CNS Notes

Stroke
- 3rd leading cause of death
- Leading cause of adult significant disability
- 7,500 new strokes annually
- 2,500 new TIAs annually
- 30,000 with stroke-related disability
- 20-25% of nursing home beds occupied
- 400-800 million euro annual cost

- TIA
o Temporary lack of oxygen/ischemia
o <24 hours
- CVA
o Sudden death of brain cells due to blockage or rupture of an artery
o Symptoms depend on part of brain affected
o Deficit develops over time
o Death or some improvements over months
o Ischemia
 Embolus
 CHD
 Afib
 LVH
 Valvular disease
 Thrombus
 Haematocrit
 Fibrinogen
o Haemorrhage
 Intracerebral – Hiba Abouk Cuts All Ties Due To Achraf
 HTN
 Amyloid – peripheral not deep, BA4 derived
 Coagulation deficits
 Aneurysm (berry), Cavernoma (popcorn type/check FH),
Tumour
 Drugs – cocaine/amphetamines increases bp and heart rate –
weaken vessel
 Trauma – SDH
 AVM – arterial blood forced into venous blood vessels under
high bp
 Subarachnoid
 50% due to hypertension  formation of Charcot-Bouchard
aneurysms that can rupture
 Anti-coagulant therapy in elderly
o ASCO
 Atherothrombosis
  Small vessel disease
 End arteries
 No collateral
 Supply critical areas
 Charcot-Bouchard aneurysm
 Lacunar infarct – devastating consequences
 Cardioembolism
 Other causes
- Frequency
o Acute ischemic 65%
o Haemorrhage 12%
 Subarachnoid 6.6%
 Intracerebral 5.1%
o TIA 21%
- Symptoms – FAST
o Face – drooping smile
o Arms – raise both arms, one drifts
o Speech – slurred
o Time – call 911 right away
- What happens if damage to:
o Motor area of right cerebral hemisphere  weakness of left arm, leg, and
face
o Broca’s area  speech problems
o Brain stem  breathing, heartbeat, swallowing, eye movements, hearing,
vertigo
o Left parietal lobe  loss of co-ordination in right arm and leg
o Wernicke’s area  difficulty in understanding speech, reading, and naming
objects
o Cerebellum  unsteadiness and poor co-ordination
- Ischemic left, hemorrhage right

- Ischemic CVA
o Emboli lodge at pre-existing stenosis – site of atheromatous plaque or at
vessel bifurcations
o Carotid artery thrombi/atheromatous plaques – arterial atherosclerosis
o Mural atheromatous plaques in heart – because of MI
o Valve disease
o Afib
o Most emboli originate at carotid bifurcation
- Supply – know for exam!
o ACA – cerebrum from ICA
o Posterior – terminal branches of basilar artery
o ICA continues as MCA – lateral portions of cerebrum
- CT scan excludes haemorrhage in at least 3 hours
- MR demonstrates ischemic changes in a few minutes
- Sites of haemorrhagic CVA with hypertension
o Basal ganglia/thalamus
o Deeper part of brain – HTN affects deep penetrating arteries
- Intracranial hemorrhage
o EDH
o SDH
o SAH – berry aneurysm rupture
 Associated with PKD
 Congenital defect
 Worst headache of my life – like an axe
 Xanthochromia
o Intraparenchymal/intracerebral hemorrhage
- Signs of raised ICP
o Headache
o N&V
o Dizziness/LOC
o Coma
o Brain herniation
o Death
- Outcomes of raised ICP – herniation
o Cingulate gyrus under falx cerebri – subfalcine herniation
o Uncinate process/uncal herniation (medial part of temporal lobe) under
tentorium – transtentorial herniation  compresses/stretches CNIII –
oculomotor – blurred vision/papilloedema
 o Tonsillar herniation into foramen magnum – coning
o Brain tissue ischemia and infarction due to reduced cerebral perfusion of
herniated brain tissue on arterial supply
- Decompressive hemicraniectomy
o Within 48 hours
o Under age of 55
o Major strokes – malignant oedema and intracranial hypertension
o Not controlled by other methods
o Over 50 – poor outcome
- Thrombolysis <60 min and clot retrieval
- Endovascular treatment
o Guided wire/catheter in artery through groin
o Clot manually removed and extracted
o Restore blood flow
o Must be done 6-8 hours within onset of a stroke

Stroke and TIA

- 10% of death worldwide
- 5.5 million deaths
- Ischemic stroke – 80%
- Haemorrhagic – 20%

- TIAs
o Risk of recurrent in first month
o 8-10% at 7 days
o 11-15% at 30 days
o Sudden onset
o Symptoms maximal at onset
o Contralateral weakness or numbness
o Dysphasia
o Hemianopia
o Ataxia, vertigo, dysarthria, diplopia
o Bilateral visual loss
o NOT SYNCOPE
o NOT SEVERE HEADACHE OR EYE PAIN
o NO LOSS OF MEMORY
o NOT GRADUAL
o No isolated dizziness, light-headedness, or vertigo
o No acute confusion or seizure
- Amaurosis Fugax
 o Embolic form
o Carotid territory
o Painless transient monocular blindness
o Curtain, shade, or mist descending over eye
- ABCD2
o Max score 7
o Age 60+
o Bp 140/80 +
o Clinical – neurological deficit
 2 points for hemiparesis
 1 for speech problem without weakness
o Duration
 2 for 60+ min
 1 for 10-60 min
o Diabetes
o 0-3 low risk
o 4-5 mod risk
o 6-7 high risk
o 5+ should have immediate Ix and Tx
- No driving for 30 days
- Urgent carotid doppler
- Secondary preventive
o Aspirin + dipyridamole
o Clopidogrel if intolerant of aspirin
o Anticoagulation in Afib
o Statin and bp control
- Endarterectomy should be performed within 2 weeks of the patient’s last symptoms
- Patent foramen ovale
o Failure of primum and secundum septa to fuse postnatally
o One way flap allows right to left shunting when RAP>LAP allowing paradoxical
embolism
- Outcome (without intervention):
o 25-30% will develop a stroke within 5 years
o 10% will develop a stroke within 3 months
- Early reperfusion therapy is the most effective therapy for acute ischemic stroke
o tPA
o IV thrombolysis
- Intra-arterial thrombolysis/thrombectomy
o Higher concentration of tPA administered
o Higher recanalization rate
o Precise imaging of clot and anatomy
- NIHSS and mRS for degree of disability/dependence after a stroke
- Apraxia: knowing what you want to do, but unable to do it
- Thrombectomy for acute ischemic stroke

Delirium and Dementia

- Dementia
o >/= 2 domains of cognition involved
o Agnosia, apraxia, aphasia, disturbance in executive function
o Memory impairment plus one of above
- MMSE
o Education-linked ☹
o Does not test executive function
- MOCA
o More sensitive
o Visuospatial
- RUDAS
o No numeracy or literacy component
o Real-world
o Reduced education 😊
- ACE III
o Takes half an hour – long
- 18 FDG PET Scan
o Concentration of glucose in brain
- Amyloid-PET
- Elevated T-tau, p-tau, tau/AB42
- Decreased AB42
- Treatment – increase acetylcholine and reduced glutamate
o Cholinesterase inhibitors
 Donepezil
 Rivastigmine
 Galantamine
o NMDA receptor antagonist
 Memantine
- Prognostic markers
o Weight loss
o Functional loss/personal care dependence
o UTI/LRTI if dependent or NH resident
o Swallow impairment
- Vascular
o 25%
o Reduced blood flow to brain – cumulative effects of many small strokes
o Deterioration – in step-wise fashion
o Tx – management of risk factors
o Use above drugs if there is Alzheimer’s dementia
- Frontotemporal
o Decision-making, behavioural control, emotion, language
o Inherited in 1/3 of cases
o No specific treatment
o Tx: reduce agitation, irritability, or depression
- Lewy Body
o 3rd most common
 o Visual hallucinations, fluctuating cognition, and parkinsonism
o Lewy bodies in brainstem and neocortex
o Survive 6-12 months
- Delirium
o Hyperactive
 Visual hallucinations, hyper alert, distractible
o Hypoactive
 Drowsy, long periods of apathy or impaired interaction
 Mistaken for depression
o Mixed
- Risk factors
o Liver disease
o Polypharmacy
o Stroke
o Frailty
o Age
o Dementia
o Parkinson’s
o Alcohol misuse
- Precipitants
o UTI/LRTI
o Sepsis
o Electrolyte abnormalities
o Medications
o Alcohol
o Stroke/MI
o Intra-abdominal bleed – PUD
o Hip or pelvic fracture
- Tx
o Stop anti-cholinergic medications
o Treat underlying conditions
- Hyperactive has better prognosis
- Attention impaired and altered consciousness unlike Alzheimer’s

Multiple Sclerosis and neurodegenerative disorders

- Immune-mediated inflammatory disease
- Demyelination
- Axons are intact
- Grey matter – neuron - in brain
- White matter – axon - in brain
- Risk of developing MS is increased 15-20 fold in 1st degree relatives
- Common presenting symptoms
o Visual loss, optic neuritis
o Acute transverse myelitis
o Trigeminal neuralgia
o Diplopia
 o Gait/balance disturbance
o Vertigo bladder dysfunction
- Lhermitte’s sign
- Uhtoff’s phenomenon
o Raised body temperature can result in an exacerbation of symptoms
- Active MS plaque
o Perivascular and parenchymal inflammation c/o lymphocytes and
macrophages
o attempt at remyelination early
o BBB  Gadolinium enhancement = active plaque
- Chronic MS plaque
o Hypocellular
o Reactive astrocytes reflect prior activity
o Some axonal loss
o Remaining axons have reduced calibre
- Macroscopic
o White matter
o Yellowish when acute
o Cavitating when old
o LFB stain for myelin
o Blue – myelinated
o White – demyelinated
- Acute plaques
o Macrophages and lymphocytes
o Preservation of axons
- Diagnosis
o McDonald
o CSF analysis and SPEP
o Visual evoked potentials – delayed P100 potentials

- Acute management
o Glucocorticoids
 IV Methylprednisolone for 3-5 days
 Oral prednisolone alternative
o Plasma exchange
 If not responding to glucocorticoid with severe relapse
 o Reduce duration of relapse
- 50% chance of walking unaided 15 years after diagnosis
- Neurodegeneration
o Neuronal loss
o Gliosis
o Intracellular protein accumulation
o Oxidative stress, excitotoxicity, programmed cell death, cytokine-mediated
o Selective neuronal vulnerability
 Specific groups of neurons/systems targeted by disease process
 Determines clinical phenotype
- Tau – Alzheimer’s
- Alpha-synuclein, Parkinson’s
o Maintains supply of synaptic vesicles in axonal terminal of neurons
- Amyloid – extracellular*
- TDP-43
- FUS
- Huntingtin
- Huntington’s chorea
o Hyperkinesia
o Basal ganglia
- Alzheimer’s disease
o Temporo-parietal degeneration
o Medial temporal lobe -hippocampus
o TAU and amyloid
o Neurofibrillary tangles and amyloid plaques
- Frontotemporal
o FTLD-TAU  Pick

Clinical features Anatomic basis Pathologic dx

Movement disorder Reference disease is in = Selective vulnerability OVERLAP+++

red
-Akinetic/ rigid Extra-pyramidal Substantia nigra & basal Lewy body disease
rigidity, bradykinesia, ganglia (ASYN) MSA-P (ASYN)
tremor, falls Progressive
Parkinson’s disease supranuclear palsy
(TAU)
-Hyperkinetic Dysregulation of Basal ganglia Huntington’s disease
movement
Huntington’s chorea

-Ataxic Cerebellar ataxia Cerebellum & its MSA – C (ASYN)

connecting tracts
-Motor neuron Motor weakness UMN +/- LMN ALS (TDP43)
disorder Motor neuron disease
Dementia

-Temporoparietal Memory +/- parietal Hippocampus & cortical Alzheimer type

dysfunction Alzheimer’s neurons pathology (TAU)

-Frontotemporal Apathy, disinhibition, Frontal & temporal FTLD – TAU (Pick)

depression, memory cortical neurons FTLD – TDP43
FTLD – Ubiq FTLD –
FUS

-Multifocal Variable cortical/ Cortical & subcortical Corticobasal

subcortical deficit neurons degeneration (TAU)

- Prion disease
o Rapidly progressive
o Behavioural symptoms, hallucinations, myoclonus
- Parkinson’s disease
o Cardinal features
 Bradykinesia
 Resting tremor
 Rigidity
o Autonomic dysfunction
o Cognitive decline
o Dysphagia
o Pale substantia nigra
o Alpha synuclein – Lewy body
- Motor neuron disease – amyotrophic lateral sclerosis
o Neurodegeneration of upper and lower motor neurons
o Spasticity, hyperreflexia
o Fasciculations
o Mean age of onset 60 years
o Progressive motor failure to include respiratory failure  cause of death
o Median survival 3-5 years

Multiple Sclerosis:
- Demyelination of both brain and spinal cord
- 2nd leading cause of physical disability in young adults in the western world
- Risk Factors
o EBV
o Smoking
o Low serum vitamin D
o Genetics – HLA DRB1*1501
- Pathophysiology
o Imbalance between
 Immunoregulatory: CD56 bright and Treg
  Proinflammatory: CD4+, CD8+, B-cell
o T cells in the periphery in the blood come into contract with antigen i.e. EBV
o Normally do not cross BBB but it is leaky
o Subsequent cascade of proinflammatory
- MS causes demyelination of the grey matter as well as the white matter in the brain
- MS plaques occur around veins in the brain and contain both lymphocytes and
macrophages
- General Symptoms – NS HUDA
o Heat intolerance – Uthoff’s phenomenon
o Depression
o Neuropathic pain
o Urinary overactivity
o Ambulatory dysfunction
o Spasms/spasticity
o Fatigue
- Optic Neuritis
o Unilateral visual loss
o Red vision affected first
o Pain on eye movement
o Not more than 2 weeks
o Positive RAPD – eyes can no longer constrict
o Optic disc swelling
- Brain stem
o Facial palsy, ataxia, diplopia, trigeminal neuralgia – brainstem/cerebellar
o Brainstem syndrome: nystagmus, INO (adduction slow)
o One-and-a-half syndrome
- Spinal cord
o Lhermitte symptoms
o Numbness
o Weakness
o Bowel constipation or incontinence
o Sexual dysfunction
- Spinal cord syndrome
o Weakness
o Increased tone +/- clonus
o Brisk reflexes
o Upgoing plantar responses
- Brown-Sequard syndrome – spinal cord syndrome
o Loss of pain, temperature, and light touch on opposite side - PLT
o Loss of motor function and vibration, position, and deep touch sensation on
same side as the cord damage
- Increased risk of conversion to MS if:
o Abnormal baseline MRI
o Asymptomatic spinal cord lesions
o Unmatched oligoclonal bands in CSF
- Relapse
 o Episode at least 24 hours
o Absence of infection
o Monofocal vs multifocal
- Space
o Periventricular
o Cortical/juxtacortical
o Infratentorial
o Spinal cord
- PPMS
o 10% have superimposed relapses
o M:F 1:1
o 1 year of disease progression
o 2 of the following
 DIS in MRI
 DIS in cord >/= 2 T2 lesions in cord
 Positive unmatched OCBs in CSF

- PPMS: Ocrelizumab PPMS

- SPMS: Siponomod
- RRMS
o 1st Line
 IFN-B
 Glatiramer acetate
 Teriflunomide – dihydroorotase dehydrogenase inhibitor
nd
o 2 Line
 Dimethyl fumarate – enhances NrF2
 Fingolimod – S1P receptor modulator
rd
o 3 Line
 Natalizumab
 Ocrelizumab
 Ofatumumab
 Cladribine
o 4th Line
 Alemtuzumab
 ASCT

Parkinson’s Disease
- Majority of cases are idiopathic
- Symptoms begin 55-60 years
- Males:Females 1.5:1
- 2nd most common neurological disorder
- 120 per 100k
- 1 million affected US
- Loss of pigmented dopaminergic neurons in substantia nigra
- 60-80% of neurons lost before motor signs emerge
- Lewy bodies in pigmented neurons!
- BRAAK staging 1-6 – clinical manifestation
- Basal ganglia
o Caudate nucleus
o Putamen
o Globus pallidus
o Control voluntary movement and establish postures
o Altered  unwanted movements
- Substantia nigra
o In midbrain
o Motor centre
o Projects into caudate nucleus and putamen
o Produce dopamine
o Lesion site in PD
o Degeneration of melanin-containing cells
o Loss of this area results in dysfunctional stimuli to basal ganglia
- Caudate and putamen = striatum
- Nigrostriatal use dopamine
- Cardinal symptoms
o Tremor – unilateral pill rolling, 4-5Hz, rapid at rest, increased with stress
o Bradykinesia
o Rigidity – asymmetrical, cogwheel (tremor and rigidity), lead pipe
o Postural instability
- Micrographia
- Hypophonia
- Drooling
- Shuffling
- Clinical diagnosis
o No lab test
o CT and MRI normal
o Can out rule multi-infarcts, hydrocephalus, and Wilson’s
- Parkinson plus syndromes
o Early postural instability and dementia
o Progress quickly
o Anti-Parkinson’s meds less effective
o Sensitive to neuroleptic medications/levodopa
o Axial> limb movement
- Multisystem atrophy
o Postural instability and hypotension
 o Bladder dysfunction
o Pyramidal and cerebellar signs
- Progressive supranuclear palsy
o Symmetrical parkinsonism
o Paralysis of upward gaze
o Dementia
o Personality change
o Speech difficulties
- Corticobasilar degeneration
o EPS and PS symptoms
o Stroke on one side, Parkinson on other
o EPS on one side, PS on other
o Rapid
o Dysphagia
o Aspiration pneumonia
o Alien limb
- Medication
o Levodopa
o Dopamine decarboxylase inhibitors: carbidopa and benserazide
o Dopamine agonists: bromocriptine, pramipexole
o MAOB inhibitors
o COMT inhibitor
o Anticholinergics for tremor/drooling: procyclidine, biperiden
- Levodopa best for initial therapy >70yoa
o Give on empty stomach
o Domperidone for transient nausea
o Long term s/e: motor fluctuations on-off, and dyskinesias
- On off
o At night – use CR nocte
o Between doses – add COMT inhibitor
o Freezing episodes
 Increase dose or frequency of levodopa
 Add COMT inhibitor, MAOB inhibitor, or dopamine agonist
 Liquid levodopa – fast onset
- Thalamotomy – reduces tremor
- Pallidotomy – reduce tremor, rigidity, bradykinesia, and dyskinesia
- Deep brain stimulation
o Reduces dyskinesias and medication use
o Improvements up to 5 years post op

Bacterial Meningitis and Brain Abscess

- How bacteria get into the CSF:
o Haematogenous spread – most common
o Sinusitis, mastoiditis
o Nasopharynx via bony defect or with head injury – cribriform plate
- Replicate in subarachnoid space causing meningitis
- All ages
o SHiN and Tb
- Neonate
o GBS, E. Coli, Listeria
- Elderly
o Strep pneumo
- Increased susceptibility to meningitis
o No spleen
o DM and alcoholism – step pneumo
o Immunosuppressive therapy/HIV – listeria, cryptococcus
o Fracture or bony defect of skull – recurrent S. pneumo
o Inherited defects in the late complement components – n. meningitidis
o Pregnancy – listeria
- Neisseria
o 15-20 yoa
o Carried asymptomatically in nasopharynx
o ABCXWY serotypes
- Strep pneumo
o Normal flora of URT
o May reach CNS, chronic ear infection/sinus infection, after head trauma,
bony defect at base of base of skull
o Acquire resistance by altering the structure of its PBPs
- HiB
o Meningitis and epiglottitis in childhood
o Poorly-resourced healthcare systems
o Deafness, seizures, intellectual impairment
- Listeria
o Zoonosis
- Cryptococcus
o Soil, bird droppings, rotting vegetation
o HIV
o Headaches
- Leptospira
o Lymphocytic pattern in CSF
o Consider if renal/hepatic failure and meningism
o Farmer, kayaking
o Jaundice
o Conjunctival infection
- Infants and young child
o Fever, cold hands and feet
o Refusing food and vomiting
- Older child and adults
o Fever, cold hands and feet
o Vomiting
o Severe headache
 o Stiff neck
o Dislike bright lights
- Meningococcal sepsis
o Purpuric
o Non-blanching
- Complications of bacterial meningitis
o Hearing loss
o Subdural abscess
o CN palsies
o Intellectual problems
o Hydrocephalus and raised ICP
o Dissemination and its consequences
o Meningococcal BSI and shock
- Diagnosis
o Clinical assessment
o Lumbar puncture/CSF
 C/I: increased ICP, coagulopathy (bleeding risk)
 Normal – water clear and colourless
 Bacterial infection – cloudy or turbid
o Blood cultures
 Part of sepsis workup
 Organisms may fail to grow from CSF but grow from blood
o Blood for PCR

Protein Glucose White cells Microbiology

Bacterial Very Low Raised, Gram stain Culture PCR

PCR ca elevated (<60% polymorphs • N. meningitidis
perfor n also be blood • S. pneumoniae
blood (n med on ext glucose) • H. influenzae
slide) • Group B
streptococcus
(neonates)

Viral Elevated Normal Raised, PCR only

lymphocytes Usually
• HSV 1&2
• Enteroviruses
• VZV

TB Elevated Low Raised, ZN or auramine TB culture

(<60% lymphocytes TB PCR
blood
glucose)

- Pre-hospital admission
 o Benzylpenicillin or ceftriaxone/cefotaxime
o Administer without delay in patients with a fever + petechial/purpuric rash
- In hospital
o IV antibiotics to cross BBB
o IV steroids
 Prior to or with first dose of antibiotics
o Fluid replacement/restriction
- Empiric IV antibiotic therapy
o Infants <3moa
 Amoxicillin (listeria) + ceftriaxone (GBS) + gentamicin (E. Coli)
o Adults and children
 Ceftriaxone and vancomycin
 SHiN and resistant pneumo
o >65 yoa or immunocompromised/pregnant
 As above plus amoxicillin
 Amoxicillin for listeria

- MenACWY first year of secondary school

- Men B and C primary childhood
- PCV13
o Childhood schedule
o CSF leak/ basal skull fracture
o >65yoa
- Prophylactic antibiotics
 o Hyposplenism/absent spleen/post-splenectomy
 Long-term with daily oral penicillin for Strep pneumo
o Close contacts
 Meningococcal meningitis and HiB meningitis
 NOT FOR PNEUMOCOCCAL DISEASE
- Droplet precautions
- Cerebral abscess
o Secondary to a focus elsewhere
o Trauma – penetrating head wound, fractured skull, post-operative
neurosurgery
o May be polymicrobial i.e. streptococci and anaerobes
o Streptococci 35% i.e. milleri
o Staphylococci 20%
o Aerobic i.e. E. Coli GNB 23%
o Anaerobes 14% i.e. Bacteroides
o Non-bacterial
 Toxoplasma gondii i.e. poorly controlled HIV
 Aspergillosis i.e. single organ or disseminated in immunosuppressed
i.e. severe and prolonged neutropenia
o Signs of raised ICP
 Headache
 Seizures
 Nausea and vomiting
 Altered mental status
 High temperatures
 Underlying condition i.e. sinusitis
o LP avoided because of high ICP  coning
o Diagnose by imaging CT/MRI
o Microbiological diagnosis
 Gram stain and culture of abscess fluid
 Bacterial/fungal/TB
 PCR of specimen – 16S PCR
 Blood cultures
o Surgical aspiration/drainage
o Antibiotics >2
o Empiric 4-6 weeks
 Cefotaxime + metronidazole + flucloxacillin (bacterial)
o Treat underlying cause i.e. sinusitis

Neuropathy/Myopathy
- Peripheral neuropathy: nerve root, plexus, peripheral nerve
- Neuropathy
o Middle age and elderly most common
o M=F
o Hereditary
 Charcot Marie Tooth
 Axonal
 Demyelinating
 Dominant, recessive, and X-linked
 Friedrich’s ataxia
 Refsum Disease
 Spinal Muscular Atrophy
 Kennedy Disease
o Acquired – Vitamin D
 Vitamin deficiencies, B1,6,12 and E
 Infection, HIV, CMV, EBV, Leprosy, Lyme
 Trauma
 Autoimmune, SLE, PAN, Churg Strauss, Wegener
 Metabolic DM, porphyria
 Infiltrative sarcoidosis, amyloidosis
 Neoplastic carcinoma, lymphoma, paraneoplastic
 Demyelinating GBS
 Drugs chemotherapy i.e. vincristine, cisplatin, thalidomide,
bortezomib, isoniazid, nitrofurantoin, metronidazole, amiodarone,
colchicine, infliximab
o Pathogenesis
 Wallerian degeneration
 Axonal degeneration – distal to proximal
 Demyelination
 Generalised Charcot Marie tooth
 Segmental acquired inflammatory demyelination-Guillain
Barre Syndrome
o Nerves re grow 1mm a day – 20cm in 200 days
o Large fibres – negative symptoms
 Weakness
 Numbness
 o Small fibres – positive symptoms
 Burning
 Pain
 Hypersensitivity
 Discomfort
 Paraesthesia
o Autonomic symptoms
 Light-headedness on standing
 Urinary or faecal urgency
 Erectile dysfunction
 Constipation
 Impaired sweating
o Length dependent neuropathy typically starts in legs due to increased
metabolic demands on the longest nerves i.e. diabetic neuropathy with
stocking/glove neuropathy
o Proximal weakness or sensory loss suggest non-length dependent such as
demyelinating neuropathies of ganglionopathies
o Asymmetrical: Lyme, Leprosy, mononeuritis complex

- Inspection – chairsaw
o Consciousness level
o Hearing aid
o Asymmetry – muscle bulk, shoulder girdle
o Involuntary movements
o Rash
o Scars
o Abnormal gait
o Walk aid around the bed
- Hereditary motor and sensory neuropathies such as CMT can cause pes cavus
o Abnormally high plantar longitudinal arch
- Neuropathic arthropathy (Charcot joint) can be defined as bone and joint changes
that occur secondary to loss of sensation and is most often associated with diabetes,
syphilis, syringomyelia, spina bifida, traumatic spinal cord injury, and leprosy.
- Pin-prick – test small fibres
- Light touch – test large fibres
- Large fibre – most common in diabetes, burning in feet
- Neurophysiology
o Decreased amplitude  axonal
o Prolonged distal latencies AND slow conduction velocities  demyelination
o Uniform and diffuse slow conduction velocities  hereditary
o Focal slow conduction velocity or conduction block acquired
- Symmetric distal weakness and sensory loss
o Commonest pattern
o DM and idiopathic
- Small motor units  eye movement
- Large motor units  legs
- Weakness generally proximal
o Difficulty getting out of a low chair
o Difficulty going up stairs
o Hanging out washing, brushing hair
- Dark urine – myoglobinuria
- Hyporeflexia
- Wasting
- Rashes
- Gower sign
- Proximal sign
- Do muscle biopsy

- EMG tests type I fibers

- Myasthenia Gravis
o Muscle weakness without wasting
o Fatiguability
o Ocular and bulbar muscles commonly involved
o Responds well to treatment
o Ptosis and diplopia
o Eye movements
o Cogans lid twitch
o Nasal voice
 o Chewing difficult
o Severe jaw weakness, jaw hangs open
o Pyridostigmine
o Anti AChR antibodies
o Anti-MuSk

Viral Pathogens of the CNS/Encephalitis

- Meningitis
o Fever
o Headache
o Neck stiffness
o Vomiting
o Photophobia
o Irritability
o Viruses
 Enteroviruses – most common cause
 Herpes, HHV6, HSV, VZV
 Mumps
- Encephalitis
o Altered mental status
o Motor or sensory deficits
o Behaviour or personality changes
o Speech or movement disorders
o Viruses
 HHV6, HSV, VZV
 Enteroviruses
 West Nile
 Japanese encephalitis
 Flavivirus – tickborne
 Rabies
- Congenital damage to the CNS
o Rubella
o CMV
o Zika virus
- Viral meningitis is more common than bacterial meningitis
o Enteroviruses – echoviruses, coxsackie B, enterovirus 71
o Herpes
o Mumps
o Arboviruses – WNV, Japanese encephalitis
- How do viruses get into the CNS?
o Via bloodstream
o Along nerve pathways – HSV, Rabies
o Olfactory mucosa
o Virus multiplication and resultant cellular damage
o Host immune response – cellular immune response and cytokines
- Viral meningitis
 o Not as sick as patients with bacterial meningitis
o Evolve more slowly – several days
o May be indistinguishable clinically from bacterial meningitis
o Supportive
o Acyclovir benefit unclear unlike HSV encephalitis which must be treated with
acyclovir
o Prevent with MMR vaccine
- Non-polio enteroviruses most common pathogens in the viral meningitis
o Mainly affect infants and young children
o Late spring to autumn
o Human only reservoir
o Faecal-oral
o Multiply in GIT but only occasionally cause GI symptoms
o Enter bloodstream – viraemia
o Hence, infection in many organs including CNS
o Enterovirus 71  a/w encephalitis esp. in East and S/E Asia
o Enterovirus D68  acute flaccid paralysis following respiratory illness
o Fever and rash
o Myocarditis, pericarditis (Coxsackie viruses, echoviruses)
o Hand, foot and mouth disease (Coxsackie viruses, enterovirus 71)

- Viral encephalitis
o Can be a/w substantial morbidity and mortality unlike viral meningitis which
is usually benign and self-limited
o Herpes simplex
 Most common cause in Europe
 HSV1 more common than HSV2
 Human-only
 Latent infection in cranial nerve ganglia
 To frontal or temporal lobes of brain
 Direct neuronal transmission of the virus via the trigeminal or
olfactory nerve to the brain
 Haemorrhagic necrosis and inflammatory infiltrates
 Acute neurologic syndrome
 Behavioural disturbance
 Hemiparesis
  Aphasia
 Focal seizures
 MRI, EEG, CSF – HSV PCR
 IV acyclovir

o Rabies
 Causes acute encephalitis
 Mostly in Africa and Asia
 Bite or direct contact with the saliva of infected animal
 Incubation period depends on the distance the virus has to travel to
reach the CNS 3-12 weeks
 No effective antiviral treatment
 Fatal within days
 Follows peripheral nerves
 Prodrome: fever, pain at bite site, salivation – ANS
 Restless/irritable/aggressive
 Encephalitis/paralysis
 PCR – CSF or saliva
 Direct immunofluorescent antibody staining of a skin biopsy from the
nape of the neck – above the hairline - standard diagnostic test
 Serology blood and CSF – if no prior rabies vaccine or post-exposure
prophylaxis
 Rabies immunoglobulin IM – post-exposure
 Rabies vaccine
o West Nile
 Arboviruses
 Birds usual host
 Transmitted via bite of an infected mosquito
 Late summer or early autumn
 Northern North America
 Tropical climates – year-round
 No symptoms – 80%
 Mild influenza-like illness – fever, headache, generalised aches and
pains – full recovery
 Encephalitis, meningoencephalitis (<1%)
 Risk increases with age + immunosuppression
 WNV IgM (blood or CSF)
 Viraemic period is short, so serology is always required
 Self-limiting/supportive
 o Japanese Encephalitis
 Closely related to WNV
 Infected mosquito, Culex species
 Pigs and wading birds
 Rice paddy fields, flood irrigation
 Incubation period 5-15 days
 Children
 Mostly asymptomatic
 <1% acute encephalitis + meningitis and acute flaccid paralysis, or
febrile illness
 Clinical diagnosis
 JE virus specific IgM detection on blood or CSF
 Culture and PCR are not sensitive
 No antiviral available
 JE vaccine
 Insecticide
o Tick borne encephalitis
 RNA flavivirus
 Infected ixodes tick
 Consumption of unpasteurised milk
 No human to human transmission
 Incubation 6-28 days
 Mostly asymptomatic
 Biphasic illness
 Initially febrile, viraemic phase
 Asymptomatic interval followed by 2nd phase when CNS is
involved
 20-30% develop second phase
 Viral RNA PCR in blood
 TBEV IgM and IgG in blood and CSF
 Convalescent serology
 Childhood vaccine
o Enteroviruses can cause encephalitis but more commonly cause meningitis
- Polio
o No or mild in 90-95%
o 1-2% biphasic
 2-3 days fever and GIT symptoms
 Appear to recover, then develop fever, severe headache, and other
symptoms
 Meningitis
 Paralytic poliomyelitis
o Paralytic polio
 Spinal polio 80%
 Asymmetric
 Usually legs
 Muscles innervated by efferent nerves from infected anterior
horn cells
  Flaccid paralysis with no sensory loss – destruction of LMN
 Bulbar polio
 Replication in motor nuclei of lower cranial nerves
 Weakness of tongue and pharyngeal muscles
 Bulbospinal – combination of above
o Post-polio syndrome
 30-40 years after paralytic polio
 Increased weakness and muscle pain
 Due to loss of neurons in initially affected nerves
o CSF – PCR
o Early in illness – viral culture, throat secretions and faeces
o Supportive – pain relief and physical therapy
o Bulbar involvement – monitor closely the CVS – bp fluctuations, circulatory
collapse, and autonomic dysfunction
- Zika
o Congenital zika syndrome
 Severe microcephaly resulting in a partially collapsed skull, decreased
brain tissue with brain damage
o a/w GBS
 Patient’s own immune cells attack and damage the nerve cells causing
muscle weakness and sometimes paralysis
 Post-infectious paralysis
- Subacute sclerosing panencephalitis – normal host
o Persistent measles virus infection in CNS
o Years after original infection
o Behavioural and intellectual deterioration and seizures
o Fatal outcome
- HIV encephalopathy - immunocompromised host
o Convulsions
o Dementia
o Motor disorders
- PML – immunocompromised host
o Reactivation of JC virus resulting in demyelination
o No treatment – reduce immunosuppression
- Transmissible spongiform encephalopathy
o Protease-resistant protein which accumulates in the brain
o Altered prion proteins resistant to inactivation by standard chemical,
thermal, and other means of inactivating microorganisms
o Incubation period months to years
o Gradual increase in severity leading to death
o Don’t evoke an immune response
o MRI
o CSF 14-3-3: non-specific
o Conclusive by histological examination at post-mortem
 Spongiform changes
 Amyloid plaques
  Prion proteins
o No proven effective therapy
o Protect blood and food supply
o Autoclaving not effect
o Destroy by incineration – surgical instruments used on brain, spinal cord,
posterior eye
o Low-risk surgical procedures – thorough cleaning, autoclave
o Sporadic/familial – cannot be prevented
 Spontaneous or inherited mutation of prion protein
 Brain and spinal cord
o Variant – can be prevented
 Ingestion of BSE- contaminated animal products + potentially, receipt
of contaminated blood products
 Brain, spinal cord, eyes, tonsil, thymus, spleen, adrenal gland, lymph
node, appendix
o Iatrogenic – can be prevented
 Transmission of altered prion protein via a medical procedure

Brain Tumours
- 2% all cancers
- 20% cancers <15 years
- Leading cause of cancer-related death in children
- Risk factors
o Increasing age
o History of radiotherapy
o Tumour predisposition syndrome
- Presentation
o Seizure
o Symptoms/signs of raised ICP
  Headache – postural/nocturnal/early morning
 Vomiting
 Clouding of consciousness/coma
 Papilloedema
o Symptoms/signs of hydrocephalus
 Increase in CSF volume within the ventricular system
o Focal neurologic deficit
- Cerebral oedema
o Vasogenic
 BBB disrupted  increased vascular
permeability  fluid escapes from
intravascular to intercellular compartments
i.e. trauma
o Cytotoxic oedema  increased intracellular fluid
secondary to cellular injury i.e. hypoxemia
o Co-exist
- Raised ICP
o Oedema
o Brain compressed
o CSF displaced to spinal compartment
o Blood volume reduced in cerebral veins
o Swelling
o Vascular compression
o Vascular insufficiency
o Exacerbates high ICP (cytotoxic oedema)
- Consequence  cerebral herniation
o Subfalcine herniation of cingulate gyrus
o Transtentorial herniation of medial part of temporal lobe
 CNIII (oculomotor)
o Transforaminal herniation of cerebellar tonsil
- Complications of brain herniation
o Vascular compression
 ACA at falx
 PCA at tentorium
 Brainstem duret haemorrhage = death
- Causes of hydrocephalus
o Disturbance of CSF homeostasis - rare
 CSF overproduction – choroid plexus tumour
 Failure of CSF absorption – arachnoid granulations, various cranial
dysplasia
o Interference with CSF flow – common
 Neoplasm
 Congenital stenosis, membrane at foramen of Monro
 Infection – scarring
 Haemorrhage
 Gliosis
- Symptoms/signs of hydrocephalus
o Infant: enlarged head, bulging fontanelle, downward eyes, sunsetting,
irritability
o Child: above + headache, blurred vision, poor balance, seizures
o Adults: above + memory loss, and bladder control problems
- Lung and Breast most commonly metastasize to brain

- Meningioma is the most common benign primary tumour

- Glioblastoma is the most common malignant primary tumour
- Grade 4 astrocytoma = GBM
- Brain tumours spread to secondary structures of Scherer – CSF pathway
dissemination
- Prognosis
o Tumour site
o Site impacts resectability
o Site impacts on morbidity
- A benign or low grade tumour can kill
- Eloquent areas
o Motor strip – can cause paralysis
o Adjacent to speech are – dysphasia
- Predict tumour behaviour
o Grade
o Grade 1 – pilocytic astrocytoma – excellent prognosis
o Grade 2 – no high grade features – 10yr median survival
o Grade 3 – mitosis – median survival 3-5 years
o Grade 4 – mitosis, microvascular proliferation, necrosis – survival less than 5
years
- Techniques in diagnostic practice
o IHC
o aCGH
 o fusion specific qPCR
o DNA sequencing NGS
o Methylation
- INI-1 IHC is absent from all tumour cells confirming the presence of SMARCB1
mutation/deletion
o Atypical teratoid rhabdoid tumour, WHO 4
o Tumour of infants/young children
o CSF dissemination
o Rhabdoid predisposition syndrome in. >1/3 cases
- Normal cells do not stain H3K27M, tumour cells express it
o Diffuse midline glioma
o H3K27M mutant
o WHO grade 4
- Oligodendroglioma
o Fried egg appearance
- 1p19q co-deletion when present with IDH1/2 mutations = oligodendroglioma
o Predicts responsive to PCV therapy when combined with RT
- NTRK targetable with NTRKi
o Use specific drugs

- Investigations
o CT brain followed by
o MRI brain w/ contrast
- Treatment
o Gross total resection except w/ lymphoma and germinoma
o +/- radiotherapy
o +/- chemotherapy (BBB challenge)
Traumatic Brain and Spinal Injury
- Leading cause of death in young people <45 years
- Men 3:!
- Falls are responsible for 2/3 TBI in Ireland
- Alcohol was a/w 1 in 4 TBI in Ireland
- Blunt force trauma
- Missile head injury – gunshot
- Contact w/ a flat surface  closed fissure fractures
- Contact w/ angled or pointed objects  localized fractures, open and depressed
- Contrecoup fractures  roof of the orbits and cribriform plates
- Base of skull fractures
o Racoon eyes
o Battle’s sign
o CSF Otorrhea
o CSF Rhinorrhoea
o Hemotympanum
- Contusion
o Bruising of the surface of the brain
o Can be a/w overlying fractures – depressed skull fracturs
o Crest of gyri
o Gray matter only
o May extend into underlying white matter and form a haematoma
o Coup and contrecoup contusions
o Dynamic
o Evolve with time
- Lacerations
o When severity has been sufficient to tear pia
o Burst lobe
o Post traumatic coagulopathy
o Mannitol
- Epidural
 o Biconvex
o Doesn’t cross suture lines
o Temporal and parietal areas
o a/w MMA
o talked and died
- Subdural
o Venous in origin sometimes arterial
o Acute
 Falls and assaults
 Rupture of bridging veins
 Mortality 30-50%
 Can resolve spontaneously – clot is absorbed
o Chronic
 Follow an episode of relatively trivial head injury
 Therapeutic anticoagulation biggest risk factor
 Granulation tissue forms
 Re-bleeding or enlargement in size
- SAH
o Sequelae of TBI commonest
o Damage to cortical vessels
o Vertebral artery dissection/fracture
o Communicating hydrocephalus
- ICH
o Deep – basal ganglia – outcome poor
o Lobar
o Cerebral amyloid and angiopathy and atherosclerotic disease make vessels
more prone to bleed
- Diffuse brain injury
o TAI
 Angular or rotational acceleration
 Focal or diffuse
 Diffuse are unconscious from moment of impact, do not experience a
lucid interval, and remain unconscious, vegetative, or at least severely
disable until death
 Macroscopically brain can look normal
 Disrupts normal axonal flow – axonal swelling, axonal varicosities,
axonal retraction bulb
 B-APP best marker
 Accumulates 35-45 min after TBI in kids, and 35 min after in adults
 Axonal loss
 Area of glial scarring within cortex
 Patchy area of demyelination within the pons
o Diffuse vascular injury
 Petechial haemorrhages in frontal and temporal white matter,
diencephalon, and brainstem
  Results from acute deformation, stretching and tearing of small blood
vessels
 Die within minutes
o Ischaemia
 In patients who have hypoxia, hypotension with SBP less than
80mmHg for at least 15 minutes, raised ICP over 30mmHg
 Earliest site – hippocampus, deep gray structures, and watershed area
in cortex
- Brain swelling and herniation are common forms of secondary brain damage
o Cerebral vasodilation and an increase in cerebral blood volume
o Extravasation of oedema fluid through the defective BBB
o An increase in water content of neurons and glia
- Spinal cord injury
o Age at time of injury
o Neurological status at time of injury
o Extent of injury

- Chronic traumatic encephalopathy

o Parkinsonism and ataxia
o Tauopathy
o P-tau in neurons, astrocytes, and cell processes around small vessels

Head Injuries
- Trauma is leading cause of death under the age of 45 and up to 50% due to a head
injury
- 28% due to falls
- Monroe-Kellie Doctrine: fairly significant changes of pressure without significant
changes of pressure up to a certain point
- Consequences of raised ICP:
 o Herniation syndromes
o Reduced cerebral perfusion
 CPP = MAP – ICP
 MAP = diastolic + 1/3 pulse pressure
 CPP = 60-90mmHg

- Prevention of secondary brain injury is the goal of management of traumatic brain

injury
- EDH
o Blunt trauma
o Linear fracture
o Usually temporal
o MMA
o Biconvex due to attachment of dura to skull sutures
o Lucid interval
o Emergency craniotomy
- Acute SDH
o Covers entire cerebral surface
o Crescent shaped
o Associated parenchymal injury
o Emergency craniotomy
- Chronic SDH
o Age, male, anticoagulants, coagulopathy, thrombocytopenia, alcoholism
o Early burr hole drainage in the presence of raised ICP or lateralising signs
- Intracerebral haematoma
o Contusions
o Diffuse axonal injury
 Prolonged unconsciousness in the absence of a mass lesion
 Petechial haemorrhage
 Basal cisterns effaced
 Ventricles compressed
 Sulci invisible
 Loss of grey/white differentiation
  Conservative, decompressive craniectomy
o SDH
o Usually conservative but evacuation of haematoma in the presence of raised
ICP or marked midline shift
- Penetrating injuries i.e. gunshot
o Wound debridement
o Removal of foreign body
o Angiography
- Medical management
o 30 degrees head up
o Mannitol
o Frusemide
o Hypertonic saline
- Long-term sequelae
o Post-traumatic epilepsy
 5% first week, 12% after
 No benefit in giving prophylactic anti-epileptic drugs
o Post-concussion syndrome
 Behavioural change, headache, dizziness, mood swings, irritability,
memory loss
 Neuropsychology input
- MRI best for brain tumours
- Glial tumour most common 60%
- GBM
o 46-60 years
o 50% of astrocytomas
o 20% of primary brain tumour
o Necrosis
o Safe resection
o Post-op radiotherapy and chemotherapy, STUPP protocol
- Low grade astrocytoma
o Peak age 30
o Transform to higher grade
- Meningioma
o Extra-axial
o Arise from cap cells of arachnoid
o Classified by location
o For residual or recurrent meningioma use radiation and/or focussed radiation
- Vestibular schwannoma
o Vestibular branch of CNVIII (vestibulocochlear nerve)
o Present with slowly progressive hearing loss bilateral in NF2
o Surgery or stereotactic radiosurgery
- Pituitary adenoma
o Non-functioning: - visual symptoms, headache, hypopituitarism
o Functioning – prolactin, GH, ACTH
o Drugs, surgery, radiation
 - Primary CNS lymphoma
o Most common in immunosuppressed patient i.e. AIDs, organ transplant
o Biopsy and chemotherapy
- Cancer spread to CNS
o Brain
o Spinal cord
o Leptomeninges
o Dura
o Pituitary gland

Paediatric brain tumours

- Paediatric glial tumour
o 2nd most common childhood tumour
o Common solid tumour
o Astrocytoma> medulloblastoma> ependymoma
- Cerebellar astrocytoma
o Most common brain tumour in childhood
o Benign, slow growing
o 90% cure
o 5-10 years
o 30% of paediatric posterior fossa tumours are astrocytomas
- Medulloblastoma
o Arises in cerebellar vermis
o Primitive neuroectodermal tumour
o Extremely malignant
o Characterised by the ability to seed along CSF pathways
o Frequently, they metastasise down the spinal axis
- Ependymoma
o Arise from cells that line the ventricles or the central canal of spinal cord
o In children and young adults
- Diffuse brain stem tumour
o Balloon the brain stem and infiltrate all layers
o Malignant
o Poor prognosis
o Cause cerebellar dysfunction, cranial nerve palsies, and paresis
- 5-ALA is a compound (swallowed by the patient before the surgery, in a liquid
solution) that causes malignant glioma cells to fluoresce. 

Epilepsy
- Seizure
o Excessive electrical discharge from the cerebral cortex
o Imbalance between excitation and inhibition
o Symptoms depend on where seizure is located
 - 10/1k people

- Non-contrast CT brain followed by MRI

- Normal EEG does not exclude epilepsy
- Inpatient video-EEG monitoring
- Acute seizures:
o 1st line IV benzodiazepine i.e. lorazepam or rectal diazepam
o Supportive care
o 2nd: phenytoin/levetiracetam/valproate

Drugs for Pain

- Acute pain  noxious stimuli
o NSAIDs and opioids
- Chronic pain  aberrations of normal pathways
o Anticonvulsants and antidepressants
- Nociceptive pain
o Nociceptive nerve fibers triggered by inflammation, chemicals, or physical
events
o Nociceptors-special receptors located at free nerve endings of A and C fibres
o Turn noxious stimuli into electrical signals to be sent to CNS
o Nociceptors can be thermal, mechanical, or chemical
o A – fast – sharp and localised pain – first pain
o C – slow – dull and burning pain – second pain
o AB fibres – mechanoreceptors
- Descending Inhibitory circuits
 o Descending spinal pathways from CNS can inhibit ascending spinothalamic
pathways
o PAG is involved in descending inhibitory modulation project from the PAG to
the dorsal horn
o Gate control theory
o At relay points, along the ascending pain pathways, there are gates that can
be closed to make it harder for nociceptive impulses to get through
o Opioids can activate inhibitory interneurons in the descending pathway
- Opiates
o Morphine 10%
o Codeine in small amounts
o Codeine synthesized commercially from morphine
o Mimi the actions of endogenous opioid found in our body
 Consists of opioid peptides that are ligands from opioid receptors
 Naturally-occurring peptides can produce morphine-like effects
 B-endorphin, endomorphin, met-enkephalin, dynorphin
o Endorphins
 Endogenous opioid polypeptide compounds
 High affinity for mu receptor
 Produced in pituitary, hypothalamus during exercise, excitement, and
pain
o Enkephalins
 Delta-opioid and mu
 Met and leu
 Control pain
o Dynorphin
 Kappa
 A and B
 Increased levels in dorsal horn after tissue injury and inflammation
o G-protein linked opioid receptors
 CNS, heart, lungs, liver, GIT, reproductive tracts
 Mu, kappa, delta
o When opioids bind to receptors, voltage-gated calcium channels on
presynaptic nerve terminals close
o Reduce NT release
o Open K channels  hyperpolarize neurons
o Inhibit action potentials postsynaptic neurons
o In the dorsal horn region of the spinal cord, opioid receptors can inhibit
transmission of pain signals
o Act directly on nociceptors – opioids inhibit transmission of pain isgnals
- Mu
o Morphine
o Methadone
o Sufentanil
o Buprenorphine – partial
o Pentazocine - partial
- Delta
o Sufentanil - +
- Kappa
o Sufentanil - +
o Pentazocine - ++

- Morphine
o Marked elevation in pain threshold without loss of consciousness
o Mu – euphoria, pleasant, floating sensation
o Kappa – dysphoria in some subjects
o Oral, SC, IM, IV
o Variable 1st pass metabolism
o 3-4hr half-life
o Sustained release oral preparations increase duration of action
o Patient-controlled IV analgesia
o Adverse effects
 Mental clouding/drowsiness
 Respiratory depression
 Dependence
 Miosis – important in diagnosis of overdose
 Constipation
 N&V
- Methadone
o Similar to morphine
o Oral most common
o 24hr half life
o Treats opioid addiction (reduces craving and symptoms)
- Fentanyl
o High lipophilicity  crosses blood-CSF barrier more rapidly and produces
analgesic effects
o Very strong
o 100x more potent than morphine
o Shorter duration of action 30-40 minutes
- Codeine
o Weak
o Low efficacy
o Mu>kappa
 o 10% converted to morphine
o Alleviation of mild-moderate pain
o Antitussive – cough suppressant
- Tramadol
o Analogue of codeine
o Weak mu through major active metabolite desmetramadol
o Moderate to severe pain
o Inhibits NA and 5-HT reuptake – some anti-depressant activity
o Side effects:
 Respiratory depression
 Increased risk of seizures
 Serotonin syndrome
 Physical dependence
- Naloxone
o Antagonist
o Administered with morphine  rapid reversal of opioid action
o Critical in acute opioid overdose
o Short half-life 1-2 hours so repeated injections necessary
- Naltrexone
o Longer half-life
o Used more commonly for withdrawal than overdose
- Buprenorphine
o Mixed agonist-antagonist
o Can be full antagonist when used with a full agonist
o Less euphoria, less sedation, milder withdrawal
o Higher affinity to receptors than other opioids
o Treats opioid addiction – combine with naloxone sublingual
o Moderate pain in non-opioid tolerant individuals – transdermal/sublingual
- Other opioid agonists
o Levorphanol – stronger than morphine, pre-operative medication
o Sufentanil – post-operative labour, 1000x morphine
o Hydromorphone – semi-synthetic from morphine
o Oxycodone – semi-synthetic from thebaine – moderate-to-severe pain
- Pentazocine – agonist/antagonist
- Tolerance to the euphoric effects of morphine develops fast
- Tolerance to the inhibition of peristalsis by morphine does not develop at all
- Tolerance develops quickly for analgesia, emesis, euphoria, respiratory depression
- Tolerance does not develop to inhibition of peristalsis – constipation, pupillary
constriction
- Withdrawal: causes series of autonomic, motor, and psychological responses
- Steroidal drugs bind cytosolic glucocorticoid receptor (GR) in the cytosol, translocate
to the nucleus, and transactivate or transrepress genes involved in inflammation
- Inflammatory mediators in nociceptive pathway:
o Substance P and CGRP
 Excites nociceptors and elicit pain
 Vasodilation and oedema
 o Histamine
 Excite nociceptors and elicit pain
o Nerve growth factors
 Binds to TrkA receptors on the surfaces of nociceptors leading to their
activation eliciting pain
o 5-HT, ACh, low pH, and ATP
 Excite nociceptors
o Arachidonic acid
 Metabolized into prostaglandins which block K+ efflux from
nociceptors following damage
 Nociceptors become more sensitive
- Corticosteroids
o Bind cytosolic GR
o Translocate to nucleus
o Transactivate responsive genes via GRE i.e. lipocortin-1 (Annexin)
o Inhibits PA2
o Reduces inflammatory prostaglandins
o Regulates pro-inflammatory transcription factors such as AP-1 and NFKB
prevent their binding to their gene target (transrepression) to GRE so COX-2
inhibited
o Decreased inflammation
- NSAIDs
o Block formation of prostaglandins
o COX inhibitors
o Non-selective
 COX-1 and COX-2
 Aspirin, ibuprofen, diclofenac
 S/E: acid secretion increased, mucus secretion inhibits, gastric ulcer,
avoid with acidic foods, do not take with acidic foods
o Selective
 COX-2
 Celecoxib
 No major effects on GIT
- Paracetamol/Acetaminophen
o COX inhibitor
o Analgesic – decrease prostaglandins and sensitise nociceptors such as
bradykinin
o Antipyretic – elevate temperature set point
o NOT ANTI-INFLAMMATORY – some selectivity for brain COX – COX3
o Hepatotoxic
- Neuropathic pain
o Actual nerve damage
o Toxins, infection, autoimmunity, cancer tumour
o Burning or heavy sensation, numbness
o Neuroimmune response
o Anticonvulsants
  Reduce neuronal excitability
 Enhance Na+ channel inactivation
 Stabilise inactive channel
 Carbamazepine, lamotrigine, and phenytoin
 Gabapentin – modulates calcium channels
 Binds to alpha2 delta auxiliary subunit of voltage-gated ion
channel
 Inhibits presynaptic calcium release
 Reduced calcium influx
 Reduced NT release
o Antidepressants
 TCA: imipramine, amitriptyline
 SNRI: venlafaxine
 SSRI: citalopram
 MAOi: inhibition of NA, 5-HT2, dopamine reuptake by blocking 1+ of
their respective monoamine transporters
 For neuropathic pain: inhibition of NA reuptake which activate pain
control circuits that descend from midbrain to spinal dorsal horn
o Anaesthetics
 Local (topical/injected) and general (injected/inhaled)
 Topical – lidocaine patches – back pain, benzocaine – throat lozenges
 These local anaesthetics block sodium channels in neurons
involved in pain pathways
 Prevents propagation of action potentials
 Non-specific
 Dental surgery
 Limb surgery – lidocaine and prilocaine
 Childbirth – lidocaine, epidural space
 Surgery to abdomen – lidocaine
 Lidocaine can be used in neuropathic pain
 S/E: if drug reaches other tissues  systemic toxicity
 Co-administer vasoconstrictor such as adrenaline to keep
anaesthetic at site for longer
 General
 Barbiturates and benzodiazepines – GABA channels, increase
Cl influx, hyperpolarisation, reduce AP
 Ketamine – short-acting – block NMDA channels, reduce AP
 S/E: sedation, amnesia, hallucinogenic
 Barbiturate – thiopental
 Dissociative – ketamine
 Opioids – fentanyl
 Benzodiazepines – midazolam
 Propofol – positively modulates GABA channels
 Inhaled
 Halothane – rarely used due to adverse effects, must co-
administer oxygen
  Sevoflurane and desflurane – rapid onset of action, rapidly
excreted, constantly applied, open GABA-A
 NO – rapid onset and recovery, block NMDA
 Gas partition coefficient – measures solubility, time of onset,
and time of emergence
 Brain partition coefficient – higher means higher the solubility
of anaesthetic in brain tissue
 Highly variable between patients – depends on body fat
 Minimum alveolar concentration – best measure
o Fraction of volume of anaesthetic present in inspired
air that provides sufficient analgesia in 50% of patients
o In 50% they will not respond to extremely painful
stimulus such as surgical skin incision
o Simple and easy to measure with small variations

Drugs that target disease of the brain

- Alzheimer’s most common neurogenerative then Parkinson’s
- 1.5x more common in men
- Median age of onset 57 years
- Often idiopathic
o Neurotoxins, familial
- Parkinson’s
o Unilateral first then bilateral
o Bradykinesia
o Hypokinesia
o Stiffness or rigidity
o 4-6Hz tremor when at rest
- Non-motor symptoms
o Depression, anxiety, fatigue
o Reduced smell
o Cognitive impairment
o Sleep disturbance
o Constipation
- 60-80% of neurons lost before disease clinically apparent
- DA neurons in substantia nigra pigmented black due to neuromelanin
- Dopamine producing cells and ability to store dopamine are gradually lost
- Loss of neurons from substantia nigra
- Drug targets to increase dopaminergic neurotransmission:
o Increase DA precursor
o Block reuptake of dopamine through DA transporter
o Block the breakdown of dopamine by MAO or COMT
o Use dopamine receptor agonists
- Dopamine metabolised to … in the brain
o DOPAC (dihydroxyphenylacetic acid) by MAO-B
o 2-Methoxyltyramine by COMT
o Homovanillic acid (HVA) is the major metabolite excreted in urine
o Administer MAO-B and COMT inhibitor
- PD treatment
o Levodopa (L-dopa)
 L-dopa is the inactive precursor of dopamine
 Dopamine cannot cross the BBB but L-dopa can
 Increased dopamine release in the brain specifically corpus striatum
region
 Given with a dopamine decarboxylase inhibitor (DDI) such as
carbidopa
 Protects levodopa from peripheral metabolism
 Increases levodopa in brain and decreases peripheral bioavailability
 Levodopa will cross the BBB and is converted to dopamine in
dopaminergic neurons
 Side effects of L-Dopa
 Dizziness, nausea, insomnia
 Confusion, disorientation, hallucinations
 Delusions, agitation, psychosis
 More common in the elderly
 Long-term use  dyskinesias (abnormal involuntary
movements that cause rapid jerking or slow muscle spasms –
limbs, trunk, tongue and orofacial region)
 On-off phenomenon
 Motor fluctuates when medication wears off before next
scheduled dose
 On – symptoms controlled
  Off – medication no longer active and symptoms such as
tremor, rigidity, and slow movement re-emerge – hypokinesia
 Apomorphine – dopamine agonist used for motor fluctuations
during hypokinesia
 Dopamine dysregulation syndrome – addictive pattern of
dopamine replacement therapy, administer more to control
their symptoms, impulsive control disorders, pathological
gambling, hypersexuality, compulsive shopping, compulsive
eating – reduce levodopa dosage
 Levodopa needs nerve terminals, as this is where it will be synthesised
into dopamine, so continuing loss of DA nerve terminals may limit
long-term effect of L-dopa
 DA agonists do not require intact DA neurons
- Dopamine agonists
o Directly stimulate striatal DA receptor
 Non-ergot derived – 1st line
 Selective D2/D3 agonists
 Apomorphine - SC also D4
 Pramipexole – oral
 Ropinirole – oral
 Rotigotine – transdermal
 Ergot derived – fibrotic reactions – lung, pericardium
 D1 and D2 agonist
 Bromocriptine – oral
 Pergolide – oral
 Cabergoline – oral
o Less motor complications (longer half-life than L-dopa)
o Used in younger patients
o Levodopa may be more suitable in patients requiring fine motor skills
o S/E similar to levodopa: drowsiness, impulse control, N&V, day time
somnolence, gambling, hyper sexuality
o Patients more likely to discontinue dopamine agonists due to adverse effects
than levodopa
o Dopamine agonist withdrawal syndrome
 Tapered dose reduction
 Vigilance for development of depression
- MAO-B
o Less severe, newly diagnosed
o Adjuvant with levodopa
o May delay need for levodopa or delay onset/reduce existing motor
complications
o S/E: nausea, dyskinesia, orthostatic hypotension, sleep disorders
o C/I: tyramine containing foods: cheese, wine, pickled foods, pepperoni
o May cause serotonin syndrome which can be life-threatening
- COMT
o To 3-MT in central brain, tolcapone
 o To 3-OMD in periphery, entacapone, tolcapone
o Improve motor impairment
o Administered with others such as levodopa/carbidopa/entacapone (Stalevo)
o S/E: dyskinesia, N&V, urine discolouration (entacapone), severe diarrhoea
(tolcapone), life-threatening hepatic toxicity (tolcapone), CVS risk with
Stalevo
- ACh-blocking drugs
o Antimuscarinic
o Reduce tremor and rigidity but little effect on bradykinesia
o S/E: dry mouth, constipation, impaired vision, urinary retention

Alzheimer’s
- Early onset – mutations in presenilins – codes for alpha secretase involved in b-
amyloid processing
- Late onset – ApoE mutations – ApoE carries cholesterol and is a/w increased
deposition of B-amyloid proteins
- Mild-moderate disease: cholinesterase inhibitor
o Donepezil
o Rivastigmine
o Galantamine
- Moderate-severe: NDMA blockers
o Memantine
 Fewer s/e: tiredness, constipation
- Epilepsy
o 2 of the following conditions are met
 At least 2 unprovoked or reflex seizures occurring more than 24 hours
apart
 One unprovoked seizure and a probability of further seizures
occurring over the next 10 years
 Diagnosis of an epilepsy syndrome
o Status epilepticus
 Continuous seizure for >5 min or recurrent seizures <5 min without
regaining consciousness
o Defective ion channels
 Genetic defects in sodium, potassium, and calcium ion channels
 Defects range from nonsense and missense point mutation to non-
functional channel subunits
 Na (SNC1A), K (KCNA1), Cl- (CLCN2)
o Imbalance in NT release
 More excitatory glutamate
 Less inhibitory GABA – GABRA1 mutation
o Paroxysmal depolarizing shift
o Prolonged depolarization of the neuronal membrane due to influx of
extracellular calcium
o Influx of calcium leads to opening of voltage-dependent sodium channels,
influx of sodium, and more Aps
o Calcium is cleared slowly from neuron – keeping neuron depolarise
o Multiple Aps
o 4 main class of agents
 Inhibit sodium channel
 Phenytoin
o Prolongs inactivation gate configuration
o Increases threshold for AP and prevents repetitive
firing
o 0 order kinetics
o Hepatic metabolism – induce CYP450 – drug
interactions i.e. OCP
 o Fosphenytoin for parental use (prodrug safer)
o S/E: nystagmus, diplopia, ataxia, gingival hyperplasia,
hirsutism, mild peripheral neuropathy, coarsening of
facial features
 Carbamazepine
o Generalised seizures
o MOA like phenytoin but structurally unrelated
o 1st order kinetics
o Induce CYP450
o Less S/E: diplopia, ataxia, agranulocytosis
 Lamotrigine
o Slows Na+ channel recovery from inactivated state
o Effective in absence
o Stephen Johnson syndrome, TEN syndrome, anaemia
 Topiramate
o Block Na channels
o Also increases GABA
o Inhibit glutamate
 Inhibit calcium channels – highly concentrated in thalamocortical
system
 Ethosuximide
o Reduce low-threshold T type currents in a voltage
dependent manner
o Absence
o EFGHIJ
o Fatigue, GI distress, Headache, Itching, SJS
 Valproic acid
o Slow rate of sodium channel recovery from inactivated
state
o Low threshold for T-type calcium channels
o Inhibit GABA metabolism
o Generalised (tonic/clonic), some mixed seizures
o GI distress, fatal hepatotoxicity, neural tube defects
(C/I in pregnancy), tremor, weight gain
o Lamotrigine safer in pregnancy
 Inhibit glutamate receptors – NMDA receptors
 Felbamate for severe seizures
 Enhance GABA inhibition
 Permeable to Cl- ions which hyperpolarize membrane and
inhibits AP
 GABAa and GABAb
 GAT help regulate EC GABA by reabsorbing the transmitter and
clearing the synapse
 Benzodiazepines
o Modulate GABAa receptors at allosteric binding sites
o Increase frequency of channel opening – Cl- influx
 o Diazepam, lorazepam – focal and tonic-clonic seizures
o Clonazepam – absence
o Tolerance and dependence
o Overdose reversed with flumazenil
 Barbiturates – phenobarbital rarely used, primidone –
alternate drug
o Increase the duration of Cl- channel stays open
o Fatal CNS and respiratory depression in overdose
 Tiagabine
o Competitive inhibitor GAT in neurons and glial
o Partial seizures with or without secondary
generalisation
o S/E: confusion, sedation, amnesia, ataxia
 Vigabatrin
o Irreversible inhibitor of GABA transaminase
o Infantile spasms and refractory focal epilepsy
o S/E: drowsiness, confusion, headache, visual field
defects
 Gabapentin
o Increase GABA levels and inhibit HVA calcium channels
o Reduce glutamate NA release
o GABA agonist
o Focal seizures, neuropathic pain
o Sedation, ataxia
o Very few drug interaction
Depression
- Diagnostic criteria
o Depressed mood and/or loss of interest in activities for at least 2 weeks
o Major depressive disorders require 2 or more major depressive episodes
o Symptoms should not be accounted for by a bereavement (life stressor)
o Determine if symptoms are not due to direct physiological effects of a
substance or other condition (hyperthyroidism)
o Core symptoms: DAL
 Depressed mood
 Anhedonia – inability to experience pleasure
 Lack of energy
o Other symptoms
 Suicidal thoughts or plans
 Sleep disturbance
 Psychomotor agitation or retardation
 Low self-esteem
 Changes in weight and appetite
 Poor concentration
 Guilt or self-reproach
o Classification
 Mild: 4 symptoms, 2 core
 Moderate: 6 symptoms, 2 core
 Severe: 7 symptoms, 3 core
- Suicide is the 8th leading cause of death in the US
- Suicide is the 3rd leading cause of death among people 15-24
- More than 90% of suicides a/w mental illness
- SSRI normally first line
o Moderate to severe depression
o >2 week before anti-depressant effect
- Electroconvulsive therapy
o Severe or resistant depression
- Monoamine hypothesis
o 5-HT
o NA
o DA
- St John’s Wort
o Hyperforin and adhyperforin
o Induce reuptake inhibition of monoamines, dopamine, norepinephrine, and
serotonin
o Induce hepatic enzymes
- Norepinephrine reuptake inhibitors
o Bupropion
o Reboxetine
o Atomoxetine
- TCAs
 o Block NA and 5-HT
o Leaves them in the synaptic cleft for a longer period where they can activate
the post-synaptic receptors
o Side effects are attributed to actions at these receptors
 Histamine 1: drowsiness and sedation
 Adrenergic 1: postural hypotension, dizziness
 Muscarinic: dry mouth, confusion, memory impairment, blurred vision
- SSRI
o Increase synaptic concentrations of serotonin
o Highly specific
o Greater therapeutic index
o Low toxicity in overdose
o Better tolerated than TCS – less anti-muscarinic and cardiotoxicity side effects
o S/E: GI/nausea, bleeding (increased with NSAIDs), headache, anxiety,
insomnia, sexual dysfunction, hyponatremia, serotonin syndrome, suicide
o Side effects with abrupt withdrawal
- SNRI
o Block transporter at NA and 5-HT synapse
o When SSRI’s ineffective
o S/E: nausea, dose-related hypertension
- MAO
o Rarely used because of toxicity and potentially lethal food and drug
interactions
o Resistant depression
o Increase concentration of 5HT and NA in the presynaptic neuron
o S/E: headache, hypotension, tyramine (cheese, wine, beer, bean), acute
hypertension, severe headache may lead to ICH
- Anxiety
o Somatic: poor appetite, tightness over chest, throbbing in neck
 B-blocker, anti-histamine
o Psychological: repetitive worrying thoughts, fear, irritability
o MSK: backache, headache, neck ache
o GAD >6 months
o Panic disorder, peaking within 10 minutes
o Noradrenaline:
 Abnormal activity in the locus coeruleus
 Stimulants and caffeine release NA increase locus coeruleus firing and
provoke anxiety
o Serotonin:
 Modulatory effects on locus coeruleus
 Dense projections in amygdala
o GABA
 Decreased
 Amygdala sensitive to GABA effects of BDZ
o SSRIs
 First line in GAD
  Suitable for long-term use
 Less S/E and no abuse potential
 2-3 week lag phase
 Co-prescribe short-term BDZ
 Sertraline first line for 2 months in GAD
 No improvement: increase dose or switch to an alternative
SSRI or SNRI (duloxetine/venlafaxine)
o TCA
 GAD and panic disorders
 Clomipramine – OCD and phobic state
 Panic attacks more common during lag phase
o MAOI
 Morbid anxiety especially with panic symptoms
o BDZ
 Severe disabling anxiety causing significant distress
 Short-term 2-4 weeks with regular review
 Lorazepam: 8-12h half-life
 Nitrazepam 16-20h
 Diazepam 20-40h
 S/E: drowsiness, confusion, amnesia, impaired coordination,
withdrawal symptoms
 Enhances depressant effect of other drugs i.e. alcohol
 Respiratory insufficiency
 Tolerance and dependence – short-term use
o Activation of GABA can cause sleep and drowsiness reducing anxiety
o Short term insomnia: hypnotic <3 week, short acting
o Chronic insomnia: TCAs
o Hypnotics: BDZ
 Nitrazepam and flurazepam – long t ½
 Hangover effect and cumulative doses
 Temazepam – shorter acting
 Little hangover but withdrawal symptoms
 Decrease time taken to sleep and increase duration
 Caution in elderly
 Flumazenil for overdose
o Hypnotics:
 Z-drugs – zolpidem and zaleplon
 GABAA
 Anti-histamines
 Diphenhydramine and promethazine
 OTC
 Melatonin
 Hormone
 Very short half-life 2-3hr
 Few s/e
o Other treatments
 B-blockers: propranolol
 Somatic or physical symptoms of anxiety i.e. tremor, sweating,
and SOB
 Buspirone
 GAD but in effective in controlling panic attacks or severe
anxiety state
 Partial agonist at 5-HT1A receptors
 Delayed onset of anxiotic action, 2-4 weeks
 Does not cause sedation, motor incoordination, tolerance, or
withdrawal
 S/E: nausea, dizziness, headache, restlessness
o Anti-convulsant
 Not first line
 Pregabalin
 Structural analogue of GABA
 Binds calcium channels reducing NT release
 GAD
 Abuse potential
 Sodium valproate
 GAD and panic disorders
 Teratogenic
 Barbiturates
 Low TI
 Phenobarbital: dangerous interactions with other drugs, lack
of safety and selectivity

Psychosis and Mania

- Schizophrenia
o Age of onset 18 in men
o 25 in women
o Paranoid, catatonic, undifferentiated
- Psychosis more than 1 symptoms, such as
o Difficulty in processing information
o Disorganized thoughts
o Distortion of reality
o Delusions, hallucinations, incoherence
o Catatonia
o Aggressive or violent behaviour
- Causes
o Genetic: 22q11.2DS
o GRIN2A, GRIA3 – coding glutamate receptors
o Environment
o Developmental factors: hypoxia, infection, stress, or malnutrition
- Positive symptoms
o Hallucinations
o Delusion
o Disorganized behaviour and speech
- Negative symptoms
o Apathy, anhedonia, blunted affect, poverty of speech
- Cognitive symptoms
o Thought disorders, bizarre behaviour
- Too much dopamine causing psychosis
o Amphetamine and cocaine at high doses have psychomimetic effects
- Dopamine antagonists relieve positive symptoms of psychosis
- Antipsychotics reduce psychotic symptoms, especially hallucinations but are unable
to treat cognitive deficits
- Dopamine receptors D1-D5
- Antipsychotics
o Typical – first-generation
 Full effect over 2-4weeks
 Large affinity for D2
 Many side effects
 Relieve positive
 Protect against future relapse
 Chlorpromazine
 Haloperidol
 EPS – pseudoparkinsonism – block dopamine in nigrostriatal pathway
 Occurs in 75% of patients shortly after starting drug or increasing dose
or sometimes after a dose level has been established (tardive effects)
 Acute symptoms: dystonia, Parkinson’s, akathisia, tardive dyskinesia
 If tardive dyskinesia, discontinue
 Anticholinergic – dry mouth, urinary retention
 Apathy, lack of initiative
 Orthostatic hypotension
 Prolactin secretion, pituitary, menstruation disturbances
 NMS
 Muscle rigidity and rapid rise in body temp
o Atypical – second-generation
 Clozapine, risperidone, olanzapine
 5HT2
 Reduced EPS
 Risperidone binds strongly to D2
 Selectivity for D2 receptors in mesolimbic system rather than
nigrostriatal system
 Effect on negative symptoms
 No effect on prolactin, less anti-cholinergic, lower CVS toxicity
 S/E: weight gain, hyperlipidaemia, hyperglycaemia, DM
 Olanzapine and risperidone increase risk of stroke in elderly with
dementia
 Clozapine increase risk of agranulocytosis – requires monitoring
 Long-term injectables
- Bipolar disorders
o No specific genes have been identified
o Switch between manic/euphoric and depressive/dysphoric
o Suicide 10-20%
o 1/3 admit to at least one suicide attempt
o Symptoms
 Decreased need for sleep
 More talkative
 Distractibility
 Increased goal-directed activity
 Excessive energy
 Flight of ideas and racing thoughts
o Manic
 1st line: haloperidol, risperidone, olanzapine
 Lithium – mood stabilizer
 Help stop cycling
 Monovalent cation that mimics role of sodium in excitable
tissue
 Partial loss of depolarisation-reduced excitability
 Can cause memory loss and confusion
 Patient compliance is an issue
 Narrow therapeutic window >2.0mmol-toxicity
 Monitoring required
 Slow onset of action, 7-14 days
 S/E: tremor, GIT, renal, coma, convulsions, dysmorphogenic in
pregnancy
 Reduce mania in acute attack but not the depressive phase
 Sodium valproate
 ECT
 Antipsychotics just for mania not cycling
o Mood stabilizers
 Prevent swings of mood
 Stop initiation of manic and depressed phases
o Carbamazepine, valproate, and lamotrigine have fewer S/E than lithium
 Prevent cycling
 Bind to channels in deactivated state
 Slow channel recovery
 Reduce number of functional channels available to generate AP
 Carbamazepine/valproate – sodium
o Depressive phase
 Anti-depressants
 Combine with mood stabiliser
 SSRI’s can precipitate mania
 SNRI’s less likely
 Rapid discontinuation if mania developed
 Anti-psychotics
 Psychotic depression and bipolar depression
 Antiepileptic – lamotrigine
 Prevent depressive episodes in patients
 o Prevent relapse
 Mood stabiliser with anti-psychotic
 Lithium
 Valproate if lithium ineffective
 Carbamazepine if patient unresponsive to lithium
 Lamotrigine – depressive symptoms
 Anti-depressants – risk of hypomania/mania
 Anti-psychotics

Drugs for addiction

- Diagnostic criteria for abuse and dependence DSM-V
o 2 of the following occurring within a 12 month period
 Tolerance
 Withdrawal
 Persistent desire or unsuccessful efforts to cut down or control
substance use
 Taken in larger amounts over a longer period
 Social, occupational, or recreational activities are given up or reduced
because of substance use
 Lots of time is spent in activities
 Continued substance use
 Substance use continued despite knowledge of harmful effects
 Recurrent use in situations
 Recurrent substance abuse
 Craving or strong desire
- Types of tolerance
o Innate
o Pharmacokinetic
o Pharmacodynamic
o Conditioned tolerance
o Acute tolerance
o Reverse tolerance
o Cross-tolerance
- Dependence syndrome
o Need of drug to be present at to maintain normal function
- Reward pathway through mesolimbic dopaminergic pathway
o VTA dopamine neurons project to NAc
- Nicotine
o Activation of presynaptic nicotinic receptors on dopaminergic axon terminal
in VTA facilitate dopamine release
o Increase BP and smooth muscle contraction
o Nicotinic receptors undergo rapid switch off after initial stimulation (receptor
desensitization) – short rush
o Chronic use – adaptive response to desensitisation
o Medication
 Nicotine replacement therapy
  Bupropion – increase dopamine in CNS
 Varenicline – nicotinic receptor partial agonist that controls release of
dopamine
- Cannabinoids
o Euphoria, relaxation, hallucination, toxic psychosis
o Smoking, ingested
o No medicine specifically for cannabis
o Activation of cannabinoid receptors at the nucleus accumbens
o Cannabinoid receptors (CB1) inhibit GABAergic neurons in the VTA
o Disinhibition  facilitate dopamine release at NAc
o Psychological dependence moderate/physiological dependence low
- Cocaine
o Intranasal, IV, smoked
o High abuse
o Blocks reuptake transporters for dopamine, NA, serotonin
o Primary NAc
o Blocks DAT, increase dopamine in DAc
o MOA on mesolimbic pathway
o Block NA and serotonin are responsible for its sympathomimetic actions
- Amphetamines
o Increase dopamine at presynaptic cleft by block DAT
o 5/5 abuse potential
o Methamphetamine, captagon
o Increase NA and dopamine in presynaptic cleft/ increase release of NT
o Overdose
 Hyperthermia
 Tachycardia
 Hypertension
 Death: HF, seizure, respiratory depression
o Treatment:
 Reduce temp
 IV fluids
 Monitor heart rate
 Oxygen
 BDZ
 Verapamil
 Rarely B-blockers
o Withdrawal
 Depletion of dopamine in synaptic cleft
 Restlessness
 Depression or anxiety
o Treatment
 Propranolol – for high bp and reduced cocaine withdrawal symptom
 Disulfiram for alcohol dependence
- Methamphetamine
o Crystal meth
 o Increased sexual desire and unprovoked violence
o High doses: psychosis, seizures, dysphoria, hyperthermia
o Highly addictive
o Physiological and psychological dependence high
o No specific medication for crystal meth withdrawal
o SSRI or diphenhydramine for symptomatic relief
- Withdrawal from pyschostimulants such as cocaine, amphetamines, meth
o Bradycardia
o Sleepiness
o Fatigue
o Dysphoria
o Anhedonia
- Opioids
o Activation of receptor occur directly
o Mu opioid receptors inhibit GABAergic neurons in the VTA
o Disinhibition
o Heroin
 <40 years life expectancy
 Skin abscesses
 Endocarditis
 Pulmonary infections
 Osteomyelitis
 Hepatitis, AIDs
o Overdose
 Pinpoint pupils
 Decreased consciousness
 Decreased body temperature
 Coma
 Respiratory depression – death
o Methadone or buprenorphine – partial mu receptor agonist
- BDZ
o CNS depressant
o 3/5
o Anti-anxiety, anticonvulsant, anaesthetic
o Short courses recommended
o Discontinued gradually
o Withdrawal: seizures, rebound anxiety, insomnia
- Alcohol
o 3/5
o Bind GABA a receptor
o Ethanol blocks NMDA receptors decreasing cellular excitation
o Chronic alcoholism
 Peripheral neuropathy
 Chronic gastritis
 Impaired testicular steroid synthesis
 Fatty liver disease
  Necrosis and fibrosis of liver
o Withdrawal
 BDZ – lorazepam – seizure and anxiety
 Haloperidol – hallucination and delirium
 Pancreatic enzyme supplementation
o Long-term relapse
 Disulfiram is a ALDH inhibitor
 Flushing, headache, nausea, vomiting
- LSF – hallucinogens
o Vision and auditory perception distorted
o Paranoid delusions
o Flashbacks
o Induce psychosis
o Widely abused
o Not addictive
o Fail to evoke dopamine release
o Increase glutamate release in cortex through a pre-synaptic effect on 5-HT2A
receptors expressed on excitatory afferents from thalamus
- MDMA
o Ecstasy
o Diminished fear and anxiety
o Euphoria
o Visual hallucinations
o Jaw clenching
o 1/5
o Serotonin release and blocks serotonin reuptake
o Decrease fear
o Increase oxytocin levels  strengthen empathy
o Increase ventromedial prefrontal activity and decrease amygdala activity 
decrease fear
o Increase NA and cortisol  increasing energy and arousal
o Weak 5-HT1 and 5-HT2 agonist  hallucinations
o Overdose
 Hyperthermia
 Seizures
 SAH
 Arrythmia
 Liver and renal failure
 Hyponatremia
o Chronic use
 Sleep disturbance
 Depression
 Anxiety
 Impulsivity
 Increased aggression and hostility
 Memory impairment
Overview of CNS
- Hydrocephalus  excess water in ventricular system
- Ex vacuo  loss of brain tissue
- Chiari malformation
o Tonsillar herniation
o Elongated brain stem
o Small 4th ventricle
o Tectal beaking
o Hydrocephalus
- Primary CNS lymphoma – immunosuppressed, AIDs, organ transplant

Multiple Sclerosis
- Relative preservation of axons
- Dysmyelination refers to malformed and defective myelin sheath as opposed to the
destruction of previously normal myelin that is seen in demyelination.
Dysmyelination disorders often arise from hereditary mutations that affect the
synthesis and formation of myelin.
- Grey matter = neuron
- White matter = axon
- CNS axons myelinated by oligodendrocytes
- Risk 15-20x in 1st degree relatives
- Relation between MS and genes related to immune function
- Symptoms
o Visual loss, optic neuritis
o Acute transverse myelitis
o Trigeminal neuralgia – severe facial pain
o Diplopia
o Gait/balance disturbance
o Vertigo
o Bladder dysfunction
o Lhermitte’s sign
o Uhtoff’s phenomenon
- Pathogenesis
o Active MS plaque
 Perivascular and parenchymal inflammation
 Lots of lymphocytes and macrophages
 Gadolinium enhancement = active plaque
o Chronic
 Hypocellular
 Reactive astrocytes reflect prior activity
 Some axonal loss
 Remaining axons have reduced caliber
o Macroscopic
 Yellow when more acute
  Cavitating when old
- McDonald
o Based on clinical findings alone or combination of clinical and MRI findings
- Acute management
o Glucocorticoids – IV methylprednisolone for 3-5 days, oral is alternative
o Plasma exchange – not responding to ^
o Reduce duration of relapse
- Long-term
o DMT for relapsing remitting MS
- 50% chance of walking unaided 15 years after diagnosis

Neurodegeneration
- Progressive dysfunction and death of neurons
- Neuronal loss, gliosis, intracellular protein accumulation – same as prion disease
- Abnormal protein production/folding
- Failure to eliminate protein
- Defective neuronal +/- glial functioning and cell death
- Oxidative stress, excitotoxicity, programmed cell death, cytokine-mediated
- TAU – stabilises microtubules
- Alpha-synuclein – maintain supply of synaptic vesicles in axonal terminal of neurons
- APP
- Selective neuronal vulnerability – determines clinical phenotype
- Akinetic and rigid – Parkinson’s
- Hyperkinetic – Huntington’s chorea, basal ganglia
- Ataxic – spinocerebellar ataxia, cerebellum and its connecting tracts
- Motor neuron disorders – motor neuron disease – UMN/LMN
- Temporo-parietal degeneration – Alzheimer’s, hippocampus and cortical neurons
- Frontotemporal degeneration – FTLD – frontal and temporal cortical neurons
- Multifocal degeneration – cortical and subcortical neurons
- Majority are sporadic
- Multiple susceptibility factors
- Single mutation – MAPT – makes instruction to make TAU
- Trinucleotide repeat – polyglutamine disorders – Huntington’s disease
- Prion
o Transmissible protein via neurosurgery, cannibalism, not DNA/RNA
o Hallucinations, myoclonus
- Dementia
o 2 cognitive areas
o Irreversible
- Alzheimer’s
o Macroscopic: medial temporal lobe – hippocampus
o Microscopic: TAU and amyloid – neurofibrillary tangles and amyloid plaques
- Parkinson’s
o Bradykinesia
o Resting tremor
o Rigidity
o Autonomic dysfunction, cognitive decline, dysphagia
 o Macroscopy
 Pale substantia nigra
o Microscopy
 Alpha synuclein – Lewy body
- ALS
o Neurodegeneration of upper and lower motor neurons
o Spasticity, hyperreflexia, fasciculations
o 60 years onset
o Respiratory failure
o Median survival 3-5 years
o Microscopy
 Anterior horn cells
 TDP43

Delirium and Dementia:

- DSM IV
o Memory impairment and
o Aphasia, apraxia, agnosia, disturbance in executive function
- Alzheimer’s 50-75%
- Vascular 20-30%
- Lewy body 10-25%
- Frontotemporal 10-15%
- Prevalence
o 4% over 65
o 20% over 80
o 50% over 90
- 18 FDG PET scan for Alzheimer’s
- Alzheimer’s/MCI: decreased AB42
- Treatment for Alzheimer’s:
o Remove anti-cholinergic
o Cholinesterase inhibitors: donepezil, rivastigmine, galantamine
o NMDA receptor antagonist: memantine
o Manage HTN
o Avoid alcohol
- Prognostic markers
o Weight loss
o Functional loss/personal care dependence
o UTI/LRTI if dependent or NH resident
o Swallow impairment
- Vascular dementia
o 25%
o Reduced blood flow to brain
o Cumulative small strokes
o Step-wise fashion deterioration
o Risk factors: diabetes, HTN, high cholesterol, obesity, smoking, AF
 o Cholinesterase and NMDA inhibitors not licensed but can be used if overlaps
with Alzheimer’s
- Lewy Body
o 3rd most common
o Triad: visual hallucinations, fluctuating cognition, parkinsonism
o Lewy bodies in brainstem and neocortex
o No cure
o Survives 6-12 years
- Frontotemporal
o Decision-making, behavioural control, emotion, and language
o Inherited in 1/3 of cases
o No treatment
o Medications to reduce agitation, irritability, or depression
- Delirium
o Hyperactive
 Visual hallucinations, hyper alert, distractible
 Better prognosis
o Hypoactive
 Drowsy, long periods of apathy, impaired interaction
 Mistaken for depression
o Mixed
o Risk factors: age, dementia, Parkinson’s, stroke, frailty, liver disease,
polypharmacy, alcohol misuse
o Precipitants: UTI, LRTI, sepsis, electrolyte abnormalities, medications, alcohol,
stroke, MI, intra-abdominal bleed, hip or pelvic fracture
o Treat underlying condition
o Stop anti-cholinergics
o Watch out for falls, swallow impairment, medication risks, DVT

Epilepsy
- Excessive electrical discharge from cerebral cortex
- Life-time prevalence: 10/1,000 population
- Ireland: 9/1,000 >5 years
- Epilepsy risk factors:
o Febrile seizures
o CNS infection
o Trauma
o Family history
o Perinatal injury/ID
- Autosomal dominant nocturnal frontal lobe epilepsy – NFLE – CHRNA2
- AD epilepsy with auditory features – LGI1
- Juvenile myoclonic epilepsy – complex
- Childhood absence epilepsy – complex
- Dravet syndrome – SCN1A, epileptic encephalopathy
- Lennox-Gastaut syndrome – DNM1, SLC6A1
- Risk factors for recurrence
o Sleep deprivation
o Inter-current illness
o Psychological stress
o Loud noise or music
o Light
o Anti-epileptic medication non-compliance
- Non-contrast CT brain followed by MRI if first seizure and when intracranial lesion
suspected
- Normal EEG does not exclude epilepsy – only 25% abnormal
- Provocation testing – sleep deprivation, hyperventilation
- Gold standard: inpatient video-EEG monitoring
- Acute seizures
o 1st line: IV/IM/Buccal/rectal benzodiazepine
o 2nd line: phenytoin/levetiracetam/valproate
- Anti-epileptic drugs
o Significant risk for recurrence
o 2+ unprovoked seizures
o Start after 1 if
 Abnormalities on EEG
 Brain tumour, brain malformation, prior CNS infection
 Abnormal neurologic examination
 First seizure occurs during sleep
- Benzodiazepines
o S/E:
 Sedation
 Respiratory depression
 Irritability
 Ataxia
 Sudden discontinuation – withdrawal seizures
 Tolerance may develop
 Not for chronic
- Phenytoin
o Acute focal and generalised seizures, status epilepticus
o 24 hour half-life
o CYP2C9, CYP2C19
o S/E
 Drowsiness
 Nystagmus
 Ataxia
 Rash
 Gingival hypertrophy
 Increased body hair
 Folic acid depletion
 Decreased bone density
 Skin necrosis/pruritus with IV infusion
 o Reduces effectiveness of most hormonal contraception
o Fosphenytoin, more rapid infusion, no skin necrosis
- Phenobarbital
o Half-life 72 hours
o Generalised and focal seizures
o S/E
 Sedation
 Respiratory depression
 Low vitamin D
 Dupuytren’s
o Hyperactivity in children
o Cheap
o Withdrawal convulsions
o Reduce effectiveness of hormonal contraception
- Primidone
o Biotransformation into metabolites phenobarbitone and
phenylethylmalonamide  anticonvulsant activity
o 10hr half-life
o S/E
 Decreased bone density
 Ataxia
 Drowsiness
 Fatigue
 Hyperirritability
 Suicidal ideation
 Vertigo
 Rash
 GI upset
 Impotence
 Haematological
 Nystagmus
 Diplopia
o May reduce effectiveness of hormonal contraception
- Carbamazepine
o Focal not primary generalized
o 8-12hrs
o CYP3A4
o S/E
 Hyponatremia
 Rash
 Pruritus
 Fluid retention
 Aplastic anaemia
 Hepatotoxicity
 GI effects
 Sedation
  Ataxia
 Nystagmus
 Depression
 Dizziness
 Diplopia
 Lethargy
 Headache
 Idiosyncratic
o Make primary generalized worse
o Reduce effectiveness of hormonal contraception
- Oxcarbazepine
o Just focal
o 8-10hours
o Better tolerated than CBZ
o S/E
 hyponatremia
 Rash
 GI effects
 Nystagmus
 Vertigo
 Ataxia
 Idiosyncratic
 Sedation
 Headache
 Dizziness
 Diplopia
- Valproate
o Generalized and focal
o 6-14 hours
o P450 inhibitor
o S/E
 GI upset
 Tremor
 Weight gain
 Hair loss
 Hepatotoxic
 Thrombocytopaenia
 Insulin resistance
 Subclinical hypothyroidism
o Neural tube defects, lower IQ in babies, a/w PCOS
- Levetiracetam
o Bind to synaptic vesicle protein
o 6-10hrs
o Renal metabolism
o S/E
 Mood disturbance
 Behavioural disturbance
  Fatigue
 Somnolence
 Dizziness
o Caution with pre-existing mood disorder
- Ethosuximide
o Half-life 30-60 hours
o S/E
 Nausea and vomiting
 Sleep disturbance
 Drowsiness
 Hyperactivity
 Lupus-like
 SLE
- Lamotrigine
o Focal, generalised, Lennox-gastaut syndrome
o 12-60 hours
o S/E
 SJS
 Tremor
 Headache
 GI
 Insomnia
 Somnolence
o Slow titration due to SJS
o Clearance increased by hormonal contraception, pregnancy
- Topiramate
o GABA, NMDA, carbonic anhydrase
o 24 hours
o S/E
 Sedation
 Cognitive slowing
 Renal stones
 Weight loss
 Glaucoma
 Paraesthesia’s
 Headache
 Fatigue
 Dizziness
 Depression
 Mood problems
 Metabolic acidosis
- Gabapentin
o Binds to calcium channel
o Refractory focal
o 5-9 hours
o Renal
 o S/E
 Sedation
 Dizziness
 Ataxia
 GI upset
 Weight gain
o Treat neuropathic pain
- Zonisamide
o Blocks sodium and calcium
o Some activity in myoclonic
o 24 hours
o S/E
 Somnolence
 Ataxia
 Cognitive slowing
 Weight loss
 Rash
 Ataxia
 Anorexia
 Confusion
 Abnormal thinking
 Nervousness
 Fatigue
 Dizziness
 Nephrolithiasis
o Not for those with moderate or severe renal insufficiency
- Vigabatrin
o Inhibit GABA transaminase
o Refractory focal seizures, infantile spams
o 5-7 hours
o Renal
o S/E
 Sedation
 Fatigue
 Depression
 Psychosis
 Headache
 Dizziness
 Weight gain
o Irreversible visual field loss in long-term exposure
o Reserved for those that are refractory to other drugs

Multiple Sclerosis
- Demyelination of brain and spinal cord
- Second leading cause of physical disability in young adults in the western world
- HLA-DRB1-1501
- Immune regulatory cells: CD56 bright and Treg
- Proinflammatory cells: CD4+, CD8+, B-cell
- Demyelination of the grey and white matter in the brain
- Plaques around veins in the brain – contain lymphocytes and macrophages
- Brainstem/cerebellar
o Facial palsy
o Ataxia
o Diplopia
o Trigeminal neuralgia
- Brain stem syndrome
o Nystagmus
o Internuclear ophthalmoplegia: cannot adduct ipsilateral eye with nystagmus
of the abducting eye
o One and a half syndrome: ipsilateral conjugate horizontal gaze palsy and
ipsilateral internuclear ophthalmoplegia
o Ataxia
- Spinal cord
o Weakness
o Increased tone +/- clonus
o Brisk reflexes
o Upgoing plantar response
o Brown-Sequard syndrome
 Loss of pain, temperature, and light touch on opposite side
 Loss of motor function and vibration, position, deep touch sensation
on same side
- Only 3 subtypes of MS
- RRMS  SPMS
o Approx. 50% by 15 years
o 85% by 40 years if untreated
- Clinically isolated syndrome
o Single clinical syndrome suggestive of demyelination with accompanying
physical signs on examination
o Increased risk of conversion to MS if:
 Abnormal baseline brain MRI
 Asymptomatic spinal cord lesions
 Presence of unmatched oligoclonal bands in the CSF i.e., present in
CSF but not in serum
- Relapse
o Episode of neurological disturbance that lasts at least 24 hours
o In the absence of infection
o Monofocal – optic neuritis
o Multifocal – partial myelitis and brain stem syndrome
- RRMS
o Clinical diagnosis!
o Based on dissemination in time and in space
o Must have accompanying physical signs on exam
- Time
 o Separated by at least one month
- Space
o Optic nerve and brain stem
o Spinal cord and cortex
o Periventricular
o Juxtacortical
o Infratentorial
o Spinal cord
- SPMS
o Progressive myelopathy
o Walking distance restricted to 500m
o Ambulatory dysfunction, urinary dysfunction/catheter, cognitive decline
o Clinical diagnosis
- PPMS
o 15% of MS cases
o Progressive myelopathy
o Mean age onset in 50s
o Disability accumulates quicker
o 10% - superimposed relapses
o M:F 1:1
o Diagnosis
 One year of disease progression
 2 of the 3:
 Evidence of DIS on brain MRI
 Evidence of DIS in the cord based on >/= 2 T2 lesions in the
cord
 Positive unmatched OCBs in the CSF
- MS
o LP for unmatched oligoclonal bands in CSF but not in serum
- Spasticity
o Baclofen
o Tizanidine
o Gabapentin
o Botulinum
o Cannabinoids
- Pain
o Pregabalin
o Gabapentin
o Duloxetine
o Amitriptyline
o Carbamazepine
- Bladder dysfunction
o Oxybutynin
o Botox
o SIC
- Sexual dysfunction: sildenafil
 - Depression/anxiety
o Venlafaxine
o Citalopram
o CBT
- Fatigue
o Modafinil
o Amantadine
- 17 DMTs for RRMS
o 1st line
 IFN-B, SC or IM
 Glatiramer acetate, SC 3 times/week
 Teriflunomide – dihydroorotase dehydrogenase inhibitor, PO
o 2nd line
 Dimethyl fumarate – enhances Nrf2 – PO BD
 Fingolimod – S1P receptor modulator – PO OD
o 3rd line
 Natalizumab - a4 integrin
 Ocrelizumab – CD20
 Ofatumumab - CD20
 Cladribine – deoxyadenosine analogue, 2x in 1 year
th
o 4 line
 Alemtuzumab – CD52
 ASCT
- 1 DMT for PPMS – ocrelizumab
- 1 DMT for SPMS – siponomod

Parkinson’s:
- Start 55-60
- 1% of 60+
- Males 1.5x
- 2nd most common neurological disorder
- 120/100k
- 1 million in US – greatest prevalence
- 60-80% of neurons lost before motor signs emerge
- Braak staging 1-6
- Basal ganglia: caudate nucleus, putamen, globus pallidus
- Substantia nigra: motor centre
o Projects to caudate nucleus and putamen
o Nigrostriatal
o Use dopamine
o Cells within nigra produce dopamine
o Degeneration of melanin-containing cells
o Loss of substantia nigra results in dysfunctional stimuli to basal ganglia
- Aetiology
o Idiopathic – most common
 o Manganese, iron, pesticides, herbicides
o Head trauma
o Antipsychotics, antiemetics, antihistamine
o Genetic, park-1,3,12 <5%
o Abnormal proteosome system
o Oxygen free radicals
- Cardinal motor symptoms – Brigit Trolls Rosa Parks
o Tremor – unilateral pill rolling, rapid at rest, increased w/ stress, 4-5Hz
o Bradykinesia
o Rigidity – asymmetrical
o Postural instability
- Non-motor symptoms
o Orthostatic hypotension
o Anosmia
o Impaired proprioception
o Seborrheic dermatitis
o Urinary incontinence
o Constipation
o Weight loss
o Sexual dysfunction
o Sweating abnormalities
- CLINICAL DIAGNOSIS
o No lab tests
o CT and MRI brain – normal
o MRI can outrule multi-infarcts, hydrocephalus, and Wilson’s
o PET/SPECT in atypical cases
- Parkinson plus syndromes
o Early postural instability and dementia
o Progress more quickly
o Meds less effective
o Patients very sensitive to neuroleptic medications/levodopa
o Axial> limb involvement
- Multisystem atrophy
o Postural instability with falls
o Postural hypotension
o Bladder dysfunction
o Pyramidal and cerebellar signs
- Progressive supranuclear palsy
o Parkinsonism – symmetrical
o Paralysis of upward gaze
o Dementia
o Personality change
o Speech difficulties
- Corticobasilar degeneration
o Extrapyramidal and pyramidal symptoms
o Stroke on one side, Parkinson on the other
 o Pyramidal weakness on one side, extrapyramidal on the other
o Dysphagia
o Aspiration pneumonia
o Alien limb
- Dopamine agonists
o Bromocriptine
o Pramipexole
o Ropinirole
o Cabergoline
o Apomorphine
- Anticholinergics – for tremor/drooling
o Procyclidine
o Biperiden
- Dopa decarboxylase inhibitor
o Benserazide
o Carbidopa
- Domperidone – transient nausea
- Levodopa for initial therapy >70 years
- Wearing off
o At night
o Add COMT inhibitor
o Freezing episodes – increase dose or frequency, add MAOB, dopamine
agonist, use liquid – fast onset
- Pallidotomy – reduces cardinal signs
- Thalamotomy just tremor

cerebellar signs is DANISH:

• Dysdiadochokinesia/ dysmetria.
• Ataxia.
• Nystagmus.
• Intention tremor.
• Speech - slurred or scanning.
• Hypotonia.

Overview
- Brain tumour
o Focal neurologic deficit
o Behavioural cognitive change
o Symptoms/signs of raised ICP i.e. morning headaches, vomiting,
papilloedema
o Seizure
o Stroke haemorrhage, pituitary, incidentaloma
- CSF flows from the lateral ventricles to the third ventricle via the foramen of Monro.
From here, it flows across the cerebral aqueduct of Sylvius to the fourth ventricle
and onto the subarachnoid space through the apertures of Magendie and Luschka 
- CSF excess
 o Overproduction – choroid plexus papilloma
o Circulation blockage – foramen of Monro, aqueduct, foramen of Luschke
o Reabsorption failure – arachnoid granulations
- Chiari malformations (CM) are structural defects where the lower part of your brain
presses on and through an opening in the base of the skull and cerebellum into the
spinal canal. 
o Tonsillar herniation
o Elongated brain stem
o Small 4th ventricle
o Tectal beaking
o Hydrocephalus
- Consequences of cerebral oedema
o Subfalcine herniation of cingulate gyrus
o Transtentorial herniation of medial part of temporal lobe
o Transforaminal herniation of cerebellar tonsil
o Cerebral fungus
o Upward herniation of cerebellum
- Meningioma – hormonal
- Cells within brain – neurons, glial, blood vessels
- Cranial nerves – Schwann cells
- Glial most common 60%
o Astrocytic grade 1-4
o Oligodendroglial
o Ependymoma
- Non-glial
o Meningioma 20%
o Pituitary
o Pineal 10%
o Nerve sheath tumours 5-8%
o Lymphomas
- Childhood
o Astrocytoma
o Ependymoma
o PNET
o Medulloblastoma
- 75% high grad astrocytomas
- 20% meningiomas
- GBM
o Necrosis
o Increased mitoses
o Increased vascularity
o Survive 9-18 months
- Vestibular schwannoma
o CNVIII
o Slowly progressive hearing loss
o Bilateral in NF2
- Pituitary adenoma
o Non-functioning
 Visual symptoms, headache, hypopituitarism
o Functioning
 Prolactin – galactorrhoea, infertility
 GH – acromegaly
 ACTH – Cushing’s syndrome
- Primary CNS lymphoma
o Immune suppressed – AIDS, organ transplant
o Immune competent
- Childhood brain tumour
o 2nd most common childhood tumour – 19%
o Leukemia – 37%
o Most common solid tumour
o Astrocytoma  medulloblastoma  ependymoma
o AME
- Trauma
o EDH – talk and die, sport, lucid interval, arterial
o Chronic subdural: elderly, minor trauma, venous leaking
o Acute subdural: falls and assaults, veins, do not talk and die
- Spontaneous
o SAH – berry aneurysm
o Intracerebral deep lobar – HTN, atheroma, tumour, prematurity, AVM,
amyloid angiopathy
- Virchow’s triad
o Endothelial damage
o Hypercoagulability
o Stasis
- ECHO or angiogram: embolus, endocarditis, old MI with LV thrombus, carotid
atheroma
- MS
o Hallmark is white matter plaque – demyelinated
o Axons intact
o 50% chance of walking unaided 15 years after diagnosis
- Huntington’s disease  caudate neurons
- Motor neuron disease  anterior horn cell
- AB-amyloid  AD and Down’s Syndrome
o Cleavage of amyloid precursor protein by gamma and beta secretase
o Amyloid plaques are toxic to nerve cells
- Tau proteins  AD, FTD, dementia pugilistica
- A-synuclein  LBD/PD
o Release of dopamine
o Aggregates form insoluble fibrils in Lewy bodies in PD
- Cerebral amyloid angiopathy
o Deposition of AB amyloid in small arteries and less frequently veins of
cerebral cortex
 o Normal healthy elderly
o Can cause intracranial haemorrhage, TIA

Brain Tumours
- 2% of all cancers
- 20% cancers <15 years
- Leading cause of cancer-related death in children
- Risk factors – IRT I react turbently
o Increasing age
o History of radiotherapy
o Tumour predisposition syndrome
- Presentation
o Seizure
o Symptoms/signs of raised ICP: headache – postural, nocturnal, early morning
o Symptoms/signs of hydrocephalus
o Focal neurologic deficit
- Vasogenic oedema = intercellular compartments i.e. trauma
- Cytotoxic = intracellular fluids i.e. hypoxia/ischaemia
- Subfalcine herniation, midline shift, measure septum pellucidum from midline
- ACA at falx
- PCA at tentorium
- Neoplasms/cysts presenting with hydrocephalus
o Posterior fossa tumour i.e. pilocytic astrocytoma, medulloblastoma
o Pineal gland neoplasm
o SEGA
o Hypothalamic pilocytic astrocytoma
o Central neurocytoma
o Choroid glioma of 3rd ventricle
o Colloid cyst of 3rd ventricle
- Hydrocephalus
o Infant: sunsetting, bulging fontanelle
o Child: headache, blurred vision, poor balance, seizures
o Adult: poor balance, memory loss, bladder control problems
- Secondary tumours account for 15% in neurosurgical (not autopsy) centres
o 50% solitary
o LB MeCKel
- Malignant
o Glioma – astrocytoma, oligodendroglioma, ependymoma
o Choroid plexus carcinoma
o Embryonal brain tumour
o Primary CNS lymphoma
o GCT
- Meningioma most common benign primary tumour
- Glioblastoma most common malignant primary tumour
- Spread to structures of Scherer or CSF pathway dissemination
- Prognosis
 o Tumour site – resectability and morbidity
- Pilocytic astrocytoma grade 1
o Blindness, pituitary failure
- Meningioma – grade 1-3
- Predict tumour behaviour
o Grade
o i.e. – glioma
 1 – pilocytic astrocytoma – excellent 5yr 95%
 2 – no high grade features – 10 years
 3 – mitosis – 3-5 years
 4 – mitosis, microvascular proliferation, necrosis – months
- INI-1 IHC absent from tumour cells  SMARCB1 mutation/deletion
o Atypical teratoid rhabdoid tumour WHO4
o Infants + young children
o CSF dissemination
o Rhabdoid tumour predisposition syndrome in 1/3
- H3K27M  tumour cells express it
o Diffuse midline glioma
o WHO grade 4
o Poor prognosis
- Fried-egg appearance
o Oligodendroglioma
o 1p19q co-deletion + IDH1/2 mutation
o Predicts response to PCV therapy
o Procarbazine, lomustine, vincristine
o Mutant better prognosis than wild-type
- GBM
o Worse prognosis
o IDM wildtype
 -
- BRAF gene fusion  90% posterior fossa pilocytic astrocytoma
- BRAF gene mutation V600  BRAFi therapy
- IDH1/2 mutation  better prognosis in glioma 2-4
- 1p19q co-deletion  oligodendroglioma
- MGMT methylation  responsiveness to temozolomide in GBM/high grade gliomas
- H3 mutation  grade 4 paediatric, dismal prognosis
- CT brain followed by MRI brain with contrast
- Surgery – not lymphoma and germinoma

Stroke
- 3rd leading cause of death
- Leading cause of adult significant disability
- 7,500 new strokes annually
- 2,500 TIA
- 7.3% of mortality
- Stroke – ASCO
o Atherothrombosis
o Small vessel disease
o Cardioembolism
o Other causes
- Risk factors
o Wall – HTN, Smoking, Atherosclerosis, Hyperlipidaemia, Diabetes
o Lumen – embolus, thrombosis
o Race + FH
o OCP
o Obesity
o Ischemic 65%
o Haemorrhage 12%
o TIA 21%
- Right cerebral hemisphere
o Weakness left arm, leg, face
- Broca’s area
o Speech problems
- Brain stem
o Severe
- Cerebellum
o Ataxia
- Wernicke’s
o Difficulty in understanding speech, reading, naming objects
- Left parietal lobe
o Loss of co-ordination in right arm and leg
- Emboli lodge at pre-existing stenosis or vessel bifurcation
- CT excludes haemorrhage, takes 3 hours
- MRI demonstrates ischaemic changes within few minutes
- Most emboli originate at carotid bifurcation
- Arterial dissection, fibromuscular dysplasia
- Perforating vessels – end arteries
- Charcot-Bouchard aneurysm – microaneurysm
- Small vessel disease – lacunar infarction
- Haemorrhagic CVA with HTN
o Basal ganglia/thalamus
o Deeper part of brain as dep penetrating arteries affected
- ICH: HA CA DT A
- Amyloid – lobar not deep – out near surface
- HTN – deep
- Cavernoma – popcorn type appearance – check FH
- SAH
o PKD
o Berry – saccular aneurysm
o Congenital defect
o Progressive enlargement in life
 o Smoking/HTN
o Worst headache
- Uncal herniation compresses/stretches CNIII
- Decompressive hemicraniectomy – within 48 hours
- Thrombolysis – within 1 hr
- Endovascular within 6-8 hours of stroke

Bacterial Meningitis and Brain Abscess

- Bacteria get into CSF
o Haematogenous spread
o Adjacent focus of infections
o From nasopharynx via bony defect or with head injury – cribriform plate
- Replicated in subarachnoid space  meningitis
- DM and alcoholism  strep pneumoniae
- Bony defect  strep pneumonia
- Neisseria meningitidis  droplets
- Strep pneumoniae  leading cause of meningitis in adults
- Cryptococcus  headache predominates, gradual onset, days to weeks
- Leptospirosis
o Lymphocytic pattern in CSF
o Renal/hepatic failure and meningism
o Conjunctival injection
- Meningitis
o Fever, cold hands, and feet
o Purpuric, non-blanching
o Hearing loss
o Subdural abscess
o CN palsies
o Intellectual problems
o Hydrocephalus and raised ICP
o BSI and shock
- Clinical assessment = mainstay!
- LP C/I if increased ICP and coagulopathy
- Fever + rash  benzylpenicillin or ceftriaxone/cefotaxime
- Infants
o Amoxicillin
o Ceftriaxone
o Gentamicin
- Adults
o Ceftriaxone and vancomycin
- Elderly
o Plus amoxicillin
- In tuberculosis, steroids reduce fibrosis and risk of secondary hydrocephalus
- N. meningitidis – 7 days
- Haemophilus – 10 days
- Pneumo – 14
 - GBS – 14-21
- Listeria – 21
- Aerobic gram neg – 21 days
- Droplet precautions
- Microbial aetiology - polymicrobial
o Streptococci - S. milleri
o Staphylococci – 20%
o Aerobic GNB i.e. E. coli
o Bacteroides
- Non-bacterial cerebral abscess
o Toxoplasma gondii - HIV
o Aspergillosis – single organ or disseminated in immunosuppressed
- Abscess
o Signs of raised ICP
o Signs of infection
o Underlying condition i.e. sinusitis
o Cefotaxime + metronidazole + flucloxacillin
o 4-6 weeks

Traumatic Brain and Spinal Injury

- 50% will have it in lifetime
- Leading cause of death in <45
- >50 million annually
- Men 3x
- Falls 2/3 TBI
- Alcohol 1 in 4
- Flat surface  close fissure fractures, extend into base of skull
- Angled or pointed objects  localized fractures, open and depressed
- Contusions
o Crest of gyri
o Superficial
o Grey matter only
o Can extend to white forming a haematoma
- Laceration - tearing of pia
- SAH – most common sequelae of TBI
o Can form communicating hydrocephalus
- EDH – skull fracture
o Temporal and parietal areas
o Laceration of MMA
- ASDH
o Can resolve spontaneously
- CSDH
o Therapeutic anticoagulation – biggest risk factor
o Granulation tissue forms a membrane around area of haemorrhage
o See re-bleeding or enlargement in size
- Traumatic basal ganglia haemorrhage
 o 59% dying
o 16% favourable recovery
- DTAI
o Unconscious from moment of impact
o No lucid interval
o Remain unconscious, vegetative, or disabled until death
o Macroscopically can look normal
- B-APP – best marker detecting disruption to normal axonal flow
- Axonal loss
o Areas of glial scarring within cortex
o Patchy area of demyelination within the pons
- DVI
o Acute deformation
o Stretching and tearing of small blood vessels
o Petechial haemorrhages – front and temporal white matter, diencephalon,
brainstem
- Ischaemia
o Hypotension with SBP less than 80 for 15 minutes
o Raised ICP >30
o Earliest site: hippocampus, deep grey structures, watershed areas
- GCS
o 3-8 severe
o 9-12 moderate
o 13-15 mild
- CTE
o Tauopathy
o a/w movement disorder, parkinsonism, ataxia
o p-tau aggregates in neurons, astrocytes, cell processes around small vessels
in an irregular pattern at depth of cortical sulci
o tau sequestered in NFTs

Viral Encephalitis
- Post-infectious encephalitis
o Measles, VZV
- HSV6 common in children
- Congenital damage to CNS - RCZ
o Rubella
o CMV
o Zika
- Viruses get into CNS
o Blood stream
o Nerve pathways i.e. HSV, rabies
o Olfactory mucosa
- Not as sick as bacteria
- Symptoms take more time
- Non-polio enteroviruses most common in viral meningitis
 o Echoviruses, coxsackie B, enterovirus 71
o Infants and young children
o Late spring to autumn
o Human only
o Faecal-oral
- E-71 – encephalitis in East and SE Asia
- E-D68 – acute flaccid paralysis following respiratory illness
- Acyclovir in encephalitis but not meningitis
- Mumps meningitis preventable by MMR vaccination
- Benign and self-limiting
- Encephalitis
o HSV
 Northern European countries
 Spread to frontal or temporal lobes of brain
 Via trigeminal or olfactory nerve
 Haemorrhagic necrosis and inflammatory infiltrates
 Acute neurological syndrome
 Behavioural disturbance
 Hemiparesis
 Aphasia
 Focal seizures
 MRI, EEG, CSF – HSV PCR
 IV acyclovir
o Rabies
 Africa and Asia
 Fatal within days
 Fever, pain at bite site, salivation
 Restless, irritable, aggressive then
 Encephalitis/paralysis
 Clinical diagnosis
 PCR – CSF or saliva
 Direct immunofluorescent antibody staining of a skin biopsy from
nape of neck – above hairline
 Serology blood and CSF – no vaccine or post-exposure prophylaxis
 Within 10 days – rabies immunoglobulin IM
 Vaccine
o West Nile
 Arboviruses
 Bird – host
 Transmitted by mosquito
 Not human-only
 Tropical – year round
 Temperate – late summer or early autumn
 No symptoms – 80%
 Mild influenza-like – full recovery
 Severe – 1% - encephalitis and meningoencephalitis
 Risk increases with age and immunosuppression
  West Nile Virus IgM – blood or CSF
 Viraemic period short
 Serology always required
 Self-limiting
o Japanese
 Similar to WNV
 Infected Culex mosquito
 Host = pigs and wading birds
 Rice paddy fields
 Flood irrigation
 Incubation period 5-15 days
 Children
 Most asymptomatic
 <1% - acute encephalitis, acute flaccid paralysis, febrile illness,
meningitis
 20-30% fatality
 30-50% survivors - serious CNS sequelae
 Clinical
 IgM – blood or CSF
 Short viraemia
 Culture and PCR not sensitive
 No antiviral
 Insecticides
 Immunisation - JE vaccine
o Tick-borne
 Eastern Europe, central Europe, Russia, Mongolia, China
 3 subtypes
 Flavivirus, member of arbovirus
 Ixodes tick
 Consumption of unpasteurised milk
 No human to human transmission
 6-28 days incubation
 60-70% asymptomatic
 Biphasic
 Febrile
 Asymptomatic interval
 CNS involved
 20-30% patients develop second phase
 Travel and exposure history
 Viral RNA PCR in blood
 TBEV IgM and IgG in blood and CSF
 No treatment
 Vaccine!
- Polio
o Mild 90-95%
o Biphasic – 1-2%, 2-3 days fever and GIT and then fever, severe headache, and
other symptoms
 o Paralytic polio
 Spinal – 80%
 Asymmetric flaccid paralysis, usually legs
 Efferent nerves from infected anterior horn cells
 Destruction of LMN
 Bulbar
 Replication in motor nuclei of lower cranial nerves
 Weakness of tongue and pharyngeal muscles
 Bulbospinal
o Post-polio syndrome
 30-40 years after paralytic polio
 Increased weakness and muscle pain
 Loss of neurons in initially affected nerves
- Zika
o Congenital: severe microcephaly, collapsed skull, decreased brain tissue,
brain damage
o a/w GBS – post-infectious paralysis
- SSPE
o Persistent measles in CNS, years after original infection
o Fatal
o Normal host
- PML
o JC virus
o Demyelination
o No treatment
- HIV encephalopathy
o Convulsions, dementia, motor disorders
- TSE
o Sporadic/familial – can’t be prevented
 85-90% of human TSE
 Brain or spinal cord
o Variant
 Can be prevented
 Ingestion of BSE
 Brain or spinal cord, and lymphoid tissue
o Iatrogenic
 Can be prevented
 Via medical procedure
o Month to years
o Gradual increase in severity
o Do not evoke an immune response
CJD
- Diagnosed histological examination at post-mortem
- Low risk – autoclave
- Brain, spinal cord, posterior eye – incineration

Stroke and TIA

- 10% cause of death, 5.5 million
- 1 in 6
- TIA
o Without acute infarction
o Amaurosis fugax
o Diagnosis made based on history not imaging
o Risk of 8-10% at 7 days and 11-15% at 30 days: recurrent
o Sudden onset
o Symptoms maximal at onset
o Carotid artery symptoms – amaurosis fugax, contralateral weakness or
numbness, dysphasia, and hemianopia
o Vertebrobasilar – ataxia, vertigo, dysarthria, diplopia, hemianopia, bilateral
visual loss
o 5-15 min
o HEADACHE NOT A FEATURE
o LOC NOT A FEATURE
o ABCD2
 Age 60+
 BP 140/80
 Clinical – 2 for hemiparesis, 1 speech problem w/o weakness
 Duration – 2 >60 min, 1 for 10-60
 Diabetes
 Max 7
 If 5+ - immediate treatment within 24 hr
o No driving 30 days
o Aspirin and dipyridamole
 o Anticoagulation in Afib
o 30-40% of patients with ischaemic stroke have had an earlier transient
ischaemic attack or minor stroke
o 90-day risk of subsequent stroke is as high as 10.5%, with almost half of these
occurring within the first 2 days
o Endarterectomy should be performed within 2 weeks of patient’s last
symptoms
o 25-30% will develop a stroke within 5 years
o 10% will develop a stroke within 3 months
- FAST: 59% increase in presentations under 3 hours during campaign
- Early reperfusion therapy most effective for acute ischaemic stroke
- Endovascular thrombectomy
o Proximal occlusions, not large core and absent collaterals
o Imaging to groin puncture <60 min
o Imaging to reperfusion <90 min
- Difficulties after stroke
o Dysphagia
o Aphasia
o Dysarthria
o Weakness
o Balance
o Coordination
o Sensation
o Continence
o Vision
o Fatigue
o Memory
o Apraxia

Head Injuries
- Trauma leading cause of death <45, 50% head injury
- Men 2x
- Commonest COD 1-15
- 2/3 15-25
- CPP = 60-90 mmHg
- CSDH – early burr hole drainage in presence of raised ICP or lateralising signs
- GBM
o 45-60
o 50% of astrocytomas
o 20% of primary brain tumours
o Necrosis
- Low-grade astrocytoma
o 15% astrocytomas
o 30
o Transform to higher grade
- Meningioma
 o Extra-axial
o Cap cells of arachnoid
- Cerebellar astrocytoma
o Most common brain tumour in childhood
o Benign, slow growing
o 90% cure
o 5-10
o 30% of paediatric posterior fossa tumours are astrocytomas
- Medulloblastoma
o Cerebellar vermis
o Children
o Primitive neuroectodermal tumour
o Extremely malignant
o Seed along CSF pathways
o Metastasise down spinal axis
- Ependymoma
o Cells that line the ventricles or the central canal of spinal cord
o Children and young adults
- Diffuse brain stem tumour
o Balloon brain stem and infiltrate all layers
o Malignant
o Poor prognosis
o Cerebellar dysfunction, CN palsies, paresis
- 5-ALA – fluorescent dye

Drugs for Pain

- Nociceptors-special receptors located at free nerve endings of A and C fibres
- Opioids can activate inhibitory interneurons in descending pathway
- Endorphins
o Produced in pituitary
o Hypothalamus during exercise, excitement, and pain
- Enkephalins
o Control of pain
- Dynorphins
o Dorsal horn after tissue injury and inflammation
- Inhibit AP postsynaptic neurons
- Morphine
o Dysphoria – k receptors
o Half-life 3-4 hours
o Variable 1st pass metabolism
o Respiratory depression
o Mental clouding
o Miosis: diagnosis of overdose
- Methadone
o Half-life >24 hours
- Fentanyl
o Higher lipid solubility
o Cross Blood-CSF barrier
o 30-40 min
o Analgesic
- Codeine
o Low efficacy/weak
o 10% converted to morphine
o Antitussive
o Mild-moderate
- Tramadol
o Moderate to severe
o Active metabolite: desmetramadol
o Respiratory depression, seizures, serotonin syndrome, physical dependence
o Some antidepressant activity
- Naloxone
o 1-2 hour half-life
o Injections – repeated administration
o Overdose
- Buprenorphine
o Mixed
o Antagonism with full agonist
o Treat opioid addiction – combine with naloxone – sublingual
o Moderate pain in non-opioid tolerant individuals
- Levorphanol – stronger than morphine – pre-operative
- Sufentanil – post-op labour, 1000x morphine
- Hydromorphone – semi-synthetic
- Oxycodone – semi-synthetic from thebaine, moderate to severe
- Pentazocine – agonist and weak antagonist
- Tolerance to the inhibition of peristalsis by morphine does not develop at all
- Substance P and CGRP – excite nociceptors and elicit pain
o Vasodilation and spread oedema
- Histamine – excite nociceptors
- NGF – bind to TrkA – elicit pain
- Prostaglandins block K+ efflux from nociceptors following damage, nociceptors more
sensitive
- Corticosteroids
 o GR
o Transactivate responsive genes via GRE
o Lipocortin
o Inhibit PA2
o Reduce prostaglandins
o Regulate AP-1 and NFKB prevent binding to gene target – trans repression
o COX-2
- Paracetamol
o COX inhibitor
o Not anti-inflammatory
o Hepatotoxic
- Neuropathic pain
o Anticonvulsants
 Carbamazepine, lamotrigine, phenytoin on sodium channels
 Reduce neuronal excitability
 Analgesic action
 Gabapentin – calcium channels, a2delta auxillary subunit
o Antidepressant
 TCA
 SSRIs
 SNRIs
 MAOi
 Inhibition NA reuptake which activate pain control
o Anaesthetic
 Topical: lidocaine patches - back pain, benzocaine - throat lozenges
 Local: block Na channels – prevent propagation of AP
 Limb surgery – lidocaine and prilocaine
 Childbirth – lidocaine
 Systemic toxicity, coadminister vasoconstrictor such as
adrenaline
 General IV or inhaled
 Barbiturates, thiopental
 Benzodiazepines, midazolam
 Ketamine – short-acting blocks NMDA – sedation, amnesia,
hallucinogenic
 Opioids – fentanyl
 Proprofol – GABA
 Inhaled
 Halothane – adverse effects, give with oxygen
 Sevoflurane and desflurane – rapid, GABA-A, constantly
applied
 Nitrous oxide – rapid onset, NMDA, another chemical route for
anaesthesia
 Potency
o Blood: gas partition coefficient
o Blood: brain partition coefficient
 o Depends on body fat
 Best measure: Minimum alveolar concentration
o Fraction of anaesthetic volume present in inspired air
that provides sufficient analgesia in 50% of patients in a
population
o 50% will not respond
o Simple and easy to measure

Drugs that target disease of brain

- Dopamine to homovanillic acid – major metabolite – excreted in urine
- Levodopa – increase dopamine release in corpus striatum
o Confusion, disorientation, hallucinations
o Dizziness, nausea, insomnia
o Delusions, agitation, psychosis
o Long-term: dyskinesia
o On-off: off – tremor, rigidity, hypokinesia
o Apomorphine – dopamine agonist – rescue therapy
o Dopamine dysregulation syndrome – addictive pattern to dopamine
o ICD – gambling, hypersexuality, compulsive eating, reduce dosage
- Dopamine agonist
o Non-ergot – 1st line – D2/D3
 Apomorphine – D4 - SC
 Pramipexole – oral
 Ropinirole – oral
 Rotigotine – transdermal
o Ergot – D1 and D2 – all oral
 Bromocriptine
 Pergolide
 Cabergoline
 Severe fibrotic reactions
o Less motor complications
o Younger patients
o Longer half-life than L-dopa
o More adverse effects than levodopa
o Tapered dose reduction
o Vigilance for depression
- MAO-B inhibitors
o Less severe
o Newly diagnosed
o Nausea, orthostatic hypotension, sleep disorders
o Serotonin syndrome
- COMT inhibitors
o Administer with other anti-PD drugs
o Dyskinesia, N&V
o Urine discolouration – entacapone
 o Severe diarrhoea – tolcapone
o Hepatotoxic – tolcapone
o CV risk with entacapone, carbidopa, levodopa
- ACh blocking drugs
o Reduce tremor and rigidity
o Little effect on bradykinesia
o Dry mouth, constipation, impaired vision, urinary retention
- Alzheimer’s
o Early onset – mutations in presenilins – code for alphas secretase
o Late onset – Apo E mutations – increase B-amyloid proteins
o Mild-moderate
 Donepezil
 Rivastigmine
 Galantamine - competitive
o Moderate-severe
 Memantine – NDMA blocker, tiredness and constipation

- Epilepsy
o 50% genetic, 50% acquired
o Children – infection, trauma, congenital
o Adults – tumour
o Elderly – stroke
o Nonsense and missense point mutation, non-functional channel subunits
o Na+ - SCN1A
o K+ - KCNA1
o Cl- - ClCN2
o Multiple Aps
o Influx of calcium causes sodium channels to open – depolarization
o Phenytoin
 Focal and secondary seizures
 0 order
 Induce CYP450
 Interact with OCPs
 Fosphenytoin
  Gingival hyperplasia, hirsutism, coarsening of facial features, mild
peripheral neuropathy
 Ataxia, diplopia, nystagmus
o Carbamazepine
 Generalised
 1st order
 Induce CYP450
 Less s/e: diplopia, ataxia, agranulocytosis
o Lamotrigine
 Slow Na channel recovery
 SJS, TEN syndrome, anaemia
 Safer in pregnancy
o Topiramate
 Block Na
 Increase GABA
- Ethosuximide
o EFGHIJ
- Valproic acid
o Slow Na channel recovery
o Limit T-type Calcium channels
o Inhibit GABA
o Generalised- tonic/clonic
o Mixed
o GI distress, hepatotoxic, neural tube defects, tremor, weight gain
- Benzodiazepines
o Diazepam, lorazepam – focal and tonic-clonic
o Clonazepam – absence
o Overdose reverse with flumazenil
- Barbiturates
o Phenobarbital
o Primidone
o Fatal CNS and respiratory depression in overdose
- Tiagabine
o Competitive inhibitor of GAT in neurons and glial
o Partial seizures with or without secondary generalisation
o Confusion, sedation, amnesia, ataxia
- Vigabatrin
o Irreversible inhibitor of GABA transaminase
o Generally infantile spasms and refractory focal epilepsy
o Drowsiness, confusion, headache, visual field defects
- Gabapentin
o Increase GABA
o Inhibit calcium channels – reduce glutamate NA release
o Focal seizures, neuropathic pain
o Sedation, ataxia
- Felbamate
 o NMDA receptors
o Severe seizures

Neuropathy and Myopathy

-
- 69/100k
- Lifetime prevalence: 3/1000
- Middle age and elderly
- M=F
- Gower’s sign = Duchenne’s
- EMG tests type 1 fibres
- SM affects 2B
- Myasthenia
o Cogan’s lid twitch
o Nasal voice, nasal regurgitation
o Jaw hang open
o Dysphagia
o Aspiration
o Neck flexors affected more than extensors
o Give pyridostigmine
o Muscle weakness without wasting

Depression
- Mild – 4 symptoms – 2 core
- Moderate – 6 symptoms – 2 core
- Severe – 7 symptoms – 3 core
- Suicide 8th leading cause of death in US
- Suicide is 3rd leading cause of death 15-24
- St John’s Wort: hyperforin
o Induce reuptake inhibition of monoamines
o Induce hepatic enzymes
- Norepinephrine reuptake inhibitors: bupropion, reboxetine, atomoxetine
- TCA
 o H1 receptor: drowsiness and sedation
o A1 receptor: postural hypotension, dizziness
o Muscarinic: dry mouth, confusion, memory impairment, blurred vision
- SSRI
o Very SPECIFIC
o Low toxicity
o Wide therapeutic index
o Better tolerated
o GI/nausea, bleeding, headache, anxiety, insomnia, sexual dysfunction
o Less common: hyponatremia, serotonin syndrome, suicide
o Taper off
- SNRIs
o Nausea
o Dose-related hypertension
- MAOi
o Headache, hypotension
o Intracranial haemorrhage
- ECT
o w/ modern anaesthesia
o acute treatment of serious major depression
o last line
- Anxiety
o NA
 Abnormal NA activity in locus coeruleus
 Stimulants, caffeine, increase NA
o Somatic symptoms
 B-blocker
 Anti-histamine
o Clomipramine – OCD
o Sertraline 1st line for 2 months in GAD
o Lorazepam – 8-12 hours
o Nitrazepam – 16-40 hours
o Diazepam – 20-40 hours
o Benzodiazepines
 Drowsiness, confusion, amnesia, withdrawal symptoms
 Tolerance and dependence
 Enhances depressant effect of alcohol
 Respiratory insufficiency
o Hypnotic
 Nitrazepam and flurazepam – long half-life
 Hangover effect
 Temazepam – shorter acting
 Little hangover but withdrawal symptoms
 Zolpidem and zaleplon
 Non-benzodiazepines
 Similar mechanism – GABAa receptor
 o Buspirone
 GAD
 Not for severe anxiety
 Partial agonist at 5-HT1A receptors
 Delayed onset 2-4 weeks
 No sedation, tolerance, motor incoordination, withdrawal
 S/E: nausea, dizziness, headache, restlessness
o Anti-convulsant
 Not 1st line
 Pregabalin – analog of GABA binds calcium channels
 Sodium valproate – teratogenic

Psychosis
- 1% of population
- 18 in men
- 25 in women
- First degree relative is greatest risk 6.5%
- 22q11.2DS in 25% cases
- GRIN2A, GRIA3 – coding glutamate receptors
- Dopamine antagonist can relive positive symptoms of psychosis
- Typical – positive – D2 – protect against future relapse
o EPS – 75% of patients
o Tardive dyskinesia – stop drug, 25%
- Atypical – both – 5HT2 more
o Risperidone also D2 and 5HT2
o Olanzapine and risperidone increase risk of stroke in elderly with dementia
o Clozapine – monitor
- Bipolar
o 10-20% lifetime risk of suicide
o 1/3 – suicide attempt
o Depression then manic episode within 5 years
o Mood-related symptoms 1/3 of the time
o <20% have 5-year clinical stability
o Rapid cycling >4 episodes/year
o Mania
 1st line: antipsychotics – haloperidol, risperidone, olanzapine (not for
cycling)
 Lithium
 Sodium Valproate
 ECT
o Cycling
 Lithium – mimics sodium – partial loss of depolarisation – reduced
excitability
 Memory loss and confusion
 Compliance in issue
 >2.0 mmol toxicity
  Monitoring required, optimise dose
 Slow onset of action 7-14 days
 Tremor, GIT, renal, coma, convulsions, pregnancy
 Antiepileptics
 Carbamazepine, valproate, and lamotrigine – fewer SE
o Depressive phase
 Antidepressants – combine with mood stabilisers
 SSRIs can precipitate mania, TCAs more so
 Rapid discontinuation if that happens!
 Antipsychotics
 Lamotrigine
o Prevent relapse
 Mood stabiliser (lithium) with anti-psychotic
 Valproate if lithium ineffective
 Carbamazepine – if patient unresponsive to lithium
 Lamotrigine – depressive
 Anti-depressants – risk of hypomania/mania
 Anti-psychotics

Drug Addiction
- All drugs of abuse activate mesolimbic dopamine pathway
- VTA projects into Nucleus Accumbens
- Bupropion – increase dopamine in CNS
- Varenicline – nicotinic receptor partial agonist, controls release of dopamine
- Cocaine blocks reuptake of dopamine, noradrenaline, serotonin (last 2
sympathomimetic actions)
- Amphetamines increase dopamine at presynaptic cleft by blocking DAT
o And VMAT
o Not glutamate
- Methamphetamine – increased dopamine and euphoria but also increased sexual
desire and unprovoked violence
o High doses: psychosis, seizures, dysphoria, hyperthermia
o SSRI, diphenhydramine for symptomatic relief
- Long-term use of heroin
o <40 years life expectancy
o Skin abscess
o Endocarditis
o Osteomyelitis
o Pulmonary infections
o Hepatitis, AIDS
- Withdrawal of benzodiazepines
o Rebound anxiety
o Insomnia
o Seizures
o Buspirone can be administered – anti-anxiety
o Propranolol
 o Carbamazepine
o Flumazenil – GABA antagonist
- Lifetime prevalence for alcohol dependence is 10-14%
o 3x men
o Genetic factors
o Ethanol blocks NMDA receptors
o Peripheral neuropathy
o Chronic gastritis
o Feminism and impotence
o Fatty liver disease
o Hepatitis
o Necrosis and fibrosis of liver
o Treatment for withdrawal
 Lorazepam – long-acting, for seizures and anxiety
 Haloperidol – for hallucinations and delirium
 Pancreatic enzyme supplementation – for alcohol-related pancreatitis
- LSD is not addictive
o Not rewarding
o Fails to evoke dopamine release
o Increased glutamate release in cortex
o Through pre-synaptic effect on 5-HT2A
- MDMA – ecstasy
o Diminished aggression, fear, anxiety
o Euphoria
o Jaw clenching
o Feeling of empathy and intimacy
o 1/5 abuse potential
o Serotonin release and block serotine reuptake
o Increase oxytocin levels – strengthen empathy
o Increase ventromedial prefrontal activity and decrease amygdala activity –
decrease fear
o Increase NA release and cortisol levels – increase energy and arousal, glucose
o Weak 5-HT1/2 agonist – hallucinations
o Overdose
 Hyperthermia
 Seizures
 SAH
 Arrythmia
 Liver and renal failure
 Hyponatremia x
o Chronic use
 Sleep disturbance
 Depression and anxiety
 Impulsivity
 Memory impairment
 Not physically addictive
  Mid-week blues – depletion of serotonin

- Contrecoup - roof of the orbits, cribriform plates – frontal lobe

- Zolpidem – different structure/similar mechanism
o Modulate benzo specific subunit sites of GABAa receptor
- Carriage rate of N. meningitidis – 25%

Eye – 4
1 – nil
2 - pain
3- speech
4 - spontaneous

Verbal – 5
1 no response
2 incomprehensible sound
3 inappropriate words
4 confused conversation
5 oriented

Motor – 6
6 obeys
5 localises
4 withdraw
3 flexor
2 extensor
1 null
 - Blocks dopamine reuptake transporter at terminals in nucleus accumbens

Kernig sign is a bedside physical exam maneuver used since its description
in the 19th century to help diagnose meningitis. A positive test is the
elicitation of pain or resistance with passive extension of the patient's
knees past 135 degrees in the setting of meningeal irritation.
LP:
Relative C/O
- platelet count 20-40
- thienopyridines therapy
Absolute C/O
- non-communicating obstructive hydrocephalus
- uncorrected bleeding diathesis
- anticoagulant therapy
- platelet <20
- spinal stenosis or spinal cord compression above level of puncture
- local skin infections
- spinal or cranial developmental abnormalities

CT prior to LP
- focal neurologic deficits
- new-onset seizures
- GCS <10 – severely altered mental status
- Severely immunocompromised

Disinfected i.e. chlorhexidine

Normal CSF volume – 125-150mL

Coenzyme Q10 – neuroprotective

Anticholinergic agents – procyclidine or biperiden

DBS – subthalamic nucleus, internal globus pallidus

Mild disease – start with MAOB-I

Moderate – impacts on quality of life

Dopamine agonists - <65 years

Levodopa and carbidopa in older >65-70 years
More potent
Drug of choice if severely affected
Higher risk of dyskinesias, and motor fluctuations after 5-10 years
Higher risk of somnolence, delirium, hallucinations, and gait freezing with dopamine
agonists

Not as potent as levodopa and patients usually need addition of levodopa after 3 years
Longer duration of action than levodopa
Fewer motor fluctuations and dyskinesias

If used with levodopa it enhances its effect and slows its oxidative metabolism and
therefore increase levodopa side effects. Solution: reduce dose of levodopa or stop MAO B
inhibitor.

Decrease central and peripheral methylation of dopamine, thereby increasing half life.
Allows reduction in levodopa dose by 30%. Used in combination with levodopa to extend its
effect; ineffective on their own.

Main side effects are due to increased dopaminergic stimulation, therefore if s/e’s, decrease
levodopa dosage.

• Biperidin, Benztropine, Procyclidine

• In PD dopamine depletion brings about cholinergic sensitivity, therefore
anticholinergics are useful.
• Most useful in those <70 years without akinetic or gait disturbances.
• Mostly used for tremor unresponsive to levodopa or DA’s.
o Side effects common and limit usage:
o Dry mouth, urinary retention, blurred vision, constipation, nausea,
tachycardia and impaired sweating
o Caution with enlarged prostates, closed angle glaucoma.
o Not suitable for elderly or cognitively impaired due to risk of progression of
memory impairment, delirium and hallucinations.

Amantadine
- NMDA receptor antagonist
- Increase dopamine release
- Inhibit reuptake
- Stimulate dopamine receptors
- May have anticholinergic properties
- Improve tremor and reduce dyskinesias
- Livedo reticularis and ankle oedema
- Confusion, hallucinations, nightmares in elderly when used with other agents

Left sided motor and sensory impairment, speech disturbance and homonymous
hemianopia is consistent with involvement of the middle cerebral artery.

CT angio – determines treatment, look for intravascular thrombus

Non-contrast CT brain – hemorrhage and/or major early ischemic changes
Ischaemic stroke: tPA, oxygen, insulin, paracetamol

Hyperglycaemia a/w increased intracranial haemorrhage

tPa WITHIN 4.5 HOURS

cannot administer heparin, warfarin, aspirin, clopidogrel, or dipyridamole for 24
hours aftereards
after 24 hours – high dose aspirin 300mg x 2 weeks
then aspirin 75mg daily long-term

status epilepticus – phenobarbital, benzo, phenytoin

primidone converted to phenobarbital and acts at gaba receptors

seizure free for 12 months

group 2 for 10 years

high-risk: sodium valproate

moderate: phenytoin, phenobarbital, carbamazepine
low risk: levetiracetam, lamotrigine

small positive symptoms, burning, acquired

large negative symptoms, dullness, ache, inherited

GBS – monophasic, acute

UMN – spastic

Charcot arthropathy – diabetes

Distal symmetrical neuropathy – sensory and motor

- Diabetes
- Alcohol
- Vitamin deficiency

Distal asymmetrical motor and sensory loss

- Vasculitis

Duchenne muscular dystrophy = Gower’s sign, weakness of quadriceps

Dark urine – myoglobinuria – myopathy

- Proximal weakness
- Hyporeflexia
- Rashes
- Wasting
Myasthenia
- Muscle weakness without wasting
- Give pyridostigmine

Absence – petit mal

Tonic-clonic/convulsive – grand mal
Atonic- drop – lennox-gastaut syndrome