Neurodegenerative disorders [12/10/20] Flashcards
Define motor neuron disease
a group of rare neurodegenerative disorders that selectively affect motor neurones
Aetiology of MND
Sporadic [unknown], familial [SOD1, C9ORF72]
Simple pathophysiology of MND
Selective loss of neurones in motor cortex, cranial nerve nuclei and anterior horn cell [grey matter]
Most common aetiology of MND
Sporadic MND
Name the 4 MND types
- Amylotrophic lateral sclerosis
- primary lateral sclerosis
- progressive muscular atrophy
- progressive bulbar palsy
Define ALS
Most common type [50%], typically both LMN and UMN signs. Worse prognosis if bulbar onset.
Define PLS
LMN signs only, affects distal muscles before proximal, carries best prognosis
Define PMA
LMN signs only, affects distal muscles before proximal, carries best prognosis
Define PBP
affects CN IX-XII, palsy of the tongue, muscles of chewing/swallowing and facial muscles due to loss of function of brainstem motor nuclei and carries worst prognosis. Can’t swallow so become malnourished.
Most common progression MND
Peripheral weakness present, then bulbar Sx after. If bulbar Sx early on, then usually worse prognosis.
Sx of MND
weakness, bulbar Sx [dysarthria, dysphagia, sialorrhoea]
Signs of MND
Asymmetric pattern of weakness. [hot bath?]. ALS = UMN and LMN signs.
Ix for MND
no Dx test, neurophysiology/EMG may detect denervation. MRI helps to exclude structural causes. LP helps exclude inflammatory causes.
Mx for MND
Riluzole, NIV, gastronomy.
Prognosis for MND
1 to 5 years, but with broad range
Epidemiology
M > W [3:2]
Dysarthria, dysphagia and siarlorrhoea shta type of Sx?
Bulbar
Define PD
Progressive, neurodegenerative disease that causes characteristic motor Sx of tremor, bradykinesia and postural instability
PP of PD
Degeneration of dopaminergic neurones in the substantiated nigra pars compacta.
Associated with Lewy bodes [tangles of alpha-synuclein and ubiquitin].
Decreased striatal dopamine levels.
Sx of PD
Tremor, slowness of movement, problems with walking [as the disease worsens, non-motor Sx become more common like neuropsychiatric complications]
Signs of PD
4Hz slow resting “pill-rolling” tremor, bradykinesia, rigidity [“cogwheel rigidity”], postural and gait disturbances [festinance, feeling, reduced arm swing], expressionless face [hypomimesis], micrographic. lateral tremor usually worse on one side. slow tremor.
what is bradykinesia?
Slowness of movement
Ix for PD
Usually clinical Dx, MRi and CT [tpyically normal], metabolic activity of dopamine transporters in basal ganglia can be measured with Pet and SPECT scans [also DaTSCAN]
Mx for PD
Levodopa, dopamine receptor agonists [e.g. ropinirole and pramipexole], MAO-B inhibits [e.g. rasagiline, selegiline], amantadine, COMT inhibitors [e.g. entacapon, tolcapone], antimuscarinics [e.g. benzhexol, orphenadrine]
What are MRI/CT/Pet and SPECT scans looking for?
Dopamine!
What are the 4 common drugs given to those with PD?
- Levodopa
- Dopamine agonists [ropinirole and pramidprexole]
- MAO-B inhibitors [selegiline, rasagiline]
- COMT inhibitors [etacapone[, tolacapone
Explain how L-dopa works
Look at diagram
What should L-dopa be combined with? And why?
Dopa-decarboxylase inhibitor [co-beneldopa or co-careldopa]. Prevent SE.
Why should dopamine agonists by trialled?
Can delay starting L-dopa in early stages of PD
Define Huntington’s disease
An inherited neurodegenerative disease characterised by chorea, dystonia, incoordination, cognitive decline, and behavioural diffuculties
Aetiology of HD
Autosomal dominant [complete penetrance], gene on chromsome 4 encodes protein called huntingtin
What is the mutant Huntingtin?
CAG trinucleotide repeat expansion, which accumulates in the brain cells causing damage. Toxic ‘gain of function’ mutation.
What is chorea?
Chorea is involuntary movement
What is dystonia?
Tensed muscle
how many faulty gene repeats do you need for HD?
over 35 CAG repeats
What does complete penetrance mean?
patient have mutation, then likely to present with the disease
Sx of HD?
Early stages, subtle changes in personality, cognition and physical skills. Uncontrollable movements [chorea].
Signs of HD
Chorea, impaired psychomotor functions, rigidity, dystonia, loss of saccadic eye movements, behavioural problems, dementia, difficulties, chewing, swallowing and speaking, sleep disturbances
Ix for HD
Genetic testing/DNA analysis, CT/MRI can show atrophy of the caudate nuclei [although the are not Dx of HD]
Mx of HD
no disease modifying Tx at present. Tx are available for treating Sx
Epidemiology of HD
5/100k about
prognosis usually of HD
survive 15-20 years, but low QoL
Define dementia
syndrome in which there is deterioration in memory, thinking, behaviour and the ability to perform everyday activities
Types of dementia
Alzheimer’s [most common at 50%], vascular dementia [25%], dementia with levy bodes [15%], frontotemporal dementia [less than 5%], mixed dementia, PD + genetic causes of dementia [AD Alzhemier’s]
Types and prevalence of potentially treatable dementias
less than 5%
Substance misuse, hypothyroidism, SOL, NPH, syphilis, vitamin B12 deficiency, folate deficiency, peliagria
Dx of dementia
comprehensive history and physical examination, a formal screen for cognitive impairment such as MMSE
Ix for dementia
dementia screen, requirement to exclude other causes of confusion/memory impairment: FBC, LFT, U&E, ESR or CRP, B12, TFT, syphilis serology, cortisol, glucose, calcium, CT brain, EEG, LP [e.g. to identify CJD]
Pharmacological Mx
- acetylholinesterase inhibitors [e.g. donepezil] for mild to moderate Alzheimer’s
- N-methyl-D-asparate antagonists [NMDA antagonists - memantine] is a second-line option where AChE inhibitors are not tolerated or CI
Case 1 [look up]: - weakness climbing stairs - fasciculations - brisk knee and ankle reflexes - positive hoffman's and babinski sensory and cranial nerves in tact
MND
- upper [babinski, upping plantars], lower [fasciculations] motor neurone signs
- MND presents with UMn and LMN lesions with NO sensory involvement
bulbar signs, such as tongue wasting and fasciculations often help Dx
Case 2 [look up]: - 69 y/o M - not been self, withdrawn, forgetful word finding problems - naked and urinating in room last week - history HTN and ex-smoker
Frontotemporal dementia
- developed change in behaviour
- initially negative Sx like withdrawn and disinterest in hobbies [as opposed to positive signs like hallucinations]
- would be depression if not for word finding difficulties and disinhibition
- no extra-pyramidal signs for LBD
- Alzheimer’s tends to effect language and memory before personality
Case 3: - 67 y/o M - sustained falls, shuffle around the house - up and down stairs - appears confused at times, forgetful names - move and follow commands slowly - resting tremor L hand - some rigidity also noted examination CN unremarkable
PD
- asymmetric tremor
- Cn normal
Case 4
- 76 y/o M
- increasing frequency falls
- pill-rolling tremor both hands, bilateral cog-wheeling
- CN normal except for upwards gaze
- speech distinct and nasal in character
progressive supranuclear palsy [PSP]
- Parkinson’s-plus syndrome
- bilateral, symmetrical Sx are uncommon in PD, particularly early on
- eye signs v unusual
- PSP patient with increasing falls near the stairs due to an impaired vertical gaze
- nasal ‘Donald-Duck’ voice secondary to pseudo bulbar palsy
- idiopathic PD don’t get CN problems
What is PSP also known as?
Steel-Richardson-olszewski syndrome
- a ‘Parkinson Plus’ syndrome
Features of PSP
- impairment of vertical gaze [down gaze worse than up gaze- pts may complain of difficulty reading or descending stairs], parkinsonism, falls, slurring speech, cognitive impairment
Mx of PSP
Poor response to L-dopa
Case 5 - 72 y/o woman - becomes confused at the end of a charity walk - asks why got here, no PMH - normal Bp and HR - neuro signs normal - gradually recovers over 3 hours Treatment given?
Reassurance
- acute onset retrograde amnesia with preserved orientation and consciousness
- transient global amnesia [TGA]
- course of TGA unknown, though aetiology may be similar to migraines
- no evidence TGA and increased risk strokes [so aspirin and clopidogrel not indicated]
- Rivaroxaban and warfarin anticoagulants so not indicated as no AF
Presentation of TGA
- transient loss of memory funciton
- patient anxious and repeatedly ask same question
- patients no recall events after attack
Aetiology of TGA
not known, thought to be transient ischaemia to the thalamus [in part. the amygdala and hippocmampus]
Case 6
- 44 y/o W
- 3m history of worsening involuntary movements of the head
- worse with stress, better with alcohol
- not present when asleep
- no other neurological Sx
- neurological examination unremarkable [other than spontaneous movements head worse when she looks either side]
- father similar complaint but never sought medical attention
- most likely Dx?
Essential tremor
- most common cause of titubation [head tremor]
- majority pts will have hand tremor, titubation can occur in isolation
- autosomal dominant in FH
alcohol and sleep relieving factors, caffeine/stress make worse
- usually affects both upper limbs
- postural tremor: worse if arms are outstretched
Mx for essential tremor
- propanolol is first-line
- primidone is sometimes used
Which of these Sx and Sx is NOT commonly Ass with parkinsonism?
- postural instability
- PEM sleep disturbance
- hypomimia
- broad-based gait
- autonomic instability
Broad-based gait
- Parkinsonian gate is typically narrow-based, not broad
- PD: stopped, masked face, back rigidity, forward tilt trunk, reduced arm swing, hand tremor, fixed elbows and rwrists, hand tremor, tremor legs, slightly flexes arms and hips, shuffling and stooped gait
Neurologisttake middle finger and flicks distal phalanx. Thumb contracts. Which reflex?
Hoffman’s: UMN lesion sign
22 y/o man with ALS, most appropriate Mx?
Riluzole
Benefits and drawbacks of riluzole
benefits
- delays onset of ventilator dependence [NIV], may increase survival by 2-3m
risks
- can cause LFT derangement; particularly hepatic enzymes
Which of the following is least associated with the development of chorea?
- ataxic telangiectasia
- SLE
- Wilson’s disease
- pregnancy
- infective endocarditis
IE
- chorea can be avery rare manifestation of IE, following embolisation to the basal ganglia. It is however the least likely of the above 5.
Define chorea
Involuntary, rapid, jerky movements, which often move from one part of the body to another.
What is athetosis?
Slower, sinus movement of the limbs from chorea
Causes of chorea
Damage to the basal ganglia [esp. the caudate nucleus]
- from Huntington’s disease, Wilson’s disease, ataxic telangiectasia
- SLE, anti-phospholipid syndrome
- RF; Sydenham’s chorea
- drugs: OCP, L-dopa, antipsychotics
- neuroacanthocytosis
- pregnancy: chorea gravidarum
- thyrotoxicosis
- polycythaemia rubra vera
- CO poisoning
- cerebrovascular disease
Which type of MND has the worst prognosis?
PSP
-swallowing difficulties
Question 6 - 76 y/o W - increasing confusion - wandering ward shouting at pts - admitted high fever and 1w history productive purulent cough - PMHx of PD - throw objects and hit staff - high HR Which first line Rx?
Lorazepam
- antipsychotics should be avoided in delirious pts with background PD
- lady has delirium [combination of dark environment+infection]
- haloperidol and other antipsychotics first-line when nursing strategies failed. but not in PD pts.
Why haloperidol and antipsychotics not first-line Tx for PD?
Strong anti-dopaminergic action, will make condition significantly worse
Why not immediate release L-dopa as an Rx for question 6?
Confusion this lady not due to PD. PD can cause behavioural changes, but they tend to be more chronic, progressive and less liable in nature.
Question 7:
- 59 y/o woman
- Dx with PD
- tremor and bradykinesia
- Sx affecting his ability to work accountant and QoL
- Tx most likely offered initially?
Levodopa
- newly Dx pts, who have motor Sx affecting their QoL
Compare levodopa, dopamine agonists and MAO-B inhibitors for impact on:
- motor Sx
- ADLs
- motor Cx
- adverse events
[look slides]
Question 8:
- 45 y/o M
- recently aggressive behaviour, depression, chorea, athetosis
- father similar Sx at 65
- neurodegenerative trinucleotide repeat expansion suspected. Which trinucleotide most likely?
CAG
- repeat expansion of CAG trinucleotide in HD
Other important commonly tested trinucleotide repeats name:
- GAA
- CTG
- CGG
GAA = Friedrich ataxia CTG = myotonic dystrophy CGG = fragile X syndrome
Define HD
inherited neurodegenerative condition. Progressive and incurable condition that typically results in death 20 years after the initial Sx develop
What is the phenomenon of anticipation can be seen in HD?
The disease presents at an earlier age in successive generations [as CAG repeat expansion]
Which neurones/brain part does HD affect?
GABAergic neurones in the striatum of the basal ganglia
Which gene and where is it found causes HD?
Huntingtin gene defect on chromosome 4
Features typically develop after 35 years of age
- chorea
- personality changes [e.g. irritability, apathy, depression], intellectual impairment
- dystonia
- saccadic eye movements
Question 9
- 90 y/o man
- worsening confusion
- nursing home resident and dependent on carers
- struggles remembering names, naming objects
- less alert than usual
- needs prompting, remain incontinent of urine
- on examination, scores 12/15 on GCS
Which would suggest Dx of delirium rather than dementia?
Impairment of conscious level
- delirium involves impairment conscious level and often involves psychotic Sx
Factors favour delirium over dementia
- impairment of consciousness
- fluctuation of Sx [worse at night, periods or normality]
abnormal perception [e.g. illusions and hallucinations] - agitation and fear
- delusions
LBD most likely to present how?
Cognitive impairment, parkinsonism, visual hallucinations
how common is LBD?
increasingly commonly recognised cause dementia, accounting for up to 20% of cases
What is the characteristic pathological feature of LBD?
alpha-synuclein cytoplasmic inclusions [Lewy bodies] in the substantial migration, paralympic and neocortical areas
Relationship between PD, LBD and AD
Complicated, dementia often seen in PD.
Also, up to 40% patients with AD have LBD.
Features of LBD
Progressive cognitive impairment
- in contrast AD, early impairments in attention and EF rather than just memory loss
- cognition may be fluctuating, in contrast to other forms of dementia
- usually develops before PD
- parkinsonisms
- visual hallucinations: other features like delusions and non-visual hallucinations may also be seen
