Neuropathology Flashcards
Head injury: types, outcomes
Penetrating injury
Crush injury
Deceleration injury (most common)
==> damaged depends on the energy of impact (mass and velocity)
Possible outcomes:
- skull fractures
- parenchymal injury
- vascular injury
Skull fractures: types, signs
Linear fracture = bursting fracture (crack skull)
Depressed fracture = skull depressed inward into the parenchyma, usually comminuted (several pieces)
Fracture of skull base
- often indicates severe head injury
- difficult to visualise in plain Xray –> use CT
- signs (tearing of dura resulting in CSF leakage)
- -> anterior cranial fossa fracture = CSF rhinorrhoea, raccoon eye (periorbital ecchymosis)
- -> petrous temporal bone fracture = CSF otorrhoea, battle sign (mastoid ecchymosis)
Note: fatal head injuries don’t always have fracture
Primary brain injuries: parenchymal injury - types, definitions, appearance of contusion and diffuse axonal injury, outcomes
Concussion
- clinical syndrome of altered consciousness secondary to head injury
- complete neurological recovery but retrograde amnesia
Direct parenchymal injury (grey matter)
- laceration: penetration of object and tearing of tissue
- contusion: bruise due to blunt trauma (mostly at frontal and temporal lobes, base of brain –> haemorrhagic lesions on top of gyri, disrupt pia arachnoid)
- coup injury: contusion at point of contact
- countercoup injury: contusion on brain surface diametrically opposite to it e.g. fall backwards –> frontal/temporal lobe contusion
Diffuse axonal injury (white matter)
- commonly rotational type injury causing tearing of axons
- -> axonal swelling (histo: axonal balls)
- -> focal haemorrhage e.g. corpus callosum, cerebellar peduncles, dorsal brainstem
- major cause of prolonged comatose state
Primary brain injuries: traumatic vascular injury (types, origin of bleed, clinical features, severity, causes)
Haematoma = collection of blood
MUST BE EXCLUDED!! (by CT imaging)
Epidural haematoma
- origin: middle meningeal artery
- features: LUCID INTERVAL (tough dura withstands pressure initially) –> subsequent rapid neurological deterioration (coma, rapid collection of blood – emergency!)
- convex shape in CT
- commonly due to fracture temporal bone
Subdural haematoma
- origin: bridging vein between dura and arachnoid membrane/superior sagittal sinus
- MC SOL in acute head injury!
- features: acute = life threatening or chronic = may cause dementia
- causes: minor HI especially in elderly with brain atrophy, rapid change in head velocity (differential movement of brain and skull)
- crescent shape on CT (crosses suture lines)
Cerebral haematoma
- origin: intracerebral vessels; contusion injury
- contusion very big that it reaches cerebral hemispheres
Primary brain injuries: spinal cord injury - cause, signs, management
Associated with transient or permanent displacement of the vertebral column e.g. hyperflexion, hyperextension
Signs:
- conscious
- respiratory compromise if above C4
- paraplegia if involve T vertebrae or below
- urinary retention if S2-S4
Management
- vertebra stabilisation
- chronic care
Secondary brain injuries (much more important and serious!!)
Sequelae of primary injury leading to further damage and neurological deterioration
Cerebral oedema
Hydrocephalus
Raised intracranial pressure and herniation
Secondary brain injuries: cerebral oedema - definition, pathways of formation, pathology (4), consequences/sequence of events
Accumulation of excess fluid within brain parenchyma
Pathways of oedema formation:
- vasogenic oedema – BBB disruption and increased vascular permeability = increase ECF
- cytotoxic oedema – generalised hypoxic and ischaemic insult = increase ICF
Pathology of generalised oedema
- flattened gyri
- narrowed intervening sulci (almost absent)
- compressed ventricular cavities
- herniation
Consequences:
- intracranial haematoma –> mass effect –> increase ICP
==> decrease CPP (CPP = MAP - ICP) –> decrease CBF –> cerebral ischaemia –> further oedema and raised ICP
==> brain shift –> brain herniation –> brainstem compression
Secondary brain injuries: Hydrocephalus
Accumulation of excessive CSF within ventricular system
- communicating = ventricular system in communication with subarachnoid space –> entire ventricular system enlarged
- non-communication/obstructive = ventricular system obstructed –> enlarge certain ventricles
Secondary brain injuries: raised ICP and herniation - signs of raised ICP, types of herniation and their effects
Signs of raised ICP
- papilledema (optic disc swelling)
- headache, projecting vomiting without nausea
- sinus bradycardia, hypertension (widened pulse pressure), irregular breathing
- herniation
Herniation = displacement of brain tissue past rigid dural folds or openings
- **Uncal/transtentorial herniation
- uncus (medial temporal lobe) through tentorium cerebelli (into brainstem)
- features: TRIAD –> fixed pupil dilation (CNIII parasympathetic supply lost), hemiplegia (cerebral peduncle), coma (midbrain RF and PCA)
Tonsillar hernation
- cerebellar tonsils through foramen magnum (into upper cervical canal and medulla)
- features: respiratory arrest and BP instability (medulla) –> death
Central herniation
- downward pressure centrally
- features: LR palsy (CNVI traction), bilateral uncal herniation
Subfalcine hernation
- cingulate gyrus through falx cerebri
- features: compression of ACA and its branches
Unchecked supratentorial pressure leads to downward displacement of brainstem and cerebellum –> stretch perforating branches of posterior circulation in circle of willis = brainstem haemorrhage = death
Implications of Head injury for clinical management: GCS, ICP, swelling, hypoxia and mass lesion
Glasgow coma scale (GCS)
- neurological function most important!!
- assessment of conscious level in response to defined stimuli
- eye response (max 4), verbal response (max 5), motor response (max 6)
- 15 = best response; <8 = comatose; <3 totally unresponsive
- monitoring and prognostic implication (>14 = 0.4% mortality; 9-13 = 4%; <8 = 45%)
Close monitoring of raised ICP (to AVOID HERNIATION AND COMA)
- intraventricular ICP monitoring
- external ventricular drainage
- emergency Burr hole
- CPP = MAP - ICP (aim ICP <20 mmHg and CPP >60 mmHg)
Reduce cerebral swelling e.g. mannitol, furosemide
Evacuate mass lesion (CT scan to screen)
Prevent hypoxia/hypercapnia (vicious cycle with oedema)
CNS tumours: epidemiology, clinical presentations, grading
Children
- most common solid cancer in children (overall 2nd after leukaemia)
- medulloblastoma is most common type
Adults
- most common type (60%) = glioblastoma multiforme
Clinical presentations
- headache (60%), seizure (>30%)
- ssx of raised ICP – usual cause of death
- focal neurological deficits
- malignant tumours usually don’t metastasise outside the brain (except medulloblastoma)
Grading
- WHO (low grade: I, II; high grade III, IV)
Glioma: nature, types
Except pilocytic astrocytoma, all other gliomas:
- are potentially malignant
- transform from low grade to high grade lesion within years
Astrocytoma
- infiltrating astrocytoma: diffuse –> anaplastic –> glioblastoma multiforme
- pilocytic astrocytoma
Oligodendroglioma (rare)
Ependymoma (rare)
Parenchymal tumours: types (4), associated effects
Primary CNS lymphoma
- 80-90% B cell origin
- without co-existing systemic lymphoma
- a/w HIV and EBV
Vestibular schwannoma (acoustic neuroma)
- benign tumour of CN VIII at cerebellopontine angle
- deafness
Pituitary adenoma
- most common is non-functioning (then PRL/GH)
- mass effect, hypopituitarism, visual effects, headaches
Arteriovenous malformation
- may cause cerebral haemorrhage or SAH
Metastatic tumours: 2 types, common primaries
Cerebral metastasis
- lung most common, breast (long latent period), colorectal, thyroid, melanoma
- good survival with chemo
Meningeal metastasis
- lymphoma, leukaemia
- always check CSF during treatment!
Astrocytoma: origin, for each type (grade, nature, age group, common sites, pathology features, prognosis)
Origin: astrocytes
Diffuse astrocytoma
- grade II
- malignant, in adults
- pathology: local hypertrophy, DIFFUSE INFILTRATION with poorly defined margins (incurable by surgery and high recurrence)
- **Glioblastoma multiforme
- grade IV
- malignant, in adults (MC primary brain cancer)
- common site: corpus callosum (butterfly lesion)
- pathology: NECROSIS with fibrillary process, ENDOTHELIAL PROLIFERATION of tumour capillaries with poorly formed BBB (contrast enhancement on imaging)
Prognosis of infiltrating astrocytomas:
- 5-7 yrs with treatment (diffuse type)
- may progress to anaplastic type (grade III, 2-3 yrs) and GBM (12-18 mths)
Pilocytic astrocytoma
- grade I
- benign, in children
- common site: cerebellum, 3rd ventricle, cerebrum
- pathology: well circumscribed cystic lesion with enhancing MURAL NODULE; bipolar spindle cells and bluish material
- prognosis: doesn’t progress
Other gliomas: oligodendroglioma and ependymoma (origin, nature, age group, common sites, pathology features, prognosis)
Oligodendroglioma
- origin: oligodendrocytes
- benign, adults
- common site: cerebrum
- pathology: CALCIFICATIONS seen on CT, CLEAR VACUOLATED CELLS
- prognosis: transform to anaplastic oligodendrogliomain 7-10 yrs (slow growing, better prognosis)
Ependymoma
- origin: ependymal cells (line ventricles)
- benign, children
- common sites: 4th ventricle, spinal cord (MC tumour of spinal cord parenchyma)
- pathology: perivascular pseudorosettes
- prognosis: transform to anaplastic ependymoma in 5-7 yrs; treatment difficult due to poor chemoRT response
***Medulloblastoma: origin, nature, age group, common sites, pathology features, prognosis
Origin: primitive cells
Malignant, most common solid tumour in children
Common site: vermis (cerebellum) – protrude into 4th ventricle (infiltrate brainstem)
Pathology: ROSETTES, small round blue cell tumour
Prognosis: METASTASIS possible to CSF, bone etc; 60-80% survival with treatment
**Meningioma: origin, nature, age group, common sites, pathology features, prognosis
Origin: arachnoid cells
Benign (grade I), adults
Common sites: EXTRA-CEREBRAL e.g. brain surface, superior sagittal sinus, spinal cord, skull base
Pathology: attached to dura mater, MENINGOTHELIAL WHORLS (nuclei wrap around themselves), Psammoma bodies
Prognosis: 10-15% recurrence
CNS germinoma: origin, nature, age group, common sites, pathology features, prognosis
Origin: germ cell (MC GCT of brain)
Malignant, children
Common sites: midline e.g. pineal gland
Pathology: identical to dysgerminoma of ovary and seminoma of testis
Prognosis: may spread to CSF; 90% cure with RT
Cerebrovascular disease definition, classification of infarcts
Injury to brain as a consequence of altered blood flow –> cerebral infarction or cerebral haemorrhage
Stroke = clinical term for acute onset of neurological deficits resulting from haemorrhage or obstructive vascular lesions
Classification of infarcts
- ischaemic necrosis of the brain (example of liquefactive necrosis)
- large vessel disease vs small vessel disease
- thrombosis vs embolism
- focal ischaemia vs global ischaemia
Cerebral infarct - Large vessel disease: distribution, pathogenesis, presentations
Distribution
- *embolism: MCA (MC; most of cerebral surfaces), ACA (medial surface of cerebral hemispheres), PCA (inferior surface of hemispheres and posterior hemisphere)
- thrombosis: MC outside brain at carotid bifurcation (cartoid bruit), vertebrobasilar artery; less common inside brain at internal carotid, MCA
Pathogenesis
- atherosclerosis (thrombosis and embolism), other causes of embolism e.g. IE/valvular disease (vegetation), AF, patent foramen ovale, drug abuse (heroin, cocaine)
Presentations: territorial infarcts
- -> MCA: contralateral hemiparesis, sensory loss in face and upper extremity, expressive aphasia, visual field defects, head and eyes deviate to side of lesion
- -> ACA: contralateral hemiparesis, sensory loss in lower extremity
- -> vertebrobasilar system: vertigo, ataxia, ipsilateral sensory loss in face, contralateral hemiparesis and sensory loss in trunk and limbs
Cerebral infarct - Small vessel disease: distribution, pathogenesis, presentations
Most common ischaemic stroke
Distribution
- mostly thrombotic
- perforators of major branches in Circle of Willis e.g. lenticulostriate arteries (from MCA at base of brain)
- lacunar infarcts - <15 mm at deep grey matter e.g. thalamus, IC, caudate nucleus, pons
Pathogenesis
- arteriosclerosis (HT)
Presentations (lacunar infarct) - asymptomatic - purely sensory loss (thalamus) - purely motor loss (posterior limb of IC - also sensory?) - mixed if larger - little alteration of consciousness - normal CT or MRI (<2cm hypodensity) - transient ischaemic attack (recovery <24 hrs) - may lead to multi-infarct dementia (cerebral haemorrhage)
Cerebral infarct - classification by cause
Focal ischaemia due to thrombosis or embolism (large and small vessel disease)
Global ischaemia/ hypoxia due to circulatory collapse, epilepsy, severe hypoglycaemia –> sudden death
- hippocampus most vulnerable (esp CA1; loss of neurons seen histologically)
Cerebral infarct - pathology: <48hrs, 48 hrs-days, 10 days-3wks (macroscopic and microsopic)
<48 hrs
- Macroscopic
- -> little change in first 6 hrs – nothing on CT/MRI but still important to image and rule out haemorrhage
- -> acute SWELLING (loss of grey-white differentiation) and herniation
- -> thrombotic = PALE infarct (no reperfusion)
- -> embolic = haemorrhagic infarct (with reperfusion at later stage)
- Microscopic
- -> RED NEURONS: acute injury and subsequent apoptosis causing pyknosis and karyolysis –> EOSINOPHILIC
- -> acute inflammation: NEUTROPHILS, oedema
48hrs-3 wks
- Microscopic: REACTIVE GLIOSIS
–> microglial cells (MACROPHAGES) engulf/lyse myelin and blood if present
–> astrocytes (REACTIVE GLIAL CELLS) with cellular processes form glial fibres at edge of infarction, taking up the role of fibroblasts
==> liquefaction and calcification of old infarct
10 days-3wks
- Macroscopic: gelatinous and friable tissue (days), LIQUEFACTIVE NECROSIS (wks)
- -> loss of tissue and fluid-filled cavity; wedge-shaped
- -> full pattern after a few months
- -> hypodense SOL on CT
Intracerebral haemorrhage: definition, causes and related pathology, common sites
Definition = haemorrhage within the brain due to rupture of a small intra-parenchymal vessel
–> HYPERDENSE SOL on CT
- *Causes
- HT
- -> MC factor a/w DEEP BRAIN parenchymal haemorrhage (basal ganglia, thalamus)
- -> pathology: hyaline arteriosclerosis, Charcot-Bouchard aneurysms (microaneurysmal outpouchings)
- Cerebral amyloid angiopathy
- -> MC factor a/w LOBAR haemorrhage
- -> commonly involving superficial cortical vessels of occipital and parietal lobes
- -> a/w Alzheimer’s disease
- -> pathology: brittle vessels with palely eosinophilic material impregnated on vessel wall
- Haematological: thrombocytopenia, leukaemia (too many WBC makes vessels bleed easily)
- Tumours: glioma (high grade), metastasis (melanoma, RCC) – also lobar haemorrhage
- Vascular: AVM
- “Congenital”: ruptured berry aneurysm
- Drug: thrombolytics
Common sites:
- BASAL GANGLIA (most common)
- thalamus
- cerebellum
- lobes of brain, brainstem
Subarachnoid haemorrhage: causes, pathogenesis and site of MC cause, complications, clinical presentations
Bleeding into subarachnoid space (basal cisterns)
Causes
- ANEURYSM
- AV malformation
- -> BERRY aneurysm most common: due to HT; structural defects of media and elastica develop over time; connective tissue disease e.g. Marfan’s
- -> 90% found in arterial branch points of anterior circulation in Circle of Willis - AComm branch MC
(note: if aneurysm is very large, it can bury into cerebral parenchyma and burst –> cerebral haemorrhage instead of SAH) - -> Fusiform atherosclerotic aneurysm (basilar artery)
- -> Infective mycotic aneurysm (SBE)
Complications:
- Early phase
= vasospasm cause irritation to basal cisterns –> additional ischaemic injury (1/3 mortality)
= cardiac arrhythmia due to brainstem hypoxia
- Healing phase
= rebleeding
= hydrocephalus (organisation of haematoma occluded CSF outflow)
Clinical presentations:
- Sudden onset of severe occipital headache (“worst headache ever”)
- nuchal rigidity due to irritation of meningeal membranes
Dementia - definition, what is MCI
Group of diseases characterised by DECLINE IN COGNITION involving one more cognitive domains. causing ADL impairment
Memory –> early presentation of Alzheimer’s disease
Language, Behavioural –> early presentation of Fronto-temporal dementia
Behavioural, Executive function –> early presentation in vascular dementia
Visual spatial
Late presentations: depression, hallucination, delusion, agitation, withdrawal
Mild cognitive impairment (MCI) = between cognitive changes of aging and early dementia – ADL not substantially interfered
Dementia - primary and secondary causes
Primary causes:
- **Common
- Alzheimer’s disease (70%)
- Vascular dementia (20%)
- Parkinson’s disease (small proportion)
- Fronto-temporal dementia
Less common
- MS, ALS, Creutzfeldt-Jakob disease, Parkinson-plus syndrome
Secondary causes:
- CNS - chronic subdural haematoma, brain tumours, normal pressure hydrocephalus
- Iatrogenic - drugs, alcoholism, Vit B12 deficiency
- Hypothyroidism
- Psychiatric disorders
- HIV infection
Alzheimer’s disease - epidemiology and risk factors
Most common cause of dementia
Risk factors:
- Sporadic type
- -> age (>80)
- -> apoE allele (epsilon 4; higher risk than 3 or 2)
- Familial early onset type(<1% cases; AD inheritance, a/w Down’s syndrome)
- -> amyloid precursor protein (APP) mutations on chr 21
- -> presenilin (PS1 & PS2) mutations on chr 14 and 1
Alzheimer’s disease - pathology: gross morphology (2), histology (3) and pathogenesis for each abnormality, staining
Gross morphology (non-specific)
- cerebral ATROPHY: narrowed gyri, widened sulci, decreased brain weight
- VENTRICULAR DILATION secondary to decrease in brain volume
Histology
- NEURITIC PLAQUES and NEUROFIBRILLARY TANGLES
- -> normally seen in the brains of elderly but exaggerated in AD
- -> HIPPOCAMPUS most commonly affected
Neuritic plaque
- EXTRACELLULAR amyloid core surrounded by dystrophic neurites (dilated, tortuous)
- pathogenesis –> abnormal cleavage of APP at cell membrane = POLYMERISATION OF A-BETA PEPTIDES (aggreggation)
- staining: silver stain, congo red stain, Ab against A-beta
Neurofibrillary tangles
- INTRACELLULAR tau-containing irregular twisted filaments in cytoplasm
- pathogenesis: HYPERPHOSPHORYLATION OF TAU protein (alters cytoskeleton microtubules in neuron = cells die)
- staining: silver stain, Ab against tau
CEREBRAL AMYLOID ANGIOPATHY
- amyloid (almost identical to A-beta in neuritic plaques) present in cerebral vessels
- weakening of vessels increases risk of haemorrhage
- staining: Ab against A-beta, congo red
Alzheimer’s disease - clinical presentations and treatment
Clinical:
- early: loss of smell, NO focal neurological deficits
- late: changes in behaviour, judgement, language
Treatment:
- cholinesterase inhibitors improve memory and reduce hallucination; S/E bradycardia e.g. donepezil
- NMDA inhibitor for moderate to severe diseases e.g. memantine
Vascular dementia: associated syndromes, clinical presentation
Group of syndromes including
- multi-infarct dementia i.e. repeated strokes (especially if sub temporal gyrus affected) – stroke increases risk of mental impairment by 4-5x
- subcortical infarcts (damage white matter)
- Binswanger disease: diffuse white matter disease (due to chronic arteriosclerosis and poor perfusion of small vessels)
- -> leukoaraiosis: demyelination of white matter particularly in periventricular region (shrinking and scarring seen as radiolucency on imaging)
Clinical presentation
- STEPWISE DECLINE in cognition in multi-infarct dementia (symptoms stay same for a while then suddenly decline)
Parkinson’s disease: pathogenesis, pathology, prevalence of dementia, cause of dementia and core features, clinical presentation of Parkinson’s
Not primary related to dementia!!
Hypokinetic movement disorder due to degeneration of dopaminergic neurons in substantia nigra (depigementation)
Pathology: LEWY BODY (alpha-synuclein inclusion in neurons; lewy neurites), TAU PROTEIN
Dementia in 10-15% patients due to:
- Alzheimer’s disease
- Dementia with Lewy body (DLB) –> Lewy body spreading from brainstem to cerebral cortex
==> core features: PARKINSONIAN features, fluctuating levels of ALERTNESS, visual HALLUCINATIONS
Clinical presentations
- cogwheel rigidity
- bradykinesia: masked face
- resting tremor (pill rolling)
- postural instability, stooped posture
- gait: difficulty in initiating first step, shuffling gait
Fronto-temporal dementia: definition, age affected, how to distinguish from AD, pathogenesis and associations
50-70 yrs old
Heterogenous set of disorders a/w focal degeneration of frontal and/or temporal lobes
Distinguished from AD:
- alterations in personality, behaviour and language PRECEDE MEMORY LOSS
- no focal neurological deficits (same as AD)
Pathogenesis and associations:
- C9ORF72 (chr9) mutation – accumulation of TDP-43; a/w ALS
- MAPT (ch17) mutation – accumulation of TAU (PICK BODIES); a/w Parkinsonism
Prion disease: nature, pathogenesis, examples of disease, causes, typical morphology, clinical presentation
Rare
Prions = infectious proteins without nucleic acids
– “infectious”: protease-resistant misfolded PrP promotes conversion of normal PrP to protease-resistant PrP
– can’t be killed with standard sterilisation techniques
– can stain with Ab (IHC), western blot
Transmissible spongiform encephalopathy/ Creutzfeldt-Jakob disease
- early old age
- TRANSMISSION through electrodes, dura mater graft (direct inoculation to brain), ingestion from infected cattle (bovine spongiform encephalopathy/ mad cow disease)
- SPONGIFORM – “bubble and holes” change in cerebral cortex and deep gray matter structures (microscopic vacuoles
- ENCEPHALOPATHY – subacute dementia, myoclonic jerks, characteristic EEG changes with periodic spikes, death <1 yr
Screening tests for dementia
MMSE and AMT for late stage dementia
HKMoCA for early stage dementia
Modified Barthel index for assessing ADL impairment
Diseases of skeletal muscles - common causes, characteristics
Main causes in adults
- usually inflammatory (part of autoimmunity)
- neurogenic diseases
- dystrophy
- metabolic disease
Characteristics
- no obvious neurological causes
- symmetrical and diffuse
- no associated sensory loss (presence of sensory loss = peripheral neuropathy)
- adult vs paediatric: early onset
- patterns of muscle weakness
- proximal weaker than distal
- face-sparing e.g. LGMD, DMD/BMD
- face involvement e.g. FSHD
Diseases of skeletal muscles - investigations
Inflammatory/auto-immune markers: ESR, antibodies
CK-MM isoenzyme: specific to skeletal muscle
Electromyography (EMG)
Muscle biopsy: definitive diagnosis for difficult cases; examined in transverse section (need snap freezing)
DNA studies
Inflammatory Myopathy: causes, age group, pathology, clinical presentation, associations, investigations, treatment
Polymyositis, dermatomyositis, necrotising autoimmune myopathy
Acquired, most common in adult/middle age
Pathology: large number of inflammatory cells migrating and damaging muscles
Clinical presentation: proximal muscle weakness and tenderness (symmetrical)
Associations:
- systemic autoimmune disease
- STATINS
- HIV
- paraneoplastic disease (especially dermatomyositis)
Investigations
- high ESR, CK
- **EMG: polyphasic units
- autoimmune Ab
Treatment: steroids, cancer surveillance (especially dermatomyositis)
Degenerative myopathy: classical example, pathogenesis, clinical presentations, pathology, treatment
Amyotrophic lateral sclerosis/ motor neuron disease
- insidious onset
- neuronal loss at ALL LEVELS OF MOTOR SYSTEM (cortex, brainstem and anterior horn cells)
- -> usually LMN first then UMN
Clinical presentations:
- LMN signs
- -> skeletal muscle weakness (asymmetric) and atrophy (extensors more affected)
- -> bulbar palsy: dysphagia, dysphasia
- -> respiratory muscle paralysis: death in 3-5 yrs
- UMN signs
- -> spasticity, Babinski sign
- Extraocular muscles, bowel/bladder muscles and sensory functions spared (parasympathetic system preserved)
- some familial cases associated with fronto-temporal dementia (TDF-43 accumulation) but otherwise cognition is normal
Pathology:
- no inflammation, reduction in number of anterior horn cells neurons
Treatment:
- Riluzole (glutamate release inhibitor)
Dystrophies
Primary muscle diseases
Duchenne/Becker muscular dystrophy
Limb-girdle muscular dystrophy
Facioscapulohumeral dystrophy
Duchenne/ Becker muscular dystrophy: pathogenesis and genetic aberration, diagnosis, clinical presentations, pathology, prognosis
Pathogenesis:
- Deletions (MC) or duplications of Dystrophin gene (Xp21 - X-linked disease)
- dystrophin acts as anchor for actin to adhere to plasma membrane allowing efficient transmission of signals
Duchenne = out-of-frame mutations ==> total truncation of protein Becker = in-frame mutations ==> milder disease
Diagnosis:
- muscle biopsy: dystrophin IMMUNOSTAINING (nothing on DMD, little on BMD)
- DNA studies: western blot
- other labs: CK very high at birth and decreases as muscles degenerate; also higher in female carriers
Clinical presentations: (male)
- symptoms occur before 5yrs old (delayed motor milestones e.g. difficulty in running/rising)
- weakness and wasting of PELVIC muscles: GOWER’s SIGN, waddling gait, toe-walking, lumbar lordosis
- CALF pseudohypertrophy due to FIBROSIS AND INFILTRATION OF MUSCLE TISSUE BY FATTY TISSUE (thigh muscles not strong enough)
- CARDIOMYOPATHY: heart failure, arrhythmia
- intellectual impairment (30%)
Pathology: increase connective tissue replacing myofibres
Prognosis: DMD death by 20s, BMD by 40-50s
Limb-girdle muscular dystrophy (LGDM) - inheritance, pattern of weakness, age group affected
AD or AR
Facial sparing, involving limb girdle (scapula/arms + pelvic/thighs)
Early or adult onset
Facioscapulohumeral dystrophy (FSHD): genetics, muscle involvement
> 1 form of disease
- one of which is AD deletion of repeat DNA sequences at chromosome 4q
Muscle involvement
- facial muscles
- upper and distal limbs: scapular winging
- pelvic girdles preserved
Floppy infant syndrome: definition, SMA (genetics, types), mitchondrial myopathy (genetics, a/w, examples, pathology), metabolic myopathy (causes)
Generalised hypotonia in newborn
Spinal muscular atrophy (SMA)
- AR deletions of SMN1 gene –> atrophic fibre GROUPS (failed development)
- type I (infantile) most common: floppy baby syndrome, CANNOT SIT UNSUPPORTED (Werdnig-Hoffman disease)
- type II (intermediate) and type III (juvenile)
Mitochondrial myopathy
- maternally transmitted diseases, gene deletions most common
- usually a/w brain degeneration
- examples: MELAS, progressive external ophthalmoplegia
- pathology: RAGGED RED FIBRES using special stain (at rim of myofibres); EM accumulation under sarcolemma
Metabolic myopathy
- symptomatic only with exercise or fasting
- glycogen storage disease, lipid storage disease (myofibres stained with lipids which can’t be metabolised)
Other causes: congenital muscular dystrophy/myopathies, perinatal asphyxia
