Neurodegenerative Diseases Flashcards
MS, MND
What is amyotrophic lateral sclerosis (ALS)?
It is the most common motor neuron disease, characterised by neurodegenerative loss of both UMN and LMN, H/E sensory neurons are spared.
Prognosis and RF for ALS?
- Most cases are sporadic, but 10% cases are familial.
- RF = >50yrs, male, Fx, smoking, exposure to heavy metals and pesticides
- Prognosis = 3-5y after Sx onset
Clinical features of ALS (4 groups of Sx)
There is NO sensory, autonomic, visual dysfunction!!!!!!!!!!!
(1. ) Limb onset
- LMN = weakness in upper limb (1st Sx seen), muscle wasting, reduced tone, hyporeflexia, fatigue: during exercise, clumsiness, dec manual dexterity
- UMN = Inc tone, spasticity, brisk reflexes, hyperreflexia
(2. ) Bulbar Sx: dysarthria, dysphagia
(3. ) Resp Sx: resp failure is common cause of death
(4. ) Cognitive Sx: frontotemporal dementia
Ix of ALS (3)
Dx = based on clinical presentations h/e Ix can help rule out other diseases
(1. ) EMG + Nerve Conduction Studies
- identify fasciculations
- motor conduction can be normal or reflect denervated muscles.
- Sensory conduction is normal.
(2. ) Genetic Testing: two most commonly identified mutations are C9orf72 and SOD1.
Mx of ALS (3)
There is no tx for halting or reversing the progression of the disease
(1. ) MDT
- Physiotherapists, speech, occupational therapists
- Dieticians: Percutaneous feeding may improve QoL and improve survival
- End-of life planning
(2. ) Glutamate release antagonist, Riluzole
(3. ) Non-invasive ventilation: Used at home to support breathing at night improves survival and QoL
Features of LMN lesions (4)
- Muscle tone reduced (flaccid)
- Muscle wasting
- Fasciculation
- Hyporeflexia
Feature of UMN lesions (4.)
(1. ) Inc muscle tone (spasticity)
(2. ) hypereflexia + brisk
(3. ) Plantar reflex demonstrate toe dorsiflexion (+ve Babinski sign) [indicate CNS damage]
(4. ) Characteristic pattern of limb muscle weakness:
- extensor weaker than flexors in upper limb
- flexors weaker than extensors in lower limb think of babinski sign
List 3 causes of UMN lesions
- Compression of brain or SC by tumour
- Degenerative Spinal disease (spondylosis)
- Neurodegenerative diseases e.g. MND + Multiple sclerosis
Where can LMN lesions occur? (5)
(1. ) lower motor neuron
(2. ) spinal root
(3. ) peripheral nerve
(4. ) NMJ
(5. ) muscle
What is multiple sclerosis?
(1. ) Inflammatory demyelinating disease specific to CNS.
(2. ) This inflammation results in formation of scar tissues on neurons which results in impaired signal transduction
(3. ) Symptoms felt by patients is due to affected sensory and motor neurons
Aetiology and RF of Multiple Sclerosis
(1. ) Cause is unknown
(2. ) Commonest cause of chronic neurological disability in young adults
(3. ) RF: Female, 20-40y, Northern European, EBV
(4. ) Genetics: HLA gene, Fx (15% chance), 30% concordance in twin studies, mutations
(5. ) Environmental: Prevalence is low near the equator (migration studies), correlation with sun exposure and vitamin D
types of multiple sclerosis
- Relapsing/remitting MS (RRMS) [85%]
- Relapses with full or partial recovery - Primary progressive MS (PPMS)
- Disease progression from onset - Secondary progressive MS (SPMS)
- Initially RRMS followed by progression
- Typically no relapses - Relapse/Progress MS
- Progressive disease from onset with acute relapses
Pathophysiology of multiple sclerosis
NOTE: There are 4 classifications for MS pathophysiology, macrophage and ab mediated are the most common.
(1. ) Entry of T-cells across the BBB –> releases cytokines –> initiate destruction of oligodendrocyte-myelin by macrophages
(2. ) Most commonly in periventricular regions of the brain, brainstem, optic nerve, SC. This affects white matter (myelinated SC tracts etc) but can also affect grey matter
(3. ) Gliosis follows after attack leaving ‘shrunken scars’ so demyelination heals poorly, eventually causing axonal loss.
(4. ) Transmission is disrupted and forced to propagate along the axon
(5. ) Remyelinated axons becomes temperature sensitive [worsening of Sx] i.e. hot showers will cause numbness, tingling, ‘Uhthoff’s phenomen’
Clinical features of MS (10.)
Plaque distribution: Cerebral, SC, Optic nerve, Brainstem, Cerebellar WM
NOTE: pt may describe it getting better and going away and then coming back
Visual Sx
(1. ) Unilateral OPTIC NEURITIS
(2. ) Nystagmus
(3. ) Double vision
Sensory Sx
(3. ) Parasthesia + Dysesthesias (abnormal sensation)
(4. ) Trigeminal neuralgia
Motor Sx
(5. ) Weakness or Spasticity or UMN lesions
(6. ) Dysarthria
Sexual/GU Sx
(7. ) Bladder Sx: Urgency, frequency, incontinence
(8. ) Erectile dysfunction
Cognitive Sx
(9.) Memory loss + Intellectual impairment (late stage, frontal lobe affected)
(10.) Sx may worsen with heat
Dx of MS
- Two separate attacks or CNS lesions disseminated in time and space
- Exclusion of conditions giving a similar clinical picture
- Dx requires: Sx, neurological ex, MRI, CSF studies, Evoked potential
Ex and Ix of MS (4)
(1. ) Neurological Ex
- look for abnormalities, changes, weakness in vision, eye movements, hand or leg strength, balance, co-ordination, speech and reflexes.
(2. ) MRI
- Important to rule out other causes
- Characteristic lesions located in: periventricular, juxtacortical, brainstem, cerebellum, SC, optic nerve
- MRI + contrast = active or chronic inflammation
(3. ) LP + CSF
- IgG Oligoclonal banding present in CSF but not in serum indicates CNS inflammation
(4. ) Evoke potentials (EP)
- Stimulation of optic nerve + calculate it’s speed to brain
- Conduction should be quick but in inflammation (i.e. MS) there will be a DELAY and this will be picked up in this test
Mx of MS
(1.) Mx of disability: MDT, physiotherapy, occupation therapy, speech therapist, aid at home
(2. ) Tx of Acute episodes:
(a. ) High dose glucocorticoids: PO, IV methylprednisolone
(b. ) Plasma exchange for short-term severe attacks
- If steroids are CI or ineffective
(3. ) Prevention of relapses
- Disease modifying therapies (DMT): alemtuzumab, natalizumab, beta-interferons, glatiramer
- Do not use in primary or secondary progressive MS
(4. ) Mx of complications
(a. ) Bladder dysfunction: Intermittent catheterisation
(b. ) Erectile dysfunction: sildenafil
(c. ) Spasticity: baclofen, gabapentine, diazepam, botulinum toxin etc
(d. ) Fatigue: amantadine
(e. ) Paroxysmal, acute pain: anticonvulsants e.g. carbamazepine
Name four movement disorders
Essential Tremor
Parkinson’s Disease
Huntington’s disorder
Dystonia
What is Parkinson’s?
(1. ) Age-related disorder
(2. ) Depletion of DA-neurons in substantia nigra
(3. ) Presence of Lewy bodies in sub.nigra, basal ganglia, brainstem, cortex.
(4. ) These increase with disease progression
Aetiology and RF of Parkinson’s
(1. ) Idiopathic
(2. ) Inherited factors: Parkinson’s genes, Susceptibility genes
(3. ) Environmental factors: RF, Toxin induced: manganese dust, carbon disulphide, severe carbon monoxide poisoning
(4. ) Mitochondrial dysfunction
(5. ) Oxidative stress
(6.) RF = Age 60y, Fx, men
Clinical features of Parkinson’s (4 Motor, 8 non-motor)
Motor Sx (1.) Bradykinesia: slowness and absent of movement e.g. problems with doing buttons, smaller writing
(2. ) Rigidity (increased tone) causes stiffness + pain
(3. ) Tremor: unilateral at rest
(4. ) Gait and imbalance: shuffling steps, difficulty turning around and difficulty stopping
Non-motor Sx
(1. ) Hyposmia (reduced sense of smell)
(2. ) Anxiety/depression, psychosis
(3. ) Reduced QoL
(4. ) GU/sexual problems: constipation, sphincter disturbance, erectile failure, loss of libido
(5. ) Fatigue
(6. ) Dysphagia, dysarthria
(7. ) Weight loss
(8. ) Cognitive impairment including dementia
- Cognitions is spared in early disease if is present consider alternative diagnosis such as dementia with Lewy bodies
Three Cardinal Sx of Parkinson’s
Bradykinesia, rigidity, tremor
Ix and Ex of Parkinson’s (4)
O/E
(1. ) Testing for bradykinesia
- Repeated movement e.g. finger tapping 10 times
- perform these big + fast
- PD: dec in rhythm + amplitude over time in hand movement the longer the pt does it
(2. ) Testing rigidity
- Look for resistant to movement (PD: inc tone + ‘lead pipe’ rigidity)
(3. ) Testing for tremor
- Look for rest + postural tremor
(4.) DaTSCAN shows reduced DA activity
Tx and Mx of Parkinsons
Initiate when sx are impacting everyday life, if tremor/PD not bothering pt don’t need to treat or change medication
(1. ) L-Dopa
(2. ) DA agonists
(3. ) COMT/MAO-Bi: Rasagiline, Selegiline
(4. ) Occupational, Speech, physiotherapy
(5. ) Mx of ANS, psychiatric, depression etc
(4) Complications of Parkinson’s Tx
Dyskinesia = involuntary movements
(1. ) Wearing off
(2. ) On-dyskinesias = involuntary, erratic, movements when starting drug
(3. ) Off- dyskinesias = medication is wearing off, painful dystonic movement
(4. ) Freezing = unpredictable loss of mobility
What is L-dopa
(1. ) It is a precursor for Dopamine
(2. ) Most effective, best tolerated and cheapest drug
(3. ) The higher the dose, the greater the risk of SE
(4. ) 3 different preparations may be used:
- ‘Kick-start’ morning dose
- Standard release, day time medication
- Slow-release, night time
What is Dopamine agonists
(1. ) Like DA, it can bind to DA-R on postsynaptic mb
(2. ) Reduces risk of dyskinesia in short-medium term
(3. ) 1st line drug in tx of younger pts <60y
(4. ) SE: tiredness, gambling, hypersexuality etc
What is an Essential tremor and RF?
- Most common cause of movement disorders
- Cause is unknown h/e there is genetic and environmental involvement
- Strong inheritance link!
- RF = increasing age, Fx, toxin exposure
- Complications: change jobs or retire early because of associated disability
Clinical features of Essential Tremor
Bilateral arm tremor
- Rarely at rest usually on movement/performing activities (unlike PD)
- Improves with alcohol (in 15%)
Ex of Essential Tremor
Look for the following:
- Postural/action tremor
- No/little rest tremor
- No inc tone
- No problems with finger movement
- No other neurological signs or deficits
Mx of Essential Tremor (4.)
(1. ) Reassure Pts
- Reassure ET is not associated with any serious underlying condition
(2. ) Propranolol (bblocker) or Primidone [1st line]
- Bblocker CI in asthma, diabetes
- Primdone start at low dose
(3.) Gabapentin, clonazepam [2nd line]
(4. ) Surgical/Referral
- Deep brain Stimulation if Sx are refractory
What is Alzheimer’s Disease
- Most common cause of dementia but not all dementia is due to AD
- Progressive neurodegenerative disorder that causes significant deterioration in mental performance.
- This leads to impairment in normal social and occupational function including memory loss, problem-solving or language.
- It has a gradual onset and is progressive
- Prevalence increases with age
Aetiology and (8) RF of Alzheimer’s Disease
Aetiology
- Exact cause is unknown
- Environmental and genetic risk factors that increase the chance of developing pathological processes
RF:
- Age
- Most cases are sporadic
- Inherited: APP, PSEN1, PSEN2 mutations
- CVD
- Depression or loneliness
- Low education attainment
- Low social engagement and support
- Others: trauma, learning difficulties
- down syndrome
Pathophysiology of Alzheimer’s Disease
(1. ) The two key pathological changes:
(a. ) Senile plaques (SP): deposits of beta-amyloid outside of neurons. NOTE: Aβ aggregates into plaques in brain so this lowers amount in CSF -> dec Aβ CSF conc.
(b. ) Neurofibrillary tangles (NFT): aggregations of hyperphosphorylated tau proteins inside neurons, occurs in areas involved in memory.
(2. ) SP and NFT result in neuronal cell death + memory failure, personality changes and problems with activities of daily living (hallmarks of dementia).
(3. ) NOTE: although these features are characteristic of AD, it is not specific as it can be seen in other neurodegenerative conditions. SP is also seen in normal ageing.
Braak Staging of AD
- It is based on amount of pathological changes (tau and amyloid) and the topographic location within the brain
- Locations: Usually starts in hippocampus -> limbic system/medial temporal lobes -> temporal neocortex -> frontal + parietal + rest of cortex (severe)
Clinical features of AD
Insidious onset + non-specific Sx
(1. ) Cognitive impairment = poor memory, language problems, disorientation etc
(2. ) Behavioural + psychological Sx = agitation, depression, anxiety, sleep disturbance, social + emotional withdrawal
(3. ) Disease-specific features
- Early AD: short-term memory loss + difficulty learning new info.
(4. ) Daily living activities
- Loss of independence
- Early: problems with higher level function (e.g. managing finances, difficulties at work)
- Later: problems with basic personal care and motor function
What is Mild cognitive impairment
Mild cognitive impairment with clinical diagnostic criteria as follows:
- Concern regarding a change in cognition
- Impairment of one or more cognitive domains.
- No functional impairment
- Not having the features of dementia
Mild cognitive impairment helps identify patients at risk of progression to dementia.
- Patients should have regular follow-up and be advised to undertake healthy brain activities (e.g. exercise, socialising).
Examinations and Investigations of dementia
(1. ) Cognitive assessment tools e.g. MMSE, MoCA
- Assess severity based on level of functional inability
(2.) Other tests to consider: ECG, Virology, Syphilis testing, CXR
(3. ) MRI
- Important to exclude other dx (e.g. brain tumour) and can be used to help characterise type of dementia (e.g. small vessel disease in VD).
- Generalised atrophy
Dx of AD
Diagnostic criteria for dementia based on DSM-V.
(1. ) Functional ability: inability to carry out normal functions. Represents a decline from previous functional level
(2. ) Cognitive domains: impairment involving ≥2 cognitive domains
(3. ) Differentials excluded: clinical features cannot be explained by another cause (esp. psychiatric disorders and delirium)
Mx of AD
- Refer to specialist memory clinic when alzheimers is suspected based on symptoms/MMSE scores
- Non pharmacology (CBT, memory aids, dance/music therapy)
- Pharmacological therapy
a. acetylcholinesterase inhibitors = mild/moderate dementia
b. Memantine = moderate-severe - IM lorazepam/haloperidol can be used for agitation/violence/aggression. Avoid IM diazepam
- Consider antidepressants
