CNS Disease meurodegeneration & tumours part 1

What is epilepsy and seizure

• epilepsy is a group of disease which exhibit unprovoked seizures

• seizure is transient occurence of signs ± sx due to abnormal excessive or synchronius neuronal activity in brain

Seizure classification and example

• focal onset : tonic, myoclonuc, sensory emotional

• generalised onset : tonic (stretch) - clonic (rythmic jerking, typical

• unknown onset

mb all have motor and nonmotor

Stages of seizure

1. Prodromal : Days to hours before, anxiety, irritability, mood changes

2. Early ictal : auras like dejavu fear (amygdala activated)

3. ictal : aura to seizure stage

4. post ictal : recovery

What form of epilepsy most common in adults + risk factors

temporal lobe epilepsy

brain injuries

Dravet syndrome

• seizures develop in 1st year of lofe

• febrile seizures, usually heat induced

• denovo variants causing scn1a defective containing na+ → inhibitory neurone cant act

CHD 2 encephalopathy

• chd 2 regulates gene expression in brain development

• mutation may lead to hyperexcitable brain

How inflammation cause epilepsy

• Disrupted gene expression from injury, stroke, infection etc

• microglial dysfunction cause alteration in synaptic structure

• Astrocyte lose ability to control, causing dysregulated synaptic reorganisation

• glutamate and gaba processing also dysregulated (more glutamate receptor while gaba a receptors internalised)

Dx of epilepsy

• EEG

• MRI, Blood test (to rule out others)

• Hx, genetic testing

Note high rate of misdiagnosis (20%)

GABA Potentiating drugs eg and moa

• benzodiazepines (diazepam, acute) , barbiturates

• Positive allosteric modulator for GAVAa receptor

• chloride ion channels open more → cl influx → hyperpolarisation

Gaba transmission targeting drugs

• Vigabatrin (1st line tx for infants): inhibits GABA- T causing less GABA metabolism

• Tiagabine : Blocks GATs causing less GABA reuptake → more GABA in synaptic cleft

Gaba transmission targeting drugs

• Vigabatrin (1st line tx for infants): inhibits GABA- T causing less GABA metabolism

• Tiagabine : Blocks GATs causing less GABA reuptake → more GABA in synaptic cleft

Ca signalling target drugs for epilepsy eg and mia

• gabapentin, pregabalin

• block vg ca ion channels → less calcium ion influx at presynaptic terminal → less exocytosis

• Felbamate (nmda, 1st for infantile partial), topiramate (ampa)

• block nmda or ampa at postsynaptic terminal → less glutamate → less excitability

Valporate MAC

M : monocarboxylic adid for tx of epilepsy

A : GABA T inhibitor, VG Na channel blocker, T type calcium channel blocker (histone deacetylase inhibitor)

C : reduce hyperexcitability (+ neurodevelopmental disprder)

Levetiracetam MAC

• focal onset Epilepsy medication

• binds to sv2a on vesicles (mainly with glutamate) prevent exocytosis

• reduce excitation

Epilepsy side effects

• sedation, fatigue

• dizziness, less coordination

• anxiety

• retinal nerve atrophy (vigabatrin)

• nausea

• excitement

other non pharmacological tx for epilepsy

• vagus nerve stimulation

• keto diet

• surgery

• gene replacemnt

• stem cell transplant

Cerebrovascular accidents classification and subclassification

• arterial : subdivided into ischaemia or haemorrhage

• venous : subdivided into ischaemia

What is a stroke

blood flow to brain is interrupted either from blockage or bleeding

defined clinically as :-

1. Acute functional neurological deficit

2. localised within cns w vascular cause

3. lasting more than 24 hours (if death does nit occur)

WHAT IS TIA

Resolutioj of all neurollgical sign and symptoms within 24hrs wo brain infarct on imaging

What happens if ACA + MCA Supply blocked

All 3 of TACS (total anterior circulation stroke) criteria

• unilateral weakness / sensory

• homonymous hemianopia

• higher cerebral dysfunction

What happen if either aca or mca supply knicked PACS

2 of TACS (total anterior circulation stroke) criteria

• unilateral weakness / sensory

• homonymous hemianopia

• higher cerebral dysfunction

What happen if lacunar stroke (deep penetrating branches)

one of :-

• pure motor/sensory stroke

• sensori-motor stroke

• ataxic haemparesis (weakness + poor movement coordinatiom in one side)

Posterior circukation stroke sx

One of :-

• CN palsy and comtra motor/sensory deficit

• bilateral motor/sensory deficit

• ocular motor / sensory deficit

• cerebellar dysfunctiom

• What cause blocked vessel

• embolism: artherosclerosis, AF, Carotid dissection

• Thrombosis.dehydration, atherothrombosis, lipohyalinosis, hypercoaguable disorder

• Vasculitis: autoimmune or infectious

• Fibromuscular dysplasia: abnormal cell growth (string of beads)

Causes of bleeding vessel

• Trauma

• HTN

• Aneurysm

• amyloid

• drugs

What are a to e

Mechanism of neuronal injury

• Neurones have less fuel and experience excitotoxicity

• Inappropriate release of excitatory neurotransmitter (glutamate)

• excessive calcium influx from nmda glutamate receptor

• mitochondrial and ~dna Damage → necrosis and apoptosis

• permanent damage

Cellular reaction of astrocyte to cns injury

• gliosis

• condensation of thick fibre ( rosenthal fibre)

• Glial cells multiply/swell to form scar like structure to protect neurone

Microglia response to cns injury

• proliferation

• nodular aggregates

• neuronophagia

Ischaemic stroke vs haemorrhagic strole infarct gross appearance

• ischaemic : pale, softened, liquefied brain

• haemorrhagic : blood clot (haematoma)

find

What is the distribution of peripheral neuropathy

• stocking glove neuropathy

• affects hands or feet first

Causes of raised icp + eg

• space occupying lesion. haemorrhage, infection, tumour

• cerebral oedema : cytotoxic, interstitial, vasogenic

• Expanded csf : reduced csf resorption, increase csf production

What is vasogenic oedema + imaging

• bbb disruption w increased vascular permeability

• fluid shift from intravascular space to parenchyma, intercellular spaces

• due to inflammation/tumout or generelosed (ischaemia)

• gray-white matter differentiation maintained

what is cytotoxic oedema + imaging

• increased intercellular fluid following neuronal/glial/endothelial injury

• caused by hypoxia or metabolic derangement

• gray-white matter differentiation lost in ct

What is hydrocephalus and types

Hydrocephalus is accumulation if excessive csf in ventricular system

• communicating hydriceohalus

1. obstructed csf :subarachnoid haemorrhage, infection

2. non obstructed : normal pressure hydrocephalus

• non communicating (obstructive)

1. colloid cyst in foramen of monro

2. aqueduct sylvius stenosis

3. compression of fourt ventricle

4. tumours

clinical consequences of raised icp (5)

• early morning headache/cephalgia

• cushings sign (brady, widened pulse pressure, irregular respiration)

• papilloedma

• n&v

• seizures, behaviour changes

What is brain herniation and type

increased icp displaces brain tissue

• subfalcine herniation : involves cingulate gyri

• transtentorial herniation : medial aspect of temporal lobe compress cniii

• tonsillar herniation : cerebellar tonsil compress brainstem → compromise resp/cardiac centre

What happens if there is panda eyes and bruising begind ear

• panda eyes/ raccoon eyes : basilar skull fracture

• bruising behind ear : battle sign due to bruise around mastoid

Intraparenchymal haemorrhage location causes, source, shape on imaging

• brain paremchyma

• htn, avm, trauma

• atrial or venous

• rounded lobes

intraventricular haemorrhage location causes, source, shape on imaging

• in the ventricle

• htn, avm, trauma, tumour

• arterial/ venous

• conforms to ventricular shape

subarachnoid haemorrhage location causes, source, shape on imaging

• between arachnoid and pia mater

• berry aneurysm, rupture, avm , trauma

• mainly arterial

• ‘star sign’

subdural haemorrhage location causes, source, shape on imaging

• between dura and arachnoid

• trauma to bridging veins

• venous source

• crescent shape

extradural haemorrhage location causes, source, shape on imaging

• between dura and skull

• trauma (pterion fracture hit mma)

• arterial mostly

• lentiform shape

Extradural haemorrhage clinical features

• brief period of unconciousness

• then lucid interval of minutes to hours

• as blood accumulates, haematoma compress brain causing worse sx

Subdural haemorrhage clinical features

• subacute w step wise deterioration + bleed

• non accidental injury (sdh _ retunal haemorrhage + encephalopathy)

• more common in older people as bridging veins stretch more

Subarachnoid haemorrhage clinical features

• thunderclap headache

• blood in csf during lumbar puncture (later xanthochromia)

match please

Hydrocephalus ex vacuo

• compensatory enlargement of brain ventricle due to loss of brain tissye

• brain volume shrink

• icp normal, no blockage nor fluid imbalance

Histological evolution of brain infarcts

• acute (6-12 hrs ) : red neurones surround oedema and neutrophils, endothelial and glial cells swell, myelinated fibre disintegrate

• subacute (48-72) : phagocytic cells clean up myelin breakdown

• healed infarct : dense network lf glial fibres + capillary and ct

Axonal loss vs demyelination difference electrophysiologically

• Action potential amplitude reduced but velocity normal for axonal loss and vv

• fibrillations present in axonal loss but absent in demyelination

Axonopathy vs myelinopathy progression

• axonopathy usually with myelinopathy

• myelinopathy +- axonopathy

peripheral innervation and patterns of injury in a muscle

when reinnervation, each axon will be associated with more motor units

one axon will innervate more myofibres

1. Paraproteinaemic polyneuropathy what and manifestations

• nerve damaging disorder due to production of paraproteins/mproteins(MAb) from plasma proteins

• demyelinating or axonopathic

• Manifest as POEMS

1. Polyneuropathy

2. organimegaly

3. endocrinopathy

4. M- Band

5. skin changes

What is gullainnbarre syndrome (4)

• acute inflammatory demyelinating neuropathy

• may spread as ascneding paralysis, cause areflexia, fatal respiratory paralysis

• preced by acute flulike illness

• increased csf protein but inflammatory cells confined to roots

Chronic inflammatory demyleinating neuropathy what

• symmetric, mixed sensorimotor polyneuropathy, >= 2 mths

• T cells, antibodies targetmolecules at schwann cell-azon junction

• complement fixing igg and igm cause recruitement of macrophages

Myasthenia gravis vs LEMS

• MG is when autoantibody bloc ACH receptors at post synaptic

• LEMS is when autoantibody block ach release at presynaptic terminal

• MG worsen when muscle exert while in LEMS, usage w muscle response improved

Genetic neuronal disorder (3)

• SCA : AR mutation in fxn gene cause degeneration in spinal cord, pns, cerebellum

• CMT :PMP22 duplication commonly causing sensorimotor demyelination → deterioration

• LHON : mitochondrial inheritance causing increased ros → apoptosis of retinal ganglion cells

Inflammatory muscle disorders (4)

• dermatomyositis : autoantibodies (anti-m2, anti-jo1) causing inflammation of bv causing perifascular atropphy

• polymyositis : dermatomyositis wo cutaneous features due to cd8+ infiltration

• immune mediated necrotising myopathy : subacute muscle weakness w increased CK assoc w autoantibody agains hmg coa reductase

• inclusion body myositis : progressive muscle weakness in older adults involving myofibres contained rimmed vacuoles (blue)

DMD vs myotonic dystrophy

• dmd early onset while myotonic dystrophy is adult onset

• X linked recessive (dmd) vs mutation in dmpk or cnbp (myotonic dystrophy)

genetic congeintal muscle disorder (-dmd ans MD) (4)

• myotonia congemita ; mutation in clcn1 for skeletal muscle

• channelopathies : hypokalaemic (prolonged) and hyperkalaemia (brief episodic weakness)

• Inborn error of metabolism : mcardles disease involving lack pf g1p

• mitochondrial disorder

what are the peripheral nerve sheath tumours (3)

• schwannoma : benign, encapsulated w either celullar (antoni A) / hypocelullar (antoni B)

• neurofibroma : benign unecapsulated spindle cell tumours

• MPNST : malignant sarcoma w aggresive behaviours

PNS muscle tumours (3)

• Rhabdomysarcoma » rhabdomyoma : mesenchymal tumours

• leiomyomas (fibroids) » leiomyosarcomas : mesenchymal tumours usually in uterus

Global standards in diagnosing tumours (3)

• WHO classification of tumour

• iccr (RCpath, RCPA, CAP)

• TNM staging ( by uicc, ajcc)

Gliomas and astricyte grading system (4)

• astrocyte, oligodendroglioma, ependymoma

• pillcytic astrocytoma = grade 1

• grade 2-4 are known as infiltrating astrocytoma

• glioblastoma is grade 4 astrocytoma wo idh mutation

clinical features of gliomas

• pilocytic astrocytoma l infratentorial mass, may exhibit rosenthal fibres

• infiltrating astrocytoma : well differentiated → anaplastic + mitosis →microvascular proliferation ± necrosis + idh1/idh2 mutant

• glioblastoma : diffuse infiltration, malignant

non astrocytoma gliomas (2)

• oligodendroglioma : grade 2 or 3, idh mutant mostly in frontal lobe, fried egg appearance

• ependymoma : grade 2 or 3 in post fossa/spinal canal, perivascular pseudo-rosette

• both have microvascular proliferation, necrosis and brisk mitosis (eho grade 3 )

meningioma(3)

• derived from meningothelial cells of arachnoid (who 1-3)

• 15 subtypes : most common meningithelial, fibrous and transitional

• grading based on atypia, mitotic figures and invasion + tert promoter region

Vestibular schwannoma (acoustic neuroma) (4)

• who grade 1

• sx : tinnitus, unilateral hearing loss, vertigo, disequilibrium

• assoc w NF2 (inactivating mutatiin of gene)

• histologically, cells kine up to form nuclear palisades

Primary diffuse large b cell lymphoma of cns

• solitary lesions, affectingcerebral hemispheres, thalamus and basal ganglia usually

• dx : aurora borealis sign on fundoscopy, angiocengric cuffs of neoplastic b cells (cd20+, cd19+)

• assoc w myd88 l265p mutation

cns metastatic tumours

• haematogenous spread

• to brain/spinal cord parenchyma : lung cancer, breast cancer in adults + leukaemias and lymphomas on childrem

• to meninges : leptomeninges, metastasis

neural tube defects (2)

• anencephaly : absence of brain and cavarium

• spina bifida: occulta (small gap in vertebrae), meningocoele (outpouching wo cns) or myelomeningocoele (+ cns extension)

chiari malformation types (2)

downward displacement of cerebellum through enlarged foramen magnum

• chiari type i : low lying cerebellar tonsil

• chiari type ii : arnold chiari, mishapen midline cerebellum w downward extension of vermis

Entamoeba histolytica pathogenesis

• exist in cyst and trophozite forms

• ingestion of cyst

• cyst in small intestine form trophozoites

• trophozoites invade and penetrate colonic mucosa

• tissue destruction → increased intestinal secretion

• ascends to portal venous system to cause liver abcess

Amoebic dysentry sx and dx

• diarrhoea (usually bloody)

• abdominal pain. weightloss

• dx by stool microscopy (3 samples from seperate days) or antigen

nb serology does not distinguish past and present infection

Amoebic liver acess epi sx dx tx

• in returning travellers

• ruq pain w fever, sometimes diarrhoea and hepatosplenomegaly

• dx by imaging on right lobe, serology or aspirate ‘anchovy paste’

• oral metronidazole (+ paromycin for intraluminak cyst)

Dementia definition

• acquired persistent loss of intellectual function

• with compromise in memory

• and at least2 other cognituve domaina such as language, visuspatial skills or executive function

Dementia beside classification and examples

• dementia w other medical disease : HIV, immune, paraneoplastic

• dementia w other neurological disease : HD,MS,STROKES (always;pften present w clonical signs)

• dementia in isolation : alzheimers, fronto-temporal

Alzheimer Amyloid cascade deposition theory

• APP gene codes for APP protein

• if cut by b secretase then gamma secretase then build up of Amyloid- beta 42protein

• Ab oligomerise then make plaques in brain

• sx depends on deposition

• ultimateky cause neurodegenration

Alzheimers tau theory

• in concussion, release of ca2+

• activate calpain → activate cdk5

• hyperphosphorylation of tau

• tau detavhed from microtubules and form clumos called neurofibrillary tangles

Fromti-Temporal dementia

Affects :-

• Language : apahasia

• Behaviou : socially inappropriate

• motor : mnd, parkimsons

Tau related, sx depends on place

Huntington disease pathophysiology

• CAG repeats of huntingtin gene (anticipatiin)

• dominang toxic gain of function

• increase cag repeats → misfolded confirmation

• at the end, produce nig insiluble aggregates

• elicits neutotoxicitu → caudate atrophy

MND factors

• genetic : C9orf72 (RAN-ATG translation aggregates cause neurotoxic)

• toxic : expsome, occupational hazards

• Metabolic : Oxidative stress, atp depletion

Parkinsons disease motor vs non motor

Motor

• Resting tremor : coarse, asymmetric

• Gait Impairment : shuffking

• Bradykinesia : flexed oosture

Non motor

• D : Depression

• A : Anxiety

• S : Sleep Rem disorder

• H : hallucination

Parkinson pathophysiology + tx

• a- synuclein metabloism and aggregatiin

• make fibril which can become lewy bodies (wo lewy bodies called Multiple system atrophy)

• Spread tp different places of brain according to stages

• give dopamkne (L DOPA)