until the very end
• Apoptosis
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Death by suicide
Normal housekeeping
Shrivel and waste
Slow death, days
No inflammation
– Nucleus affected from
the beginning
– More prevalent in
early development
Cerebrovascular Damage
• Brain is wellprotected against
vascular problems.
• Bilateral independent
arterial supply both
front and back.
• Circle of Willis
Cerebrovascular Damage
Cerebrovascular Damage
• Aneurysms = weakened/expanded blood
vessels
– Take up space normally occupied by brain.
• Ruptured aneurisms = hemorrhage
– Stroke / cerebrovascular accident (CVA).
• Arteriosclerosis
– Hardening/narrowing of arteries.
• Cerebral thrombosis
– Lodged embolus causes ischemia and infarction.
Aneurysm
• Weakened and/or
expanded blood
vessels, or pouches.
• Can burst causing
hemorrhage, infarction
& ischemia.
Aneurysm of aortic arch
Arteriosclerosis
• Arteries get clogged
– Fat & cholesterol
• Blocks oxygen delivery.
• Partial obstructions
require increased blood
pressure to push blood
past obstruction.
• Elevated BP can rupture
aneurysms.
Thrombosis
• Floating body lodges in vessel.
• A 70-year-old woman
presented to the emergency
room with an acute onset of
left arm weakness, difficulty
walking and slurred speech.
• DX: Acute cerebral infarct
from right MCA thrombosis.
Thrombosis
Thrombosis
Cerebrovascular Damage
• Formerly assumed that most damage was
due to decreased oxygen and/or glucose.
• Now appears that most cerebrovascular
damage is due to excess glutamate release
by blood-deprived neurons.
• Excess Ca++ and Na+ influx, especially
through NMDA receptors, kills cells.
• Hippocampus is particularly affected.
• Ca++ channel & NMDA receptor blockers
helpful in preventing post-stroke damage.
Head Impact Injuries
• Car accidents
• Household accidents
– Falling down stairs
– Bike/scooter/Rollerblade accidents
• Shaken baby syndrome
• Physical abuse
Head Impact Injuries
• Contusions (= bruise)
– Damage to the vascular
system.
– Hematomas - localized
collections of blood.
• Subdural - beneath
(inside) the dura
• Epidural - on top of
(outside) the dura
– Many are contrecoup,
opposite to blow.
Head Impact Injuries
• Concussion
– Disturbance of consciousness without evidence
of contusion or other structural damage.
• Common assumption is temporary
disruption with no long-term damage.
– Punch-drunk syndrome suggests otherwise.
– Boxers show cerebral scarring with dementia.
Other CNS Injuries
• Primarily spinal cord
• Slipped disk
– Intervertebral disk
presses into cord.
• Vertebral fracture
– Spinal cord can be
transected, with
varying disabilities.
Infections
• Bacterial
– Streptococcus
• Sore throat, OCD, ADHD
– Syphilis (shown)
• General pariesis –
insanity and dementia
– Neisseria meningitidis
– Campylobacter jejuni
• Common intestinal bacteria
– Clostridium tetani (tetanus)
• Neurotoxin that blocks
cholinesterase
Infections
• Viral
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Rubella (German measles)
Rubeola (measles)
Varicella/Zoster (chicken pox/shingles)
Mumps
Poliomyelitis
Cytomegalovirus (CMV)
Epstein-Barr virus
Rabies
Herpes
Infections
• Encephalitis - inflammation of brain
– Bacteria and/or viruses – herpes (shown)
measles, chicken pox, mumps, etc.
– Sometimes passed by mosquitos or animals.
– Can have high mortality rate.
Infections
• Meningitis - inflammation of the meninges
– Bacteria, viruses, funguses, toxins.
– Bacterial form (Neisseria meningitidis) most
common.
– Viral form most deadly.
– Often mistaken for flu: fever, aches, stiffness.
– Drowsiness, stupor, seizures, then coma.
Effects of Brain Damage
• Kill neurons
– Damage to nerve itself
– Damage to glial cells/altered environment
– Damage to pre-/post-synaptic nerves
• Crowd out or put pressure on the brain
• Disable neurons
– Often by interfering with myelin
Recovery of Function
Recovery of Function
• What happens after (or during) brain damage?
– Degeneration
– Regeneration
– Reorganization
• Can anything be done to aid recovery?
Degeneration
• Damaged neurons
degenerate over days
by the process of
phagocytosis:
• By astroglia in CNS.
• By Schwann cells in
the PNS.
Degeneration
• Anterograde – segments distal to soma:
– Always die thru Wallerian degeneration.
• Swell within hours, fragment within days
– Distal neurons can also be affected.
• Retrograde – segments proximal to soma:
– Might die, might live.
• Early swelling = regeneration likely
• Early shrinking = degeneration likely
– Proximal neurons can also be affected.
Regeneration
• Damaged neurons may regrow.
• Regeneration is well developed in invertebrates.
– Accurate in both the CNS and PNS.
– Accurate even when not in a myelin channel.
• Mammals seem to lose their regeneration
capabilities during maturation.
– Almost non-existent in mammalian CNS.
– Hit-or-miss in mammalian PNS.
Regeneration
• Regeneration in mammals depends on the
balance of two competing factors:
– Growth promoting factors (higher in PNS)
• Neural growth factor (NGF)
• Brain-derived neurotrophic factor (BDNF)
– Growth inhibiting factors (higher in CNS)
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Nogo
Myelin-associated glycoprotein (MAG)
Chondroitin sulfate proteoglycan (CSPG)
Oligodendrocyte myelin glycoprotein (OMG)
Regeneration in PNS
• If myelin sheaths remain intact, nerve can
regrow at mm/day to original destination.
• If nerve sections are separated by more than
a couple mm, they can grow back thru the
wrong myelin tunnels.
• If nerves sections are widely separated, both
sections will die, or regenerating axon tips
will grow wildly into a spaghetti patch.
Regeneration
• Collateral sprouting
– When axons degenerate, adjacent healthy neurons send out
axon branches from terminal end or nodes of Ranvier to
sites vacated by the dying neuron.
– Appears to be mediated by neurotrophic factors released
by the denervated target tissue.
Neural Reorganization
• aka. Plasticity
• The ability of the brain to remap its functioning.
• 2 Mechanisms:
– Rapid reorganization
• Altered synaptic strengths
– Gradual reorganization:
• Establishment of new connections
• Collateral sprouting, etc.
• Damage repair
Neural Reorganization
• The extent and mechanisms of neural
reorganization are still being debated.
• 3 general conclusions
– Bona fide recovery is rare.
– Small lesions are more likely to be recovered.
– Recovery is more likely when young.
Therapeutic Implications
• Promotion of recovery by neurotransplantation
– PNS neurons secrete NGFs and will cause nearby
CNS neurons to grow.
– Cheng, Cao & Olson (1996) cut an optic nerve,
spliced in a PNS nerve segment, and found retinal
axon cells projecting to superior colliculus 4 months
later.
– NGF injection into human CNS promotes a little
growth. Anti-nogo allows ~5% regrowth.
Therapeutic Implications
• Promotion of recovery by rehabilitative
training.
– At least in motor cortex, greater use = less loss
of function (or greater recovery).
– Recovery of monkeys with hand motor cortex
lesions improved with hand motor tasks.
– Humans with spinal cord injuries learn to walk
better with rehabilitative treatment than with
just physiotherapy.
Therapeutic Implications
• Promotion of recovery by genetic engineering.
– The promise of the future.
– Since CNS nerves do not grow because of lack of
neural growth factor (NGF), the idea is to
introduce some from stem cells or altered viruses.
– Nogo also prevents the growth of nerves. Maybe it
can be artificially inhibited. Experimental nogo
antagonists have been found.
Myelination Disorders
Myelination Disorders
• Dysmyelination – poor myelin formation
– Early in life, mostly genetic.
– Many disorders
• Many affect connection between myelin layers.
• Demyelination – myelin destroyed
– Later in life, some genetic, mostly autoimmune.
Myelination Diseases
• Dysmyelination
– leukodystrophies (ALD, PMD, Krabbe) - CNS
• Demyelination
– Guillan-Barré Syndrome (GBS) - PNS
– Acute Disseminated Encephalomyelitis (ADEM) CNS
– Multiple Sclerosis (MS) - CNS
• Combination
– Charcot-Marie-Tooth Disease (CMT) – PNS
Adrenoleukodystrophy (ALD)
• Rare genetic dysmyelination
disorder of the CNS with
progressive dysfunction of
the adrenal gland made
famous in the movie
“Lorenzo’s Oil.”
• (Lorenzo will be 29 in May, 2007. He can no
longer speak, see or move on his own, but he
can communicate by finger tapping and eye
blinking.)
Adrenoleukodystrophy (ALD)
• Etiology
– A genetic defect on Xq28 causes peroxisomes to lose
the ability to breakdown very long chain fatty acids
(VLCFAs). The accumulating VLCFAs degrade both
myelin and the adrenal gland.
• Course
– Poor prognosis, typical 1-10 years till death.
– Progresses to blind, mute and tetraplegic.
• “Treatment”
– Lorenzo’s Oil, lovastatin, bone marrow transplant
Acute Disseminated
Encephalomyelitis (ADEM)
• CNS demyelination, especially in corpus callosum
and white matter in the brain around veins.
– analogous to Guillan-Barré Syndrome in PNS.
• Probably autoimmune, often appears 1-3 weeks
after an antecedent infection or vaccination.
• measles, mumps, rubella, varicella, smallpox, herpes, etc.
• Monophasic, 30% mortality or 2 week recovery.
• A significant number will later develop MS.
• SX: fever, visual neuritis, ataxia, stupor, seizures
Charcot-Marie-Tooth Disease
• Affects the PNS only.
• Most common inherited disorder 1 : 2500
• Characterized by:
– Progressive muscle dystrophy, starting with
distal extremities.
– Loss of proprioception and vibration.
– No loss of pain and temperature (no myelin).
Charcot-Marie-Tooth Disease
• Hereditary
– Variety of genes, some dominant, some recessive.
• 2 major types:
– Demyelinating or hypertrophic type
• The myelin dies off or doesn’t form properly.
• Includes CMT 1, 3, 4 and most X forms.
– Axonal type
• The axon dies off, leaving the myelin intact.
• Includes CMT 2, 5, 6 and some X forms.
CMT-X
• Etiology
– All are mutations in
Connexin-32 gene.
– Thin myelin sheaths and
“onion bulbs.”
– CMT-X1, Xq13.1
• point mutation,
duplication, or deletion
– CMT-X2, Xp22.2
– CMT-X3, Xq26
Multiple Sclerosis
• Autoimmune disease of the CNS causes:
– Multiple white matter lesions (plaques).
– Multiple episodes of neurological deficits.
• 1:1000, F = 2xM, MZ = 25%, onset 20-50
• Most common neurological disorder in young
Canadians.
• Mild neuritis and paresthesias progress to ataxia
and paraplegia, with cognitive problems.
Multiple Sclerosis
• 5x more prevalent in
temperate than tropical
zones.
• Residence at puberty
determines risk.
• White>black>asian
• Native Eskimos, Bantu,
American (N&S) Indians
have very low risk,
despite area.
Multiple Sclerosis
• Etiology
– Autoimmune attack assumed.
– There is some genetic and environmental
predisposition.
– The DNA of HHV-6 (childhood roseola) has
been found in plaques.
– Proteins of the coronavirus have been found to
mimic the structure of MBP.
– Antibodies to nerve cells are often found in MS
patients.
Multiple Sclerosis
Plaques in actual brain slice and MR scan of MS brain