Nervous system

nervous system embryology

develops from Ectoderm (week 3-4)

• Nerural tube → CNS

• Neural crest → PNS

3 primary brain vesicles during embryonic development + further divisions

• Prosencephalon (forebrain) → Cerebrum + diencephalon

• Mesencephalon → Midbrain

• Rhombencephalon (Hindbrain) → pons, cerebellum + medulla oblongata

Significance of Notochord

• Arises from axial mesoderm day 16 (developed by w4)

• determines orientation of vertebral column → via sonic hedgehog

• evolves into nucleus pulposis

Stages of neurulation (development of neural tube)

1) ectoderm → thick neural plate

2) plate becomes long + narrow

3) neural plate → neural folds

4) fusion of neural folds (lateral apical surface) → neural tube

occurs week 3-4

What are Neural tube defects (NTDs) + risk factors

developmental defects of CNS → result of failed closure of the neural tube

• folate deficiency

• maternal obesity + diabetes

• genetics

• medications → sodium valproate, methotrexate

Anencephaly

Neural tube defect - infant born without most of brain, overlying skull + scalp

Typically fatal after birth

spina bifida pathology

• most common NTD

• abnormal vertebrae → meninges/spinal cord herniate through spinal canal

• usually lumbosacral

• 3 classifications: occulta, meningocele, myelomeningocele (most severe)

spina bifida clinical presentations

• lower limb weakness

• deformities: hip dysplasia, club foot, scoliosis

• Dysaesthesia

• Incontinence

• paralysis

spina bifida investigations + treatment

• x-ray,CT, MRI

• increased AFP (not in occulta)

• surgery + physical therapy

Cerebral palsy pathophysiology

Neurodevelopmental disorder → non-progressive motor deficits (lesion to developing brain)

variation in severity + symptoms

• Spastic (most common): damage to upper motor neurones = hypertonia + reduced function

• Dyskinetic: damage to basal ganglia = involuntary movements

• Ataxic: damage to cerebellum = incoordination

• Mixed

Cerebral palsy causes

• maternal infections - rubella, toxoplasmosis

• Pre-term birth

• IUGR

• Meningitis

• Severe neonatal jaundice

Clinical presentations of cerebral palsy

• Failure to meet milestones

• Hypo/hypertonia

• Coordination, speech or walking problems

• Learning difficulties

• Difficulty feeding/swallowing

Cerebral palsy management

• speech therapy

• Occupational therapy

• Physical therapy

• Muscle relaxants/botulinum

Myasthenia Gravis pathophysiology

• Type 2 hypersensitivity reaction → autoantibodies bind to nicotinic receptors

• blocks Ach = no muscle contraction

• classical complement pathway activated → inflammation = less Ach receptors

Clinical features of myasthenia gravis

• muscle weakness

• extraoptic → ptosis + diplopia

• trouble breathing (resp acidois)

• slurred speech

Myasthenia gravis investigations

• ACh receptor antibodies

• CT → abnormal thymus

• Electromyography

• Edrophonium test: rapid onset cholinesterase inhibitor = prolonged Ach in neuromuscular junction

Myasthenia gravis management

• cholinesterase inhibitors (pyridostigmine)

• immunosuppressants (corticosteroids)

• thymectomy

Multiple sclerosis pathophysiology

autoimmune demyelination of CNS → Type IV hypersensitivity

• T cells break through blood brain barrier

• Cytokines = inflammation + damage to oligodendrocytes

• B cells + macrophage infiltration

Clinical features of MS

• optical neuritis → unilateral reduced vision

• Parasthesia

• Ataxia

• Lhermitte’s sign (electric shock travels down spine + limbs)

MS risk factors

• EBV

• Vitamin D deficiency

• Smoking

• Genetics

• Obesity

MS investigations

• CSF → oligoclonal bands

• MRI → plaques/lesions

MS management

• physical therapy

• Corticosteroids

• Interferon

• Monoclonal antibodies

Guillain-Barre syndrome pathophysiology

autoimmune demyelination of PNS (molecular mimicry)

• myelin autoantigen presented to T helper cells

• Production of cytokines → activate B cells + macrophages

• Attack myelin sheath = affects nerve conduction velocity

Infections associated with guillain-barre syndrome

• EBV

• Cytomegalovirus

• Mycoplasma pneumoniae

Clinical features of Guillain-Barre syndrome

• reduced reflexes (areflexia)

• Parasthesia

• Muscle weakness

• Postural hypotension

• Blurred vision

Guillain-barre syndrome investigations

Brighton criteria:

• nerve conduction studies

• CSF → raised proteins

Guillain-barre syndrome management

• supportive care

• VTE prophylaxis (PE risk)

• IV immunoglobulins

• Plasmapheresis

Motor neurone disease (MND) + most common types

Group of degenerative disorders → progressive muscle weakness + disability

• amyotrophic lateral sclerosis (ALS)

• Progressive bulbar palsy

Amyotrophic lateral sclerosis (ALS) pathophysiology

• affects upper + lower motor neurones (sensory spared)

• Superoxide dismutase 1 (SOD1) mutation = increased free radicals → neurone injury + death

• C9orf72 mutation (40% cases)

Risk factors associated with MND

• smoking

• Heavy metal exposure

• Pesticides

• Genetics (5-10% cases)

Clinical presentations of ALS/MND

• dysarthria

• Clumsiness

• Lower: flaccid paralysis, muscle atrophy, fasciculations, hypoactive reflexes

• Upper: spastic paralysis, hyperactive reflexes, babinski sign

MND investigations

• History

• Neurological exam

• Muscle biopsy

• Electromyography

ALS management

• riluzole (slows progression)

• Benzodiazepines

• Antimuscarinics + antispasmodics (baclofen)

• Non-invasive ventilation

• Palliative care

Charcot-Marie-Tooth disease pathophysiology

• Autosomal dominant motor + sensory neuropathy

• Genetic mutation = defective functioning proteins in myelin sheath/axon (PNS)

• onset 10-30 y/o

Clinical presentations of Charcot-marie-tooth disease

• muscle atrophy

• Distal muscle weakness

• Reduced reflexes (areflexia)

• Foot abnormalities → pes cavus, foot drop

• High stepping gait

Charcot-Marie-Tooth syndrome management

• physical/occupational therapy

• Analgesia

• Orthotics

• orthopaedic surgery

Charcot-Marie-Tooth disease investigations

• nerve conduction study

• Genetic testing

Botulism pathology

• clostridium botulinum → neurotoxin A,B,E + F

• BoNT blocks Ach neurotransmitter signalling in peripheral alpha motor neurones

Clinical presentations of botulism

• muscle weakness leading to paralysis

• effects on ANS

• dry mouth

• postural hypotension

• respiratory failure (severe)

Botulism management

• botulinum antitoxin - A,B,E antibodies

• supportive care

• respiratory monitoring/ventilation

• surgical treatment

What types of cells make up the nervous system

• neurones (10%): react to stimuli, impulse conduction + emit chemical regulators

• Neuroglia (90%): maintain ionic state, scaffolding + aid recovery/restructure + nourish neurones

What cells myelinate neurones in PNS + CNS (neuroglia)

CNS → oligodendrocytes

PNS → schwann cells

Examples of neuroglia

• astrocytes (CNS): maintain electrochemical environment

• Microglia (CNS): form immune system of brain

• Satellite (PNS): astrocyte equivalent

Where is CSF produced + reabsorbed

• Ependymal cells → choroid plexus (3-500mls/day)

• Reabsorbed via venous sinuses in arachnoid granulations

CSF functions

• cushioning

• Immune function

• Nutrition

• Homeostasis

• Removes waste metabolites

Examples of excitatory neurotransmitters

• Ach

• Glutamate

• Catecholamines

• Serotonin (5-HT)

• Histamine

• ATP

Examples of inhibitory neurotransmitters

• GABA

• Glycine

Examples of both inhibitory + excitatory neurotransmitters

• nitric oxide

• Endocannabinoids

• Neuropeptides

What arteries make up cerebral circulation

• internal carotid (x2) → anterior circ.

• Vertebral (x2) → posterior circ.

• Anastamosis of terminal branches = circle of Willis

• Receives 17% of total CO

Internal cerebral artery entry + branches

• ICA enters skull via carotid canal

• Divides into anterior + middle cerebral arteries

• Occurs after exiting cavernous sinus

What nerves are the ICAs in close proximity to

• abducens

• Ocularmotor

• Trochlear

• Trigeminal → ophthalmic + maxillary

Vertebral artery branches + entry

• Arise from subclavian a. + pass up via transverse foramen

• enters skull via foramen magnum

• Divide → posterior inferior cerebellar + anterior spinal a.

• VAs merge at ponto-medullar junction = basilar a.

Cortical homunculus

visually portrays neurone distribution perceived within the brain → helps explain symptoms in stroke pts

• motor: frontal lobe

• Sensory: parietal lobe

How do cerebral veins differ

No valves → bidirectional blood flow possible

No muscular layer

Arteriovenous malformation pathology

• abnormal formation between artery + vein → no capillary bed

• Arteriovenous fistula + nidus (tangled vessels)

• Cont. high pressure = fibrosis of vessels

• AVM expands + compressed surrounding tissue → reduced blood flow → ischaemia

Clinical presentations of AVM

• Bruits on auscultation

• Neurological deficits

• Seizures/epilepsy

• Severe headaches (indicates subarchnoid haemorrhage)

AVM investigations

• angiography

• CT/MRI

AVM treatment

• radiosurgery

• Endovascular embolization

Grey vs white matter

• grey: neurone rich region

• White: myelinated axons

Meningeal layers (deep to superficial)

• pia matter

• Subarachnoid space

• Arachnoid space

• Dura matter

Types of sensory receptors

• mechanoreceptors

• Thermoreceptors

• Nociceptors (pain)

• Chemoreceptors

• Photoreceptors

Types of mechanoreceptors: function + location

• Meissner’s corpuscle: hairless dermis→ light touch (fingertips, lips, soles, palms)

• Merkel’s discs: hairless epidermis → distinguish shapes + textures, pressure

• Pacinian corpuscle: deep dermis, ligaments, joints → vibration

• Ruffini’s corpuscle: dermis + joints → proprioception, stretching

Types of somatosensory fibres

• A alpha: large myelinated = fastest → proprioception

• A beta: large myelinated → vibration, fine touch

• A delta: small myelinated = fast → sharp pain, gross touch, cold temp

• C: unmyelinated= slowest → hot temp, gross touch

Adaptation of sensory receptors

Fewer signals sent in response to a continuous stimulus over time

• fast/phasic: high sensitivity → firing stops quickly

• Slow/tonic: constant sensitivity

What is lateral inhibition

1st order neurone releases inhibitory internurones = prevents multiple neurones firing

Thermoreceptors

• detect changes in skin temp

• TRP ion channels → heat transduction = TRPV, cold transduction= TRPM8

• At extreme temps channels become inactive

Ascending somatosensory pathways + functions

• dorsal column- medial lemniscal: conscious fine touch + proprioception

• Spinothalamic: conscious crude touch + pressure (anterior), Sharp pain + temp (lateral)

• Spinocerebellar: unconscious proprioception from muscles to cerebellum

Brown-Sequard syndrome pathophysiology

• spinal cord hemisection

• DCML → ipsilateral loss of fine touch + proprioception (decussates in medulla)

• spinothalamic → contralateral loss of temp + pain (decussates in spinal cord)

Cauda Equina syndrome + causes

Compression/irritation of lumbosacral nerves below L2 (cauda equina)

• disc herniation (most common)

• spinal stenosis

• spondylolisthesis

• trauma

• tumours

Cauda Equina syndrome clinical presentations

• severe back pain

• incontinence (reduced sphincter tone)

• sexual dysfunction

• lower limb weakness

• saddle anaesthesia

Cauda Equina investigations + management

• neurological exam + MRI

• surgical decompression (w/in 48hrs)

• NSAIDs + corticosteroids

Blood brain barrier

• selective barrier → CNS homeostasis

• nutrient passage, controlled fluid movement, toxin protection

• permeability may change due to inflammation, tumours, irradiation

Blood brain barrier structure

• tight junctions: between capillary endothelial cells

• basement membrane

• astrocytes: supporting structure

Brodmann’s areas

areas of brain that are histologically similar → neurones arranged in same pattern

Syringomyelia pathophysiology

• CSF filled cyst around spinal cord central canal

• Accumulated fluid = increased pressure

• Causes damage to spinothalamic tract

Syringomyelia clinical presentations

• loss of pain + temp

• Loss of crude touch

• Muscle atrophy

• Weakness/paralysis

• Dysethetic pain

Syringomyelia causes

• chiari malformations (most common)

• Spinal tumour

• Spinal cord trauma

• Spinal cord abscess

Primary headaches

Not assoc. with underlying condition → common, chronic/recurrent

• tension

• Cluster

• Migraine

Secondary headaches

precipitated by a condition/disorder → acute

• subarachnoid haemorrhage

• Intracranial mass

• Giant cell arteritis

• Meningitis

• Sinusitis

Tension headache clinical presentations + triggers

• bilateral tightness → band like

• Slowly progressive → 30min to 1 week

• Stress, dehydration

Migraine clinical presentations

• severe unilateral

• Pulsating pain

• Photophobia/phonophobia

• +/- nausea + vomiting

• +/- aura

• 4-72hrs

Cluster headache clinical presentations

• Unilateral excruciating stabbing pain behind eye

• 15min-3hr

• Autonomic symptoms on affected side → ptosis, miosis, lacrimation, nasal congestion

Red flag headache symptoms

• New/sudden onset

• Worsening severity

• Increased frequency

• Systemic symptoms → weight loss, fever

• Neurological symptoms → weakness, vision loss

• Hx trauma

Saccular/berry aneurysm pathology

• Haemodynamic stress overtime = gradual ballooning of vessel wall

• Thickening of intima + adventitia

• Present at bifurication of arteries → anterior communicating most common

• Rupture = subarachnoid haemorrhage

Allodynia pathology

• pain in response to typically non-painful stimuli (eg light touch)

• Central sensitisation: CNS amplifies signals → hypersensitivity

• Persistent transmission of nociception = cortical reorganisation in sensory + motor regions of brain

Extradural haematoma pathology

• damaged blood vessel (middle meningeal a.)

• Blood accumulates between skull + dura matter

• Skull limits expansion = increased intercranial pressure

• Slow accumulation → lucid interval

• Biconvex shape on CT (doesn’t cross sutures)

Extradural haematoma clinical presentations

• loss/decreased consciousness

• Lucid state

• Headache

• Nausea/vomiting

• Cushing’s triad → bradycardia, hypertension, irregular breathing

Subdural haemorrhage pathology

• blood accumulates between dura + arachnoid matter

• Ruptures bridging veins in subdural space → pooling (haematoma)

• Acute = symptoms within 3 days, chronic = after 21 days

• Crescent shaped on CT (can cross sutures)

Intracranial bleed investigations

• CT

• Angiography

• Bloods→ FBC, U+Es, LFTs, coagulation, group + save

• Lumbar puncture → blood/xanthochromia (subarachnoid haemorrhage)

Intracranial bleed management

• craniotomy

• Burr hole

• Reverse anticoagulant (vitamin K)

• Antihypertensives

Subarachnoid haemorrhage pathology

• bleeding in subarachnoid space

• Blood released into CSF = increased intercranial pressure

• Compresses surrounding blood vessels → less o2 delivered to brain

Subarachnoid haemorrhage clinical presentations

• thunderclap headache

• Altered mental status/consciousness

• Nuchal rigidity

• Seizures

• Nausea/vomiting

intracranial bleed causes/risk factors

• head trauma

• Ruptured aneurysm (berry, cerebral)

• Arteriovenous malformations

• Alcohol abuse

• Elderly

• Coagulopathies

Intracerebral haemorrhage pathology

• ruptured blood vessel w/ in cerebrum

• Intraparenchymal accumulation (only in brain tissue) or intraventricular

• Herniation on CT

Glasgow coma scale (GCS)

Neurological assessment determines conscious level after brain injury (3-15) 

• eye movement

• Verbal response

• Motor response

Transient Ischaemic attack (TIA)

• temporary neurological dysfunction (<24hrs) due to focal ischaemia without infarction

• Blood vessel occlusion/stenosis = reduced blood flow

• Crescendo: 2+ TIAs within a week

Stroke pathology

• ischaemic: acute + complete artery occlusion → endothelial cell dysfunction/atherosclerosis or embolism/thromboembolism

• Haemorrhagic

• Decreased blood flow = hypoxia + infarction

Stoke risk factors/causes

• atrial fibrillation

• Smoking

• Hypertension

• Hyperlipidaemia

• Diabetes

• Carotid artery stenosis

Stoke clinical presentations

• facial drooping

• Arm/limb weakness

• Speech disturbances (dysphasia)

• Visual field defects

• Sensory loss

Stroke investigations

• CT/diffusion weighted MRI

• Angiography

• ECG