Neurology Flashcards
(275 cards)
1
Q
What is a unique aspect of muscle strength testing or deep tendon reflex testing in patients with Lambert-Eaton myasthenic syndrome?
A
Post-exercise (or post-activation) facilitation - vigorous, brief muscle activation (e.g. maximal isometric contraction of the relevant muscle for 10 to 15 seconds) can sometimes lead to temporary reappearance of previously depressed or absent deep tendon reflexes, and to temporary improvement of muscle weakness
2
Q
What cancer is paraneoplastic Lambert-Eaton myasthenic syndrome most commonly associated with?
A
Small cell lung cancer (mostly), occasionally lymphoproliferative diseases including Hodgkin’s Lymphoma - rarely atypical carcinoid, Merkel cell etc
3
Q
What are the causes of Lambert-Eaton myasthenic syndrome?
A
- Paraneoplastic phenomena secondary to small cell lung cancer or lymphoproliferative malignancies
- Autoimmunity secondary to thyroid disease or T1DM
- Toxic secondary to immunotherapy/immune checkpoint inhibitor therapy
4
Q
What is the pathophysiology of Lambert-Eaton myasthenic syndrome?
A
LEMS is the result of reduced ACh release from the presynaptic nerve terminals, despite normal ACh vesicle number, normal ACh presynaptic concentration, and normal postsynaptic ACh receptors. It results from autoimmunity with antibodies directed at the P/Q subtype of Voltage Gated Calcium Channels which interferes with the normal calcium influx required for ACh release
5
Q
Is the age of onset of paraneoplastic Lambert-Eaton myasthenic syndrome younger or older than non-paraneoplastic LEMS?
A
Older
6
Q
What percentage of Lambert-Eaton myasthenic syndrome is paraneoplastic?
A
50%
7
Q
What are the key clinical features of Lambert-Eaton myasthenic syndrome
A
Consider in patients presenting with proximal muscle weakness, dry mouth, hyporeflexia, and any combination of oropharyngeal muscle weakness or ptosis
Key features:
1. Slowly progressive proximalmuscle weakness (lower extremity > upper extremity) - typically describe an alteration in gait or difficulty arising from a chair or managing stairs
- usually symmetrical
- may describe muscle pain/stiffness/cramping or fatigability
- degree of weakness on exam usually less than would expect based on disability
- usually limited muscle atrophy
- Distinctive autonomic findings
- dry mouth
- sluggish pupillary response
- erectile dysfunction - Smattering of oculobulbar findings
- typically less severe or striking than in myasthenia gravis
- ptosis or diplopia are most common
- excessive or paradoxical eyelid elevation with sustained upward gaze - Depressed or absent deep tendon reflexes
- classical feature is “post-activation facilitation” which refers to recovery of lost deep tendon reflexes or improvement in muscle strength with vigorous, brief muscle activation - Respiratory failure
- often late in illness
- need to consider in differential diagnosis of patients presenting with neuromuscular respiratory failure
8
Q
How do you diagnose Lambert-Eaton myasthenic syndrome?
A
Electrodiagnostic studies, including repetitive nerve stimulation (RNS), and anti-P/Q-type voltage-gated calcium channel (VGCC) antibody testing
The diagnosis of LEMS is confirmed on high-frequency RNS by a reproducible postexercise increase in compound muscle action potential (CMAP) amplitude of at least 100 percent compared with pre-exercise baseline value
A high titer P/Q-type VGCC antibody result is strongly suggestive of LEMS in the appropriate clinical setting -However, P/Q-type VGCC antibodies are present in a variety of clinical situations where LEMS is not present.
9
Q
Is a high titre of P/Q-type VGCC antibodies diagnostic of Lambert-Eaton myasthenic syndrome?
A
No - whilst present in approximately 85 to 95 percent of patients with LEMS and considered confirmatory if clinical and electrophysiology features of LEMS are also present they are also found in a variety of other conditions/clinical situations where LEMS is not present including: healthy control patients, in patients with myasthenia gravis, motor neurone disease, other malignancies
10
Q
What percentage of patients with Small Cell Lung Cancer also have Lambert-Eaton myasthenic syndrome as a paraneoplastic syndrome?
A
3%
11
Q
What test should you order in patients diagnosed with Lambert-Eaton myasthenic syndrome?
A
CT chest, abdomen, and pelvis looking for malignancy
Also consider:
1. Magnetic resonance imaging (MRI) of the brain and/or spinal cord should also be obtained if there are focal neurologic symptoms or signs suggesting involvement of the central nervous system (CNS).
- 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) if high risk for malignancy but CT scan non-diagnostic
12
Q
What factors are associated with a higher risk of SCLC in Lambert-Eaton myasthenic syndrome?
A
A high Dutch-English LEMS Tumour Association Prediction (DELTA-P) score
And
Presence of SOX antibodies
13
Q
How do you treat Lambert-Eaton myasthenic syndrome?
A
Symptomatic management:
- Mild weakness - monitor only
- Moderate to Severe weakness - Amifampridine or pyridostigmine
Refractory disease:
- IVIG
- Prednisolone
- Azathioprine
- Mycophenolate
- Rituximab
14
Q
How does Amifampridine for the treatment of Lambert-Eaton myasthenic syndrome work?
A
Amifamipridine blocks potassium channels which significantly prolongs the presynaptic nerve terminal membrane depolarization, enhancing calcium entry and thereby improving the release of acetylcholine.
15
Q
What are the main side effects of Amifampridine?
A
Perioral and extremity paraesthesiaes
Headache
Nausea
Abdominal pain
Diarrhoea
Elevated liver enzymes
Seizures
16
Q
What are the main side effects of Amifampridine?
A
Perioral and extremity paraesthesiaes
Seizures
Headache
Nausea
Abdominal pain
Diarrhoea
Elevated liver enzymes
17
Q
Is the presence of Lambert-Eaton myasthenic syndrome a good or poor prognostic marker in Small Cell Lung Cancer?
A
Good - the presence of LEMS in SCLC is associated with prolonged survival
18
Q
Does treatment of small cell lung cancer result in resolution of Lambert-Eaton myasthenic syndrome in those patients with paraneoplastic LEMS?
A
Not necessarily - evidence of partial remission in weakness or EMG-abnormalities but often weakness persists despite SCLC treatment
19
Q
What non-pharmacological measures are there for the management of neurogenic orthostatic hypotension?
A
- Remove offending medications
- Increase oral fluid and salt intake
- aim 1.5-3L fluid daily
- aim 6-10g salt daily - Compression stockings
- Modify activities
- arise slowly
- measures to clench abdominal and leg muscles when standing
- avoid valsalva eg coughing, constipation etc
- limit walking in hot weather
- increase head of bed to 30-45deg (decreases nocturnal diuresis)
- cardiovascular exercise - can be seated or swimming
Also important to:
1. Treat intravascular volume depletion
2. Address underlying medical conditions eg anaemia, CVD, adrenal insufficiency
20
Q
What is the pharmacological treatment of neurogenic orthostatic hypotension?
A
- Fludrocortisone
- Sympathomimetic eg midodrine or droxidopa
- atomoxetine - a noradrenaline uptake inhibitor
21
Q
What is the effective dose range and main issues with Fludrocortisone treatment for neurogenic orthostatic hypotension?
A
Fludrocortisone is a synthetic mineralocorticoid that increases sodium and water reabsorption by the kidneys therefore increasing effective circulating volume and blood pressure in all positions.
Starting dose = 50micrograms
Max dose = 200 micrograms (little benefit going above this)
Takes 5-7 days to take effect so don’t make dose adjustments more frequently than weekly
Main side effects are:
1. Hypokalaemia
2. Ankle oedema
3. Supine hypertension
Long term, fludrocortisone exacerbates hypertension and organ damage, including left ventricular hypertrophy, congestive heart failure, and kidney failure and is associated with a higher risk of all-cause hospitalization in patients with nOH
22
Q
What is the “escape phenomenon” that occurs with Fludrocortisone therapy?
A
After a few weeks of Fludrocortisone therapy, blood volume returns to pre therapy levels but a pressor response remains (presumably due to increased vascular resistance) which may mediate its long term adverse effects
23
Q
How does Midodrine work?
A
Midodrine is a prodrug that is metabolised to desglymidodrine, the active alpha-adrenergic agonist. It is rapid absorbed in the GIT, does not cross the blood brain barrier and causes both arterial and venous vasoconstriction
24
Q
What are the main side effects of Midodrine therapy?
A
Supine hypertension
Piloerection
Pruritis
GI symptoms
Urinary retention
25
What is the effective dose range of Midodrine?
2.5mg to 10mg TDS
26
What are the core clinical features of Dementia with Lewy Bodies (DLB)?
- Cognitive fluctuations
- Recurrent visual hallucinations
- REM sleep disorder
- 1 or more Parkinsonism features eg
Bradykinesia
Rest tremor
Rigidity
Supportive clinical features:
- Sensitivity to antipsychotic agents
- Postural instability
- Falls
- Syncope
- Autonomic dysfunction
- Delusions
- Non-visual hallucinations
- Apathy
- Anxiety
- Depression
27
Which core clinical features typically occur early and persist in Dementia with Lewy Bodies?
Fluctuating cognition
Recurrent visual hallucinations
REM sleep disroder
28
Is DLB or AD more likely to present as amnestic mild cognitive impairment?
AD
29
What is the aetiology of DLB?
Unknown
Almost all cases are sporadic although occasional familial clusters ?related to alpha-synuclein gene on chromsome 4 and apolipoprotein E e4 allele
30
What is the pathophysiology of DLB?
It is a neurodegenerative disease characterised by the accumulation of Lewy Bodies in vulnerable sites (thereby mimicking the pathology of Idiopathic Parkinson's disease).
Lewy Bodies are composed of alpha-synuclein protein - this protein normally transports synaptic vesicles and synaptic plasticity
31
Is co-existing Alzheimer's dementia pathology common in DLB?
Yes, overlap syndrome or coexistent disease is very common and often results in an atypical clinical syndrome
Vascular dementia is also present in up to 1/3rd of patients
Neurofibrillary tangles tend to be less severe in DLB than typical AD
32
What are the typical (neuro) biochemical abnormalities in DLB?
Cholinergic deficit
Dopaminergic deficit
33
How do you differentiate Parkinson's disease dementia from DLB?
Can be complicated and difficult
Depends mostly on relationship of timing of dementia to motor symptom onset
DLB if dementia present at symptom onset or within 1 year of Parkinsonism onset whilst Parkinson's disease dementia if parkinsonism present >1yr before onset of dementia
34
What is the definition of dementia?
A progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational functions or with usual daily activities
35
What do fluctuations in cognition, attention and arousal look like in patients with DLB?
Delirium-like
Episodes of inconsistent behaviour
Altered attention
Incoherent speech
Staring/zoning out
Daytime drowsiness/lethargy
Disorganised speech
36
What are the typical features of hallucinations in DLB?
Complex visual hallucinations that may resemble children or small animals
37
How does REM sleep behaviour disorder in DLB manifest?
Excessive jerking and complex movements during REM sleep eg falling out of bed, kicking, punching, jumping up, running, talking, yelling, swearing
Duration is brief and patients regain full awareness when they wake
38
Why is REM Sleep disorder important to identify in DLB?
Because it is drug-responsive
Also, 90% of patients diagnosed with idiopathic REM sleep disorder eventually develop DLB or another synucleinopathy
39
What blood tests should be performed for all cases of suspected dementia?
TSH - hyper/hypo-thyroidism
B12 - B12-deficiency induced dementia
FBC - to exclude anaemia
eLFTs - to assess major organ failure
Folate - folate def
Syphillis
Urinalysis - exclude UTI
HIV - HIV infection
Urine drug screen - exclude drug abuse
40
What structural imaging feature is characteristic of DLB?
There are none
41
How might Functional Dopamine transporter imaging with ioflupane (I-FP-SPECT) help differentiate between DLB and AD?
Typically normal in AD
May show low striatal activity in DLB or Parkinson's
Note reduced dopamine transport uptake in basal ganglia sens 78% and 90% spec for DLB relative to AD
42
What finding on FDG-PET may be related to DLB (correlates with visual cortex pathology at autopsy)
Occipital hypometabolism
43
What finding on EEG may be a useful biomarker of DLB?
Evidence of prominent posterior slow-waves with periodic fluctuations in the pre-alpha/theta range
44
What finding on polysomnography may be indicative of DLB?
REM sleep disorder without atonia
45
What clinical features are usually absent in AD but present in DLB?
REM sleep disorder
Motor symptoms
46
What imaging features may be present on SPECT/PET in AD?
Decreased perfusion in temporoparietal region
47
What features may suggest Frontotemporal dementia rather than DLB?
Earlier onset eg in 50s
Rapid progression
Impulsivity
Socially inappropriate
Emotional lability
Personality changes
Blunting of verbal and language skills
Apathy and self-neglect
Parkinsonism in FTD often associated with eye movements (eg PSP) or asymmetric onset (eg CBS)
Imaging
CT/MRI -B - atrophy of frontal lobes
SPECT/PET - reduced brain activity in frontal and temporal lobes
48
What features may suggest Prion disorders rather than DLB?
Rapidly progressive dementia
Myoclonus and gait disorder and occasional visuospatial impairment
Diffusion weighted MRI - basal ganglia, thalamic, cortical changes
CSF - 14-3-3 protein
EEG - characteristic periodic complexes
49
How do you treat DLB?
Supportive care incl education, support, future planning, discussion re advanced care plans, legal matters, driving restrictions
Environmental review eg home safety evaluation, falls prevention, safe sleeping environment
Support for family and carers
Non-pharm mx
- CBT - improve cognition and behavioural disturbance + reduced anxiety/depression
- exercise - improve cognitive decline, ADLs, motor disturbances
Pharmacological mx
1st line = cholinesterase inhibitor (eg donepezil, rivastigmine, galantamine)
2nd line =NMDA receptor antagonist (eg memantine) - but evidence weak
50
What are some common adverse effects of cholinesterase inhibitor use?
N&V
Hypersalivation
Vivid dreams
Drowsiness
Orthostatic hypotension/syncope
Weight loss
Runny nose
Muscle cramps
51
Why should you try to avoid antipsychotics in DLB?
They are associated with an increased mortality and adverse effects
- rigidity
- immobility
- confusion
- sedation
- postural falls
- weight gain
- diabetes
Should avoid typical antipsychotics particularly
52
If you do choose an antipsychotic in DLB, which one is best?
No evidence supporting the use of a particular atypical antipsychotic
Quetiapine = well tolerated incl that it does not worsen motor function but uncertain efficacy
Risperidone = improves agitation but assoc with extra-pyramidal side effects
Clozapine = effective, ?tolerability
53
How do you treat REM sleep behaviour disorder in DLB?
Clonazepam
OR
Melatonin
54
Do you treat DLB with Levodopa?
Not usually - due to possible worsening of cognition, hallucinations and behaviour only tend to treat if motor symptoms are severe and interfere with ADLs
Response is seen in 1/3rd patients
Younger patients seem to respond better
Benefit for limited duration only
55
What are the main complications of DLB?
Aspiration pneumonia
Institutionalisation
Dysphagia
Antipsychotic sensitivity
Urinary incontinence
Falls
Elder abuse
56
What is the median survival of patients with DLB post-diagnosis?
5 years
57
What is the second most frequent primary neurodegenerative brain disease in adults <65 years of age?
Frontotemporal dementias - after Alzheimer's disease
58
Is FTD more commonly diagnosed in people <65yo or >65yo?
>65yo - whilst typical early onset, does not imply FTD is an exclusively early-onset form of dementia
59
Which gene mutations are implicated in inherited cases of FTD?
MAPT (microtubule-associated protein)
GRN (progranulin)
C9orf72 (chromosome 9 open reading frame 72)
60
What is the most common cause of genetic FTD?
C9orf72
(chromosome 9 open reading frame 72)
61
What are the major molecular subtypes of Frontotemporal lobar degeneration (FTLD)?
FTLD-tau (36-50%)
FTLD-TDP/FTLD-U (50%)
FTLD-FET (4%)
62
What are the subtypes of FTLD-tau (tauopathies - due to abnormal accumulation of hyperphosphorylated tau)
Pick's disease
Corticobasal degeneration
Progressive supranuclear palsy
Globular glial tauopathy
Autosomal dominant familial tau
63
What are the hallmark lesions in FTLD-TDP?
Neuronal cytoplasmic inclusions and dystrophic neurites that are immunoreactive for TDP-43, ubiquitin, and p62, but negative for other neurodegenerative disease-related proteins
ie tau-negative, ubiquitin positive inclusions; so called TDP-43 proteinopathies
64
What genes are associated with FTLD-FET ?
FUS (fused in sarcoma)
EWS (Ewing's sarcoma)
TAF15
65
How can FTD be classified?
Clinically:
Behaviour variant FTD
vs
Primary progressive aphasia
OR
Behavioural presentation:
Apathetic
vs
Disinhibited
vs
Sterotypic forms
OR
Whether manifests with Parkinsonism
FTD with Parkinsonism
vs
FTD without Parkinsonism
OR
Tauopathies
vs
TDP-43 proteinopathies
66
What are the common clinical features that may be found in FTD?
Insidious onset of coarsened personality and changes in social behaviour and habits
Gradually progressive loss of language fluency or comprehension
Progressive self-neglect and abandonment of work, activities, social contacts
67
Which comes first in FTD - personality changes or memory impairment?
In FTD, changes in personality, language, habits, and activity generally precede the development of memory impairment, disorientation, or apraxias
68
What other conditions are important to exclude in a patient suspected of having FTD?
Hyperthyroidism (presentation can mimic FTD)
ALS - characterised by progressive asymmetrical weakness of spinal or bulbar muscles which may be accompanied by bulbar weakness
Normal Pressure hydrocephalus
Primary brain tumour (frontal lobe)
HIV dementia
Neurosyphillis
69
What CSF marker may have value in diagnosing FTD?
NfL (neurofilament light chain)
NPTX2
Higher levels of NfL and amyloid + Lower levels of amyloid precursor protein (sAPPb) may help distinguish FTD from AD
70
What imaging abnormalities are often present in FTD?
bvFTD - atrophy (on MRI) and hypometabolism (on FDG-PET) in prefrontal cortex and anterior temporal lobes with relative sparing of more posterior regions of the brain incl occipital lobe
semantic dementia - atrophy (on MRI) and hypometabolism (on FDG-PET) in temporal lobes
Primary progressive aphasia - focal patterns of atrophy (on MRI) and hypometabolism (on FDG-PET) in left posterior frontal lobe
71
Most of the gene mutations associated with FTD are present in patients with strong family history, but which one can be seen in sporadic disease?
C9orf72
72
Which patients with FTD should have genetic testing performed?
All patients with probable or possible bvFTD
Suspected bvFTD with strong psychiatric features and 1+ affected family members
73
Is there any drug treatments indicated for treatment of FTD?
No - no evidence for effectiveness of drug treatment and in fact, acetylcholinesterase inhibitors and memantine (NMDA receptor antagonist) may hasten cognitive decline or worsen behavioural symptoms
Should try to limit medication use
74
What antibiotics are associated with psychotoxicity?
Fluoroquinolones
75
Do patients with FTD or AD have shorter survival and faster rates of cognitive and functional decline?
FTD
76
Which gene mutations in FTD are most likely to result in FTD with Parkinsonism?
MAPT gene mutations
77
Which gene mutations in FTD are most likely to result in behavioural FTD phenotype associated with marked impairments of semantic knowledge ie semantic dementia?
GRN gene mutations
78
Mutations in C9orf72 gene in FTD are most likely to result in which subtypes/variants?
bvFTD
FTD with motor neuron features
79
What is the typical regional atrophy pattern of Alzheimer's dementia?
Temporal (incl hippocampal) and parietal with sparing of sensorimotor strip + occipital lobe
80
What is the typical regional atrophy pattern of bvFTD?
Prefrontal and anterior temporal lobe
81
What is the typical regional atrophy pattern of Huntington disease?
Head of the caudate
82
What is the typical regional atrophy pattern of nonfluent variant primary progressive aphasia?
Dominant perisylvian
83
What is the typical regional atrophy pattern of PSP?
Diminished midbrain anteroposterior diameter
84
What is the typical regional atrophy pattern of semantic variant primary progressive aphasia?
Anterior inferior temporal lobes
85
Is hippocampal atrophy pathognomonic for AD?
No - can also be seen in mesial temporal lobe sclerosis, temporal lobe epilepsy, certain vascular insults
86
What is the typical triad in Normal Pressure Hydrocephalus?
Dementia
Gait disturbance
Incontinence
87
What is the role of LP / CSF analysis in the evaluation of dementia?
LP is typically performed to exclude infectious, inflammatory or neoplastic process.
Often only in the setting of a rapidly progressive ԁеmentiа, or in a younger patient, or as a follow-up to another abnormality identified on clinical history (eg, HIV), examination, laboratory testing (eg, abnormal syphilis serology), or ոеսrοimagiոg (eg, meningeal enhancement)
CSF biomarkers have a limited role in diagnosis of AD or DLB
88
What is a Prion Disease?
A group of uniformly fatal neurodegenerative diseases characterised by progressive dementia and motor dysfunction
Also known as transmissible spongiform encephalopathies
89
What percentage of Prion diseases are genetic?
10-15%, rest are sporadic. Very rare to be acquired
90
What is the lifetime risk of developing a Prion disease?
1 in 30,000 to 1 in 60,000
91
Genetic mutations on what chromosome may cause genetic Prion disease?
Chromosome 20
Gene mutations encoding PRNP (endogenous prion protein)
92
How are acquired cases of Prion disease usually transmitted?
Either iatrogenic via medical procedures eg cadaver-derived corneal grafts, dura mater grafts or neurosurgery involving prion-contaminated surgical instruments (can be very hard to sterilise)
Or
Ingestion of prion-contaminated beef
Or
Transfusion of affected blood products
93
What is the pathophysiology of Prion diseases?
Prion diseases are caused by the conversion of healthy endogenous prion proteins (largely alpha-helix structure) into a pathogenic form (largely beta-pleated sheet)
Once converted, these misshapen proteins initiate a transformational cascade converting other nearby prion proteins
The resulting accumulation of pathogenic prions in the CNS causes nerve cell injury and eventual death
During the process of nerve cell injury, fluid filled vacuoles appear in the dendritic tree of neurons - has a spongiform appearance on microscopy hence alternate name for Prion diseases
- they are considered a hallmark characteristic of Prion disease
94
Prion disease secondary to consumption of Bovine Spongiform Encephalopathy (BSE, mad cow disease) contaminated beef causes what subtype of Prion disease?
Acquired (rather than sporadic or genetic)
Also called variant CJD
95
Fatal familial insomnia is a type of genetic prion disease - what are the clinical hallmarks?
Begins with increasing insomnia, anxiety and dysautonomia
Progresses to ataxia, hallucinations, weight loss, dementia and eventual death
96
How does sporadic Crutzfeldt-Jakob disease typically present?
Subacute (but more rapid development than most of the other forms of dementia) cognitive decline in a patient in their 60s
Cognitive -
Memory loss
Aphasia
Executive dysfunction
Motor -
Parkinsonism
Myoclonus
Limb/gait ataxia
Behavioural change incl agitation, depression
Vertigo/dizziness
Headaches
Visual - diplopia, hallucinations, distortions
97
How does variant CJD present differently to sCJD?
Typically affects young adults / teens (as opposed to 60 yo)
First symptoms psychiatric (profound depression) and mild cognitive impairment (whereas cognitive impairment prominent early feature in sCJD)
Later develop dementia, ataxia, painful sensory symptoms, movement disorder
May have hx of potential exposure eg consumption of beef in UK
98
What is the first test you should order in a patient you suspect has CJD and what is the typical abnormality?
MRI-Brain
Often demonstrates hyper intensity of cerebral cortex (cerebral ribboning), basal ganglia and thalamus on DWI and FLAIR and hypo intensity on ADC
99
How sensitive and specific is MRI for CJD?
Sens 92-96%
Spec 93-94%
100
What are the typical findings on EEG in CJD and are these sens or spec for the diagnosis?
Generalised slowing, focal or diffuse
Periodic sharp-wave complexes
Moderately specific, only 60% sens
101
Can CSF biomarkers definitively diagnose or rule out prion disease?
No - unclear sens and spec
14-3-3 protein (ie western blot) may be positive (but variable accuracy and guidelines shifting away from its use)
Total tau and neuron-specific enolase may be elevated and support the idea of rapidly progressive neuronal deterioration
Quaking-induced conversion (QuIC) may be positive
102
Other than brain biopsy, what other tissue can be sampled and be diagnostic of prion disease in variant CJD?
Tonsil biopsy
103
How can you differentiate CJD from DLB, AD or FTD?
Usually via MRI demonstrating typical signs of a specific condition
104
How can CJD be distinguished from Hashimoto’s encephalopathy?
AntiTPO and/or anti-TG antibodies may be positive in Hashimoto’s
There may or may not be assoc thyroid dysfunction
MRI will show characteristic abnormalities in CJD but not if Hashimoto’s
105
What is the classic triad of Wernicke’s encephalopathy?
Nystagmus
Ataxia
Memory loss
106
What is the classic triad of Pellagra (Vit B3 deficiency)?
Dermatitis
Diarrhoea
Dementia
107
What are the classic features of PSP?
Unprovoked backward falls (within first 1-3 years)
Vertical Supranuclear palsy (slow vertical saccades and difficulty with downward gaze)
Symmetric Parkinsonism incl axial rigidity and poor or transient response to levodopa
Speech or language disorders
Swallowing difficulties
108
Are there any approved treatments for CJD?
No
Treatment is supportive
SSRIs for mood/insomnia
Clonazepam for insomnia/myoclonus
109
What is the typical prognosis in CJD?
<1 year
110
What is the hallmark finding in PSP?
Supranuclear opthalmoparesis - but it may take 10 years to develop
Earliest manifestation = slowing of vertical saccades (ask patient to look straight ahead then follow your finger up and down - should be smooth and quick; if slow or require more than one step to reach target = suggestive)
This typically progresses to restricted saccadic range (ie inability to look fully upwards or downwards; lateral gaze less affected) - may manifest as slow, jerky movements
Interestingly, the opthalmoparesis of PSP can be overcome by oculocephalic / doll’s eyes manoeuvre
111
What is the classic facial expression in PSP?
Perpetual surprise or astonishment
- rare blinking, facial dystonia with eyelid retraction and gaze abnormalities
112
The classic phenotype of PSP is also known as ?
Richardson syndrome
113
What is the classic gait abnormality in patients with PsP?
A stiff, broad-based gait
May pivot quickly and become unstable “drunken sailor gait” and tend to be impulsive ie jump out of the chair “rocket sign”
(Knees and trunk extended and arms slightly abducted)
Differs from typical PD in which they demonstrate flexed posture
114
How is postural instability tested for in PsP?
Pull test (stand behind px and exert gentle but firm tug backwards on px shoulders)
In PSP often take multiple steps backwards to regain balance (>2 steps is abnormal) although some may “fall like a tree”
115
How is postural instability tested for in PsP?
Pull test (stand behind px and exert gentle but firm tug backwards on px shoulders)
In PSP often take multiple steps backwards to regain balance (>2 steps is abnormal) although some may “fall like a tree”
116
What clinical features suggest PSP rather than Parkinson’s disease?
Absent resting tremor
Absent, poor or transient response to levodopa
Preservation of olfaction
Oculomotor abnormalities
Absent autonomic dysfunction or visual hallucinations
117
What features might suggest Multisytem atrophy rather than PsP?
Younger Onset (ie in 6th decade)
Prominent early autonomic symptoms
Ultimately tho may be difficult to distinguish in early course
118
What features might suggest Multisytem atrophy rather than PsP?
Younger Onset (ie in 6th decade)
Prominent early autonomic symptoms
Ultimately tho may be difficult to distinguish in early course
119
What are the four core domains affected in PSP?
Oculomotor dysfunction
Postural instability
Akinesia
Cognitive dysfunction
120
What are the diagnostic criteria (Gold Coast criteria) for Motor Neurone Disease?
Progressive upper and lower motor neuron symptoms and signs in one limb or body segment, OR
●Progressive lower motor neuron symptoms and signs in at least two body segments, AND
●Absence of electrophysiologic, neuroimaging, and pathologic evidence of other disease processes that might explain the signs of lower and/or upper motor neuron degeneration
121
What are the typical Nerve Conduction Study abnormalities in Motor Neurone Disease?
Sensory and motor nerve conduction studies are typically normal although can get reduced compound muscle action potentials
May get reduced motor unit numbers prior to clinical weakness - changes in motor unit numbers often used as clinical trial endpoint in MND
122
What are the EMG abnormalities in MND and are they pathognomonic for MND?
No - typically demonstrate acute or ongoing muscle denervation, as indicated by the presence of fibrillation potentials and positive sharp waves, in multiple muscles
123
What is the purpose of MRI in MND and what will the typical result be?
To exclude alternative causes of UMN pathology rostral to area of clinical findings
It will typically be normal in MND
124
Why is it important to consider and differentiate Multifocal Motor Neuropathy with conduction block from MND? How may you do it?
Important because MMN with conduction block is potentially treatable with IVIG and immunosuppression
How?
Clinically MMN often presents with subacute onset with asymmetric weakness and lower motor neuron signs producing arm and hand weakness without associated sensory loss
NCS should show conduction block
Anti-GM1 antibodies often present
125
Which condition may be mistaken for MND because it can produce LMN signs at the level of the lesion with UMN signs below the level?
Cervical radiculomyelopathy
However MRI should readily diagnose this and hence differentiate it from MND
126
Under what circumstances might Myasthenia Gravis and MND be difficult to differentiate and how may you differentiate them?
If MG presents without ocular signs may simulate bulbar-onset MND.
Features that suggest MG instead of MND include:
- absence of both upper and lower bulbar motor neuron signs
- ocular findings eg ptosis
- diurnal variation
Testing for anti-ACHr and anti-Musk abs might help differentiate (positive in MG, negative in MND)
NCS particularly repetitive nerve stimulation and single fiber EMG may help differentiate (should show progressive reduction in the amplitude of the compound muscle action potential in MG) but may be abnormal in both.
127
What percentage of MND cases are familial and what are the most common genetic abnormalities in MND?
5-10%
C9ORF72, SOD1, TARDBP, and FUS
128
What gene abnormality is the most common cause of familial MND and often implicated in Frontotemporal Dementia and MND-FTD?
C9ORF72
129
Compared with sporadic ALS, ALS due to C9orf72 is associated with …
earlier disease onset
bulbar disease
higher frequency of comorbid FTD
shorter age-matched median survival
130
What subtype of FTD is most common in px with MND?
Behavioural variant FTD
131
What disease-modifying treatments are indicated for MND?
Riluzole
Edaravone
Tofersen
132
What are the main adverse effects of Riluzole?
asthenia
dizziness
gastrointestinal disorders
LFT derangement
Rarely neutropenia
133
Which patients with MND should be offered treatment with Riluzole?
All living px with MND
134
Which MND patients may not derive benefit from Riluzole?
Those with tracheostomy for ventilation
135
How does Riluzole work in MND?
Unknown - perhaps reduced glutamate-related excitotoxicity by reducing glutamic acid release, some NMDA receptor blocking properties and sodium channel blocking actions
136
How does Edaravone work in MND?
Free radical scavenger that is thought to reduce oxidative stress which may be implicated in pathogenesis of MND
137
What is the main issue with Edaravone treatment in MND?
Generally has to be given as daily IV medication - oral form exists but data isn’t that strong for benefit
138
What are the main adverse effects of Edaravone?
injection-site contusion
gait disturbance
headache
Asthma exacerbation
139
139
What are the main adverse effects of Edaravone?
injection-site contusion
gait disturbance
headache
Asthma exacerbation
140
Which MND patients should be given Tofersen?
Patients with SOD1 mutations
141
What two medications are potentially disease-modifying in Alzheimer’s dementia?
lecanemab and donanemab
142
What is the role of amyloid-targeted therapies (lecanemab and donanemab) in AD?
They are recombinant monoclonal antibodies (delivered via fortnightly or monthly IV infusions) that are directed against amyloid beta that are potentially disease modifying - been shown to reduce amyloid plaque burden on PET but evidence for benefit on clinical outcomes is more modest
143
What is the clinical benefit of amyloid-targeted therapies in AD?
Modest
May slow progression by approximately 25 to 30 percent in carefully selected patients, and they are associated with risk for significant adverse effects
144
What px with AD should be offered amyloid-targeted therapy?
Px with MMSE >22 or MOCA >17 (ie MCI or mild AD) who have amyloid plaques demonstrated on PET or LP and no contraindications (incl pregnancy, MRI abnormalities, APOE gene homozygosity)
145
What are the main adverse effects of amyloid-targeted therapies?
Infusion reactions
Allergic reactions
ARIA - amyloid-related imaging abnormalities
146
What is ARIA and what does it mean?
Amyloid related imaging abnormalities (ARIA) - occur in px treated with amyloid targeted therapies often within first 3-6 mths of tx
Subtypes = with edema (ARIA-E) or with haemorrhage / haemosiderin deposition (ARIA-H)
Risk factors =
- Treatment with amyloid-targeted therapies vs placebo
- donanemab more frequently than with lecanemab
- APOEe4 positivity (esp homozygosity)
Whilst most cases of ARIA are asymptomatic and resolve over months, some can be symptomatic (seizures, encephalopathy, focal neurological deficits), irreversible or result in death
In this way can resemble cerebral amyloid angiopathy with inflammation
147
How do you treat ARIA?
Asymptomatic with mild MRI abnormalities - observe closely but can often continue treatment
Symptomatic or moderate-severe MRI abnormalities - withhold amyloid-targeted therapy and monitor (serial neuroimaging), can consider resuming once resolves (but recurrence risk)
Severe / serious ARIA - withhold amyloid-targeted therapies (and never resume) and consider IV methylpred if significant cerebral oedema / raised ICP
148
How do you treat status epilepticus?
Position patient on left side
Protect airway
Oxygen
Obtain Iv access plus bloods
10mg Midazolam via any route
Then
Keppra 60mg/kg up to 4.5g or sodium valproate 40mg/kg up to 3g
149
What are the complications of seizures, especially long lasting seizures?
Aspiration
Physical injury eg posterior shoulder dislocation
CNS injury
Noncardiogenic pulmonary oedema
Rhabdomyolysis
Hyperthermia
150
How do you treat Greater Occipital Neuralgia (shooting or stabbing paroxysmal pain affecting unilateral occipital region)?
1 - greater occipital nerve block
2 - pregabalin/gabapentin
151
What are the features of Tolosa-Hunt syndrome and how do you treat it?
Severe pain in or behind the eye assoc with 3, 4, 5 or 6th nerve neuropathy; due to idiopathic granulomatous inflammation of the cavernous sinus;
Treat with steroids
152
What are the clinical features of Idiopathic Intracranial Hypertension?
Young overweight woman (altho can develop in males) with recent weight gain
Headache typically worse in the morning and when lying down, improved by upright posture. Aggravated by cough, straining and Valsalva manoeuvre.
May be associated with transient visual obscuration, pulsatile tinnitus and papilloedema.
153
What do you need to exclude in patients with suspected Idiopathic Intracranial Hypertension?
Perform MRI and MRV to exclude space occupying lesion, venous sinus thrombosis or obstruction,
Exclude use of drugs such as OCP, tetracyclines and vitamin A analogues (eg isotretinoin, acitretin) as these can cause raised ICP
154
How do you diagnose Idiopathic Intracranial Hypertension?
Typical clinical presentation plus exclusion of alternatives plus confirmed by LP demonstrating opening pressure >250mmH2O in lateral decubitus position
155
How do you treat Idiopathic Intracranial Hypertension?
1 - weight loss (incl consideration of bariatric surgery)
2 - acetazolamide (to lower intracranial pressure; role is best defined for those with visual symptoms / deficits)
+\- adjunctive frusemide
Topiramate considered alternative to acetazolamide but evidence not as strong
All need opthal review
If persistent or progressive visual deficits - refer urgently for expert advice and possible surgery (eg ventriculoperitoneal shunting, optic nerve fenestration)
Temporising measures where urgent control is needed include:
IV methylpred + acetazolamide OR
Serial lumbar punctures
Also:
Screen for OSA - can be exacerbating factor
Treat underlying headaches (often have migraine or mediation overuse headaches) as per standard
156
What is the diagnostic criteria for Idiopathic Intracranial Hypertension called?
Modified Dandy criteria
157
Other than severe intractable headaches, why is Idiopathic Intracranial Hypertension not benign ?
Due to risk of severe permanent visual loss in 5-15%
158
What are the risk factors for severe permanent visual loss in IIH?
Severe papilloedema
Visual loss or symptoms at diagnosis
159
How does acetazolamide appear to work in Idiopathic Intracranial Hypertension?
As a carbonic anhydrase inhibitor it is believed to slow CSF production
Most benefit seems to be in improving vision based outcomes
160
Can you prescribe acetazolamide to patients with a sulfa allergy?
Controversial - little pharmacological basis for cross reaction risk but if someone has severe reaction to sulfa drugs eg SJS, anaphylaxis then most clinicians would not prescribe acetazolamide
161
Can you use acetazolamide in pregnancy?
Relatively contraindicated before 20 weeks gestation but may use if benefits outweigh risks
162
Can you prescribe acetazolamide to patients with a sulfa allergy?
Controversial - little pharmacological basis for cross reaction risk but if someone has severe reaction to sulfa drugs eg SJS, anaphylaxis then most clinicians would not prescribe acetazolamide
163
Can you use acetazolamide in pregnancy?
Relatively contraindicated before 20 weeks gestation but may use if benefits outweigh risks
164
What are the main side effects of acetazolamide?
digital and oral paresthesias, anorexia, malaise, metallic taste, fatigue, nausea, vomiting, electrolyte changes, mild metabolic acidosis, and kidney stones.
165
What are the indications for surgical treatment in Intracranial Idiopathic Hypertension?
Worsening vision despite medical therapy
Presence of visual loss attributed to papilloedema
166
What is the treatment of choice for idiopathic hypersomnolence or narcolepsy?
Modafinil
167
What is the classic clinical feature of essential tremor?
A postural or kinetic tremor at 4-12Hz is typical
Rare to have resting tremor unless severe disease
Positive family hx and Improvement after drinking alcohol are common
168
What is first line treatment for essential tremor?
Propranolol
169
What is second line treatment for essential tremor?
Primidone
170
What is Sydenham chorea?
An autoimmune movement and neuropsychiatric disorder triggered by Group A strep/strep pyogenes infection
It is one of the major manifestations of acute rheumatic fever
171
When is treatment Indicated for Sydenham chorea?
When symptoms disabling that they interfere with daily activities
172
How do you treat moderate to severe Sydenham chorea?
Symptomatic tx with Carbamazepine (or sodium valproate)
PLUS
steroids/immunosuppression (hastens recovery by 50%)
PLUS
long term antibiotic treatment and prophylaxis against GAS infection (ie monthly IM benpen)
173
What is chorea?
involuntary brief, random, and irregular movements of the limbs and face
174
In acute rheumatic fever, what are the antibodies directed against?
N-acetyl-beta-D-glucosamine (NABG or GlcNAc), the immunodominant carbohydrate antigen of GAS
Different subsets of NABG antibodies appear to correlate with distinct clinical manifestations of ARF.
175
What antibodies appear involved in the pathogenesis of Sydenham chorea?
Subsets of NABG antibodies directed at lysoganglioside and the intracellular tubulin
176
When does Sydenham chorea tend to develop in patients with acute rheumatic fever?
1-8 months after infection, as opposed to carditis and arthritis which tends to develop within 21 days
176
What type of dystonias are most common?
Focal dystonias eg blepharospasm, cervical dystonia (spasmodic torticollis) or occupational dystonias eg writers cramp
177
How do you treat focal dystonia?
First line is Botox injections except for wrist dystonias which respond poorly to Botox injections
178
If Botox injections fail in a patient with cervical dystonia, what other treatment may be effective?
Deep brain stimulation
179
What is the critical first step in the evaluation and treatment of a patient with generalised dystonia?
Establishing of the dystonia is responsive to levodopa
180
Besides antipsychotic medication exposure, what are the risk factors for tardive dyskinesia?
- Older age
- Longer treatment/exposure
- First generation antipsychotics (cf second gen - however difference is not as great as initially thought, perhaps 25% higher)
- Female gender
181
What is one of the main issues with treatment of tardive dyskinesia?
Treatment for established tardive syndromes is often ineffective, so prevention and early detection are important.
182
What is the prognosis of treated Sydenham chorea?
Symptoms generally improve within 12 weeks
Full recovery is achieved in most but rarely symptoms can persist for 2 years
High incidence of recurrent chorea (15-30%)
183
What is one of the main issues with treatment of tardive dyskinesia?
Treatment for established tardive syndromes is often ineffective, so prevention and early detection are important.
183
What is the most common cause of recurrent chorea in a patient with Sydenham chorea?
Recurrent strep pyogenes/GAS infection
184
What is tardive dyskinesia?
A medication induced hyperkinetic movement disorder caused by exposure to dopamine-receptor antagonists (eg antipsychotics, metoclopramide, aripiprazole) that persists for at least a month after discontinuation of the offending agent
185
What are the features of tardive dyskinesia?
Hyperkinetic movement disorder eg chorea, athetosis, stereotyped behaviors, dystonia, akathisia, tics, respiratory dyskinesias, and very rarely tremor
- Oral, facial, and lingual dyskinesia are the most common manifestations of TD
Onset is insidious and usually much later into therapy compared with other extrapyramidal symptoms but can arise as early as 1-6 months after starting therapy
186
How do you treat Tardive dyskinesia?
Mainstay = Stop offending agent asap if possible
NB TD is not always permanent and the earlier the offending agent is stopped, the greater the chance of symptom resolution
However this must be weighed against risks of stopping treatment ie underlying mental health
Antipsychotics must be weaned slowly as abrupt discontinuation may precipitate or worsen TD
187
Why might a patient with TD develop new-onset or worsening dyskinesia once the offending agent has been discontinued?
Due to a phenomenon known as ‘withdrawal-emergent dyskinesia’
These usually clear spontaneously over a few weeks and do not require specific treatment
188
What is the second line or symptomatic treatment for Tardive dyskinesia?
VMAT2 inhibitor eg tetrabenazine
189
What is the usual cause of hemifacial spasm?
Neurovascular compression of the facial nerve in the posterior fossa
190
What is the primary treatment of hemifacial spasm?
Botox injections
Rarely microvascular decompression of the facial nerve
191
What are the characteristic clinical features of hemifacial spasm?
involuntary synchronous spasms of one side of the face, usually beginning around the eye
They are typically brief, irregular clonic movements but are occasionally tonic.
Onset is most common in midlife and usually unilateral
192
What is the treatment of choice for tics in adults?
Clonidine
193
What is Parsonage-Turner syndrome?
Acute brachial neuritis or neuralgic amyotrophy
An uncommon painful plexopathy that is probably immune mediated
It usually presents with acute severe pain (often at night) in the shoulder girdle and lateral upper arm on one side, sometimes after antecedent URTI
May develop patchy weakness, winging of the scapula, paraesthesiaes/numbness and muscle wasting
May be bilateral in 30% but often asymmetrical
194
What is the main imaging finding on MRI in Parsonage-Turner syndrome?
Acute brachial neuritis
MRI may demonstrate T2 hyperintensity in affected nerves and oedema in affected muscles, and helps exclude nerve root compression
However often insensitive in acute phase
195
What is the main treatment for Parsonage-Turner syndrome?
Physiotherapy
Neuropathic analgesia
Oral steroids - may relieve pain and improve time to recovery but unclear if improves the extent of muscle recovery
196
What is the main treatment for Parsonage-Turner syndrome?
Physiotherapy
Neuropathic analgesia
Oral steroids - may relieve pain and improve time to recovery but unclear if improves the extent of muscle recovery and data is sparse
197
What is the prognosis of Parsonage-Turner syndrome?
Most recover but usually slowly over 1-3 years
Few have residual symptoms
198
What drugs should be avoided or used with caution in patients with myasthenia gravis?
Botox
D-Penicillamine
Interferon-alpha
Neuromuscular blockers
Depolarising and non depolarising agents
Aminoglycosides
Fluroquinolones
Macrolides
Quinine
Iodinated contrast
199
What is D penicillamine and what is it used for?
A copper chelating agent
Wilson’s disease
200
What drugs should be avoided or used with caution in patients with myasthenia gravis?
Botox
D-Penicillamine
Interferon-alpha
Neuromuscular blockers
Aminoglycosides
Fluroquinolones
Macrolides
Quinine
Iodinated contrast
Beta blockers
Immunotherapy
Magnesium
Statins
Glucocorticoids
Iron chelators
201
What is interferon alpha and what is it used for?
Recombinant cytokines used (or previously used) in the treatment of:
Essential thrombocytopenia
Systemic mastocytosis
Melanoma
Bechets disease (mucocutaneous disease)
202
What is myotonic dystrophy?
Autosomal dominant conditions that represent the most common cause / form of adult-onset muscular dystrophy (ie they are a subtype of muscular dystrophy)
203
What is the cause of myotonic dystrophy type 1?
expansion of a cytosine-thymine-guanine (CTG) trinucleotide repeat in the 3'-untranslated region of the dystrophia myotonica protein kinase (DMPK) gene on chromosome 19q 13.3
204
What is the cause of myotonic dystrophy type 2?
CCTG expansion in the area encoding the CNBP gene
205
What is the underlying pathophysiology of myotonic dystrophy?
Mutant genetic abnormalities - repeat expansions - result in RNA toxicity; they are not translated and exert a toxic effect on other genes
206
How common is myotonic dystrophy?
1 in 2100 to 1 in 10000
207
What is the underlying pathophysiology of myotonic dystrophy?
Mutant genetic abnormalities - repeat expansions - result in RNA toxicity; they are not translated and exert a toxic effect on other genes
208
Does the clinical phenotype correlate with expansion repeat size in myotonic dystrophy?
In type 1 - yes to a large extent with greater repeat size = greater clinical severity and earlier onset although some variation due to somatic mosaicism
Doesn’t seem to correlate so well in type 2
209
Is myotonic dystrophy a single system disease?
No it is multi system including skeletal muscle, cataracts and cardiac conduction abnormalities
210
The majority of affected infants with congenital myotonic dystrophy 1 have what facial abnormality?
A characteristic V shape of the upper lip due to facial diplegia
211
What is the clinical hallmark of congenital myotonic dystrophy 1?
Hypotonia
212
The majority of affected infants with congenital myotonic dystrophy 1 have what facial abnormality?
A characteristic V shape of the upper lip due to facial diplegia
213
When and how does classical myotonic dystrophy type 1 present?
In 2-4th decades of life with skeletal and respiratory muscle weakness, myotonia, cataracts, cardiac arrhythmia and excessive daytime somnolence
214
What is the characteristic pattern of weakness in type 1 and type 2 myotonic dystrophy?
Type 1 - facial weakness (producing typical facial appearance - long and narrow face, high arched palette, hollowed cheeks, jaw sags, ptosis, SCM muscle wasting)
PLUS SCM + distal muscles of forearm and intrinsic hand muscles + ankle dorsiflexors
Type 2 - neck flexors, elbow flexors, finger flexors, hip girdle
215
What is myotonia?
Slowed relaxation following a normal muscle contraction
Affects 100% of px with type 1 myotonic dystrophy and 75% of px with type 2.
Often exac by cold and stress
Don’t usually report symptoms related to it although may describe muscle stiffness
216
What endocrine abnormalities might be seen in myotonic dystrophy type 1?
Primary Hypogonadism
Testicular atrophy and low sperm count
Insulin hypersecretion and resistance (but rarely overt diabetes)
217
What important GI manifestations may occur in type myotonic dystrophy and what do they correlate with?
Dysphagia (with inc risk of aspiration)
Gallstones
iBS
Correlate with duration of disease NOT severity of skeletal muscle disease
218
What is the gold standard test for myotonic dystrophy?
Genetic testing for specific genetic repeat expansions
219
What is the cause of Duchenne’s and Becker’s muscular dystrophy (DMD and BMD)?
They are X-linked recessive conditions resulting from mutations of the DMD gene that encodes dystrophin and are therefore named dystrophinopathies
220
Which muscular dystrophy is associated with the more severe clinical phenotype - duchennes or becker’s)
Duchennes
Becker’s tends to be later older and milder
There is also an intermediate phenotype between the two
221
What is the primary symptom in DMD and BMD?
Muscle Weakness
Usually becomes evident between 2-3 years of age
Selectively affects the proximal before distal and legs before upper limbs
Therefore affected children often have difficulty running, climbing stairs, jumping or arising from the floor (need to use their arms to push themselves up - Gower’s sign)
222
What is Gower’s sign?
Refers to children with muscular dystrophy using their hands to help push themselves into an upright position when arising from the floor
223
What are the common examination findings in muscular dystrophy?
pseudohypertrophy of the calf and (occasionally) quadriceps muscles
lumbar lordosis
a waddling gait
shortening of the Achilles tendons
hypotonia
hyporeflexia or areflexia
224
What does the “honeymoon” period refer to in DMD/BMD?
Transient Improvement in symptoms between 3-6 years of age (when normal motor development outpaces disease)
However motor gains soon plateau then start to decline
225
What blood markers may be elevated in DMD?
CK - often prior to clinical disease, peak at age 2 then gradually fall and eventually normalise
Serum aldosase
LDH
AST
ALT
(Classically AST>ALT)
226
What does the “honeymoon” period refer to in DMD/BMD?
Transient Improvement in symptoms between 3-6 years of age (when normal motor development outpaces disease)
However motor gains soon plateau then start to decline
227
Other than muscle weakness what other abnormalities are usually seen in kids with DMD?
- Growth delay
- Dilated cardiomyopathy (frequently asymptomatic until late in the disease when may experience HF and arrhythmias)
- Fractures
- scoliosis
- mild cognitive impairment
- global developmental delay
228
What are the characteristic features of the dilated cardiomyopathy in DMD?
extensive fibrosis of the posterobasal left ventricular wall, resulting in the characteristic electrocardiographic changes of tall right precordial R waves with an increased R/S ratio and deep Q waves in leads I, aVL, and V5-6 (
229
What is the typical prognosis of kids with DMD?
Wheelchair bound by 11-13
Die in late teenage years or 20s due to respiratory insufficiency or cardiac failure
230
What is the typical prognosis of kids with DMD?
Wheelchair bound by 11-13
Die in late teenage years or 20s due to respiratory insufficiency or cardiomyopathy
231
What are some of the key differences between BMD and DMD?
BMD tends to develop later and overall result in milder phenotype with less muscle weakness and preserved ability to walk until late teens or adulthood (ie unlike DMD where wheelchair bound by 13) with survival into 30s and even beyond (cf death in late teens-20s in DMD)
CK levels elevated but not as high (5x ULN cf 10x)
Cognitive impairment and developmental delay not as common
Dilated cardiomyopathy often predominant feature
232
Can females be affected by muscular dystrophy?
Yes - approx 22% of female carriers of the mutated dystrophin gene display clinical symptoms - some mild, others classical DMD
233
What are some of the key differences between BMD and DMD?
BMD tends to develop later and overall result in milder phenotype with less muscle weakness and preserved ability to walk until late teens or adulthood (ie unlike DMD where wheelchair bound by 13) with survival into 30s and even beyond (cf death in late teens-20s in DMD)
CK levels elevated but not as high (5x ULN cf 10x)
Cognitive impairment and developmental delay not as common
Dilated cardiomyopathy often predominant feature
234
When should you suspect muscular dystrophy?
Failure to reach appropriate motor developmental milestones in px with fhx of muscular dystrophy
Failure to walk by 16-18mths
Gower’s sign
Pseudohypertrophy of calves
Toe walking
Unexplained LFT abnormalities
235
What should you do if you suspect a kid has muscular dystrophy?
Perform CK - if elevated then genetic testing + specialist review
236
Is a muscle biopsy required for diagnosis of muscular dystrophy?
Not in current era due to availability of genetic testing
237
What is the rough rule of thumb for dystrophin values on muscle biopsy in the different forms of muscular dystrophy?
<5% dystrophin = DMD
>20% dystrophin incl abnormal molecular weight = BMD
In between = intermediate phenotype
238
Is a muscle biopsy required for diagnosis of muscular dystrophy?
Not in current era due to availability of genetic testing
239
What are the differences between spinal muscular atrophy and muscular dystrophy?
Spinal muscular atrophy (SMA) is autosomal recessive rather than X-linked
SMA may achieve independent sitting but never standing or walking (unlike muscular dystrophy)
Diffuse areflexia
Tongue fasciculations
SMA is characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem, which results in progressive muscle weakness and atrophy
240
Are there any disease modifying therapies for muscular dystrophy?
Yes
Glucocorticoids are the mainstay
There are also genetic therapies that involve exon skipping etc which appear promising and improve dystrophin expression but clinical benefit has not been established
241
What are the differences between spinal muscular atrophy and muscular dystrophy?
Spinal muscular atrophy (SMA) is autosomal recessive rather than X-linked
SMA may achieve independent sitting but never standing or walking (unlike muscular dystrophy)
Diffuse areflexia
Tongue fasciculations
SMA is characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem, which results in progressive muscle weakness and atrophy
242
What are the benefits of glucocorticoids in muscular dystrophy?
improving motor function
Improve pulmonary function, reduce the risk of scoliosis,
delay the loss of ambulation,
possibly delay progression of cardiomyopathy
improve survival
243
What other therapies (besides glucocorticoids & multidisciplinary rehab) are indicated for patients with muscular dystrophy?
ACEI by age 10 (may help prevent cardiomyopathy/HF)
Yearly influenza and pneumococcal vax
244
Is there any disease modifying therapy for myotonic dystrophy?
No
Can trial mexiletine for myotonia in adults (except if 2nd or 3rd deg AV block as can be pro-arrhythmic)
245
What do all patients with myotonic dystrophy and second- and third-degree AV block require, even if asymptomatic?
Permanent pacemaker insertion due to the unpredictable risk of progressive AV block
246
What are the 4 main classes of dopaminergic therapies for Parkinson Disease?
Levodopa
Dopamine agonists (eg pramipexole, rotigotine)
MAO B inhibitors (eg rasagiline, selegiline, safinamide)
Dopamine promoter with anticholintergic effects (eg Amantadine )
247
When should you commence medical therapy for PD?
Timing varies greatly amongst patients but is influenced by:
- effect of disease on dominant hand
- degree of impairment
- presence of significant bradykinesia or gait disturbance
- px values
Px with very mild signs and symptoms not interfering with QOL may not require antiparkinson therapy
248
Is there any truth to the idea that a patient's responsiveness to levodopa is finite and therefore therapy should be rationed and saved until more severe disease?
No - this is unproven
Levodopa sparing approaches not believed to affect the natural history and can cause undue harm by depriving px of beneficial effects of levodopa on motor function and QOL
249
What is the natural history of motor complications with symptomatic medical therapy for PD?
Substantial number (~50%) develop levodopa-related motor complications within 5-10 years incl motor fluctuations (wearing off), dyskineisia etc
250
What is the preferred initial medical therapy for PD?
Levodopa
- most effective
- superior effects on motor function, ADLs, QOL cf other drugs/classes
However:
- requires the most frequent dosing
- assoc with highest risk of dopaminergic motor complications such as wearing off and dyskinesia
251
When should levodopa be taken with respect to meals?
In early disease - with meals to minimise nausea and improve adherence
In later disease - on empty stomach because concurrent ingestion of dietary protein may block the effect of a dose of levodopa
252
Why is levodopa combined with a peripheral decarboxylase inhibitor?
A peripheral decarboxylase inhibitor (eg carbidopa or benserazide) blocks the conversion of levodopa to dopamine in the systemic circulation and liver in order to prevent nausea, vomiting and orthostatic
By preventing peripheral conversion to dopamine (which does not cross the BBB), carbidopa allows a smaller amount of levodopa to be administered systemically to produce the desired therapeutic effect centrally
253
What is the recommended way to initiate levodopa therapy?
Start low, go slow
Assess response after several days to weeks before adjusting dose (typically see substantial clinical benefit within days to 2 weeks but maximal benefit may take months)
Majority of px with idiopathic PD will enjoy significant benefit with total daily doses of levodopa in 300-600mg range (indeed lack of response to doses in this range should cause you to reconsider diagnosis)
254
Does controlled release formulations offer any long-term advantage in terms of motor fluctuations over immediate release formulations in PD?
No
255
What are the main side effects of levodopa therapy?
Common:
Nausea, somnolence, dizziness, headache
Serious:
Confusion, hallucinations, delusions, agitation, psychosis, orthostatic hypotension, increased homocysteine/hip #, B12 deficiency, sensorimotor peripheral neuropathy
256
Are there any circumstances where you may elect for an alternative class of medical therapy than levodopa for PD?
Mild symptoms, preference for once daily meds - consider MAO B
Younger px at high risk for dyskinesia = consider dopamine agonist or amantadine
Px with tremor-predominant disease = consider amantadine monotherapy
257
What are the device-assisted/surgical treatments available for advanced PD?
Deep brain stimulation [DBS]
Focused ultrasound therapy [FUS],
Continuous levodopa-carbidopa intestinal gel [LCIG] infusion
Continuous subcutaneous apomorphine infusion [CSAI]
258
Why do motor fluctuations in response to levodopa therapy occur in PD?
Due to PD progression - as nigrostriatal dopaminergic neurons degenerate, the presynaptic neurons lose their ability to store and release levodopa after enzymatic conversion to dopamine - as a result, the response to standard levodopa begins to mirror its short half-life (rapid cycling kinetics and pulsatile stimulation)
Additionally, levodopa levels are highly dependent on intestinal absorption which can be impaired in PD by poor gastric emptying, slow intestinal transit, competing dietary protein, SIBO
259
What is dyskinesia and what does it represent?
Dyskinesia = abnormal, involuntary movements (overexpression of movement)
Represents dopamine receptor hypersensitivity to dopamine and relative excess of dopamine levels
Tends to be dose-dependent and more problematic in younger px
260
What are the risk factors for earlier/more severe motor complications in PD?
Younger age at disease onset
Longer disease duration
More severe nonmotor symptoms (such as anxiety and depression)
Levodopa dose and responsiveness
Overall disease severity
261
What does wearing off phenomena refer to?
The reemergence of parkinsonian symptoms as the effect of levodopa diminishes near the end of the dose
It is the first and most commonly encountered fluctuation in PD px
262
What is a signature and disabling symptoms of the "off" state in PD?
Freezing of gait - inability to step and advance, usually occurring during initiation, turning or when encountering transition points in the environment
263
How do you manage wearing off in PD?
Individualised, trial-and-error approach incl
1) Dietary adjustments eg timing and amount of protein consumption in relation to levodopa + off symptoms
Consider H pylori eradication or SIBO treatment
2) Adjust dose of levodopa - increase dose, shorten the dosing interval (ie smaller but more frequent doses)
3) Consider extended-release tablets (not controlled release - nil evidence of benefit for them in reducing wearing off)
4) Consider adjunctive therapy eg add dopamine agonist, COMTi, MAO-Bi to levodopa regime (although may worsen dyskinesia and nonmotor dopaminergic side effects); no class clearly superior, rather base decision on side effect profile
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What are some of the main side effects of dopamine agonists?
Visual hallucinations
Oedema
Excessive daytime somnolence Hypotension
Impulse control disorders
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What are COMT inhibitors and what are their most common side effects?
Entacapone
Dyskinesia
Visual hallucinations
Nausea
Orthostatic hypotension
Somnolence
Orange urine
Diarrhoea
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How do MAO B inhibitors work?
Rasagiline, selegiline, safinamide - block MAO B which is response for degrading dopamine centrally
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Do MAO B inhibitors pose a high risk of tyramine-related hypertensive crisis?
No because they selectively target MAO B
Tyramine-related hypertensive crisis due to non-selective older MAO inhibitors which inhibited MAO A in the gut
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What are the indications for device-assisted therapies in PD?
Severe, troublesome motor fluctuations despite optimal oral/transdermal levodopa or adjunctive therapies
Motor fluctuations causing disability or reduced QOL
Inconsistnet response to tx
Dyskinesia or motor fluctuations that require frequent treatment adjustment without benefit
Levodopa dosing >QID
Severe medication-refractory tremor
(NOTE - for them to be effective, px should still retain a response to levodopa; exception being in case of disabling medication-refractory tremor which can respond well to DBS)
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How do you manage troublesome therapy-related dyskinesias?
Reduce the dose of levodopa
Shorten interval between doses and reduce dose (esp if concurrent wearing off)
Eliminating adjunctive drugs
Paradoxically, adding low-dose dopamine agonist (particularly long-acting eg transdermal rotigotine or extended-release pramipexole) can help both dyskinesia and wearing off by providing more continuous rather than pulsatile dopaminergic stimulation and allowing levodopa levels to be reduced below a dyskinesia threshold
Adding amantadine
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What is the mainstay of treating severe freezing of gait in PD?
Physical therapy and management of treatable comorbidities
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Whilst most patients with PD can go without antiparkinson meds for <24hrs when NBM or seriously ill, what condition can be precipitated by the sudden withdrawal or dose reduction of antiparkinsnism medications?
Parinsonism-hyperpyrexia syndrome (essentially neuroleptic malignant syndrome)
Management involves replacing antiparkinson medications at the dose used prior to onset of syndrome + admit to ICU + aggressive supportive care
If fail to respond, consider dantrolene, bromocriptine or amantadine to minimise neuroleptic malignant syndrome impact
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