Central nervous system

What is the blood brain barrier

Blood brain barrier: connections bwt epithelial cells → tight junctions → stops many substances from passing from blood to brain → hard to get drugs into brain ( transportation: carrier mediated + glial cells support ) 

Intracranial fluid dynamics

Blood from blood reservoir of body → arteries → capillaries in brain → fluid leak across BBB into interstitial space → flows across ependymal lining to ventricles/ pial-glial lining to subarachnoid space → spinal cord /  fluid directly  become cerebrospinal fluid in choroid plexus/ fluid flows from ventricles to subarachnoid space 

→ fluid in interstitial space/ from subarachnoid space is reabsorbed through veins into body 

Features of brain

1. High demand for O2 + glucose 

2. X effective storage mechanism 

→ need continuous + copious blood supply 

3. Inhomogeneous tissue → neurons/ glial cells/ grey matter/ white matter/ extracellular matrix 

Biomechanical behaviour of brain

Effects of external loading	Definition
Direct contact	Displacement/ deforming skull/ intracranial partitions   → high focal KE + low cranial momentum
Differential motion bwt skull/ dura + intracranial contents	Acceleration/ deceleration forces  → large momentum + rotational + tensile + shear forces  → low KE  → contents in brain lag behind motion of head

Biomechanical features of brain 1

Biomechanical features of brain	Details
Poroelastic + fluid saturated solid	Has viscoelastic behaviour  → infants are insensitive to strain rate but children + adults are
Very low permeability	Great resistance to fluid movement
High bulk modulus	Apply pressure to both sides of brain → volume X change much
Extremely compliant	Deformed easily

Biomechanical features of brain 2

Very low shear modulus	X resistant to shear forces  → different layers of brain tissue moves differentially to each other → fine connections break easily
White matter stiffness > grey matter	White matter: anisotropic → stiffness depends on direction  Corpus callosum: oriented coronally  Coronal radiata: multi-axial  Brainstem + internal capsule: vertically oriented  → varied organisatio Grey matter stiffness = CR but 2x stiffer than CC  CC is more anisotropic than CR  Brain + spinal cord at right angles → increase rotational shear forces

How does direction of force affect degree of injury

 

Linear force: force in same axis as center of gravity of the head 

Rotational force: force causes rotation of brain inside skull

e.g. 

1. Strain in bridging veins: 

Strain in AP force < rotational force 

→ corpus callosum oriented horizontally → greater strain from injury of coronal rotation than  sagittal rotation 

2. More likely to have skull fractures 

→ linear impact than oblique impact → brain takes more strain in oblique impact 

→ brain is more susceptible to severe injury in oblique impact/ shear forces 

3. Free to move head: more likely to lose consciousness / fixed head: localised impact 

Define traumatic brain injury

Traumatically induced structural injury/ physiological disruption of brain function as a result of external force

Signs: 

1. Loss or decreased level of consciousness 

2. Loss of memory before/ after injury 

3. Alteration of mental state at time of injury 

4. Neurologic deficits 

Describe types of acquired brain injury w/ reference to mechanism of injury + pathology 

Mechanism of injury	Definitions	Effects
Focal	Single point of impact → contusions/ penetrating	Epidural/ subarachnoid/ subdural/ intraventricular/ intracerebral contusions
Diffuse	Multiple points of impact → a blast/ abusive head trauma/ shaken baby syndrome	Concussions  Diffuse axonal injury
Multifocal	A few different focal injuries

Type of injury matching to type of impact

Type of impact	Type of injury
Linear	Skull fracture  Contusion  Epidural haematoma
Oblique	DAI  Contusion  Subdural haematoma  Intracerebral haematoma

Epidural haematoma ( causes/ shape/ presentation/ structures containing haematoma/ blood vessels ruptured )

Causes	Shape / presentation	Structures containing the haematoma	blood vessel ruptured
Traumatic head injury w/ skull fracture	Biconcave + mass effect → haematoma pushes brain to the side	Tight adherence of dura to skull	Middle meningeal artery

Subdural haematoma ( causes/ shape/ presentation/ structures containing haematoma/ blood vessels ruptured )

Causes	Shape / presentation	Structures containing the haematoma	blood vessel ruptured
Violent shaking of head ( trivial head trauma ) → deceleration injury	Cresent  Mass effect → midline shifts	X contained by dural sutures  X cross falx/ tentorium	Bridging veins from venous sinus in dura layer to subarachnoid space → severed

Subarachnoid haematoma ( causes/ shape/ presentation/ structures containing haematoma/ blood vessels ruptured )

Causes	Shape / presentation	Structures containing the haematoma	blood vessel ruptured
Hemorrhagic stroke/ bleeding of arterial aneurysm → superficial contusions	Vasospasm in areas of focal ischaemia( brain tries to limit amount of blood flow to area /  blood mixes w/ CSF		Cerebral blood vessels in subarachnoid space

Blood vessels ruptured in intracerebral haemorrhage

Small arterioles + capillaries in parenchyma

Contusions and lacerations

Contusions: bruising 

Most vulnerable areas: temporal + frontal lobe 

Presentation: wedge shaped 

Location: crests of gyri 

Effects: cell death/ bleeding/ oedema 

Descriptions: 

Coup: contusions under site of impact due to compression forces 

Countrecoup: opposite → less severe injury compared to coup

Lacerations: 

Cut/ torn pia mater/ arachnoid membranes bc foreign object/ bone fragment from skull fracture

How to know if TBI likely to progress + need neurosurgical intervention

1. Base deficit( blood turns acidic → how much alkali need to be added to blood to get it back to normal pH ) >/= 4

2. Displaced skull fracture 

3.  Subdural / epidural haematoma >/ = 10mm 

Mortality rate: if return to consciousness < 6 hours → lower rate 

What are the effects and symptoms of the most common TBI

Most common type: moderate TBI 

Symptoms: loss of consciousness < 30 mins/ post traumatic amnesia < 24 hours + X macroscopic damage 

Effects 

Physical: 

1. Fatigue

2. Nausea 

3. Altered equilibrium/ vision/ hearing 

Cognitive: 

1. Attention ( common ) 

2. Memory processing ( common ) 

3. Reasoning 

Mood: 

1. Insomnia 

2. Irritability 

3. Depression 

→ mostly subdural haematoma + very little subarachnoid ( but most commonly in moderate to severe TBI ) 

What is ischaemic stroke + effects

Sudden blockage of blood flow to CNS by a  Thrombus: blood clot  Embolus: piece of plaque/ thrombus travelling from og site + blocks downstream artery  Can be transient → embolus temporarily blocks the vessel + moves away → causes: atherosclerosis

Infarction( injury/ death of tissue )  of predictable territory  → neurological deficit relates to location of infarct  → location + size of infarct related to site of occlusion along artery

What is haemorrhagic stroke

Rupture of blood vessels in brain  Intracerebral: bleeding directly into brain tissue → clot in brain  → causes: mostly hypertension  → high morbidity + mortality  Subarachnoid: bleeding fills subarachnoid space: → causes: rupture of intracranial aneurysm  → spontaneous haemorrhage: X external forces applied but sudden bleeding  Causes:  Hypertension  Rupture of aneurysm  Vascular malformation  Complication of anticoagulation medications

Effects of haemorrhagic

Spontaneous intracerebral haemorrhage:  Common sites:  Basal gnaglia  Thalamus  Lobar Cerebellar  Pontine → highest mortality lowest incidence  Process:  Haematoma expansion  Cell death caused by mechanical forces + chemical toxicity( reactions of brain due to trauma )   Perihematomal oedema → increases intracranial pressure → herniation

What is early brain damage + delayed cerebral ischaemia effects + systemic response + diagnosis of spontaneous subarachnoid haemorrhage

Spontaneous subarachnoid haemorrhage: 

Early brain injury: 

1. Transient global ischaemia → vasospasms + constricts the healthy blood vessels

2. Toxic effects of blood in subarachnoid space 

Delayed cerebral ischaemia: 3-14 days after haemorrhage bc toxic effects of blood in CSF + breakage of BBB

Systemic response: 

1. Higher sympathetic NS activity 

2. Angiotensin system activates 

3. Inflammatory cytokines 

Diagnosis: 

1. Most severe headache 

2. Sudden onset 

3. Neck pain/ stiffness 

4. Non-contrast CT + lumbar puncture

What is an aneurysm + common types

Saccular cerebral aneurysm: branch point in blood vessels esp circle of Willis → blood hitting the branch → blood vessel balloons + fills w/ blood → internal elastic lamina degenerates w/ secondary thinning/ loss of tunica media → ruptures

—> common in spontaneous subarachnoid haemorrhage

Other types: 

1. Fusiform: all sides of the blood vessel balloons out

2. Saccular

How vascular malformation contribute to strokes

Arteriovenous malformation → arteries + veins are in more direct contact to each other → blood passes through capillaries quickly by bypassing usual capillary network + puts more pressure on intermediary vasculature → swelling + dilation + degradation → rupture + haemorrhage

What is a primary CNS injury

Immediate damage at the moment of injury

Examples: Focal brain contusion  Vascular and blood-brain barrier rupture  Haemorrhage  Neuronal + axonal injury  Release of cytokines + chemokines + damage associated molecular patterns

What is a secondary CNS injuries

Damage happen subsequently bc primary injury

Examples: Excitotoxicity  Oxidative stress  Inflammation  Apoptosis Demyelination  Autoimmunity  Neurodegeneration

What are neurological deficits

Resulting issues of primary + secondary injuries

Loss of neurological function  Cognitive decline  Psychological alterations  Chronic disability

Impacts of focal primary injury 1

1. BBB break down 

→ excessive release of excitatory amino acids 

→ Excitotoxicity → excessive glutamate → neurons over-excited → excessive calcium released → enters state of reactive oxidative series + activates caspase → sets off apoptotic pathway 

1b) influx of immune cells → induce neuroinflammation → tissues swell → immune cells that don’t normally enter the brain now enters brain ectopically to cause damage

→ apoptosis: controlled + cell programmed death → neatly packaging nucleus → membrane blebs + becomes fragments 

→ days/ weeks later due to secondary injury

Impacts of focal primary injury 2

1. Necrosis: uncontrolled cell death → signals set off chain reaction → reversible → involving swelling of ER + mitochondria + blebbing of membrane → cell membrane bursts + cell contents leak 

→ in early stage 

Impact of diffuse primary injury

Secondary effect: 

1. Damage axonal cytoskeleton → plastic deformation → axonal undulation + misalignment 

2. Mechanical damage to sodium channels → large sodium influx 

→ axonal swelling → triggers calcium influx → proteolysis activated → further damage to cytoskeleton 

3. Impaired axonal transport mechanisms 

4. Accumulation of proteins in axonal swellings 

5. Secondary axotomy 

6. Demyelination → less efficient firing

Differences bwt necrosis + apoptosis

	Necrosis	Apoptosis
Size	Cellular swelling  Many cells affected	Cellular shrinkage  One cell affected
Uptake	Cell contents ingested by macrophages  → significant inflammation	Cell contents ingested by neighbouring cells  → X inflammatory response
Membrane	Loss of membrane integrity  → cell lysis occurs	Membrane blebbing but integrity maintained  → apoptic bodies form
Organelles	Organelle swelling + lysosomal leakage  → random degradation of DNA	Mitochondria release pro-apoptotic proteins  → chromatin condensation + non-random DNA degradation

Treatments 1

1. Prevention: 

→ seat belt intervention 

→ X drink driving 

2. Develop biomarkers to predict outcome/ personalise treatment → know quickly how severe the injury is 

3. Manage/ ameliorate secondary injury: anti-oxidants: stop action of reactive oxygen species; memanite: binding to excitatory amino acid receptors to stop them from binding ; calcium channel blocker to stop effect of influx of Ca2+  in secondary injury caused by focal primary injury

Treatment 2

1. Repair consequences of injury 

→ stem cell therapy → get stem cells that can differentiate into different cells + transplantation  into the damaged tissue / recruitment of endogenous stem cells → grow or regrow damaged connections 

→ encourage brain plasticity in rehabilitation → harness healthy population of neurons to take over to do the task + consolidate the connections 

e.g. exercise → prompt endogenous neurons to make new neurons / healthy diet/ sleep

→ surgical interventions: remove blood from haematoma to release pressure → early intervention 

2. Treat ongoing symptoms of injury: 

→ different symptoms based on where the injury is 

→ retrain brain to deal w/ physical symptoms/ pharmaceuticals

What is excitotoxicity? 

Excessive glutamate → neurons over-excited → excessive calcium released → apoptosis